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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 identied 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 identied with an ACS, 2010–2014. Serious bleeding was dened 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% condence 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 risk1–3. Bleeding is associated with
both morbidity and mortality4–6. Previous studies have found that bleeding aer 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 studies8–10, and
up to one-third of patients discharged on dual antiplatelet therapy (DAPT) are reported to have had a bleeding
complication within 12months post-discharge8. Comparison of bleeding incidences among studies is dicult
because of dierences in the studied populations, follow-up times, in-hospital management, antithrombotic drugs
used, and bleeding denitions11,12. 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 1year 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
identied 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)
value16–20. 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 1year. 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 identied with an ACS during the inclusion
period of the Nurse-Based Age-Independent Intervention to Limit Evolution of Disease Aer Acute Coronary
Syndrome (NAILED-ACS) Risk Factor trial. Briey, 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 dened 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 denition 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
identied 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 identied bleeding diagnosis
(TableS1) 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. Identication and review of potential endpoint events were performed by three medical doctors,
all members of the study team. e review process followed a standardized workow routine, and events were
strictly evaluated according to study outcome denitions. Each reviewer worked with their assigned cases inde-
pendently, but consecutive meetings were held to reach consensus in complicated cases.
Serious bleeding was dened as an intracranial hemorrhage (ICH), bleeding that required hospital admission,
or bleeding that required transfusion or surgery. All bleeds were subclassied as intracranial (epidural, subdural,
intracerebral hematoma, subarachnoid bleed), GI (upper, lower, or non-classied), and other serious bleeding
(intraocular, retroperitoneal, or urinary tract bleeding). e classication was made according to International
Statistical Classication of Diseases and Related Health Problems (ICD-10) codes (TableS1).
Clinical baseline characteristics and medications at discharge were extracted from the NAILED-ACS data-
base. e variable “smoking” was dened as smoking during the past month. e variable “atrial brillation”
was dened 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 dened as ≤ 60mL/min/1.72
m2. e limit for obesity was set to a body mass index ≥ 30kg/m2. e value of systolic blood pressure was taken
from the day before discharge and thus aer the acute stage. In Sweden, elementary school lasts 9years; to study
if education level aected 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 dened 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
stratied by age (cuto, 75years). 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-signicant
variables were excluded stepwise according to their level of signicance during subsequent runs until reach-
ing only signicant predictors. e assumption of proportional hazard was veried 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% condence intervals (CIs).
Statistical analyses were performed using SPSS (version 25.0; IBM Corp, Armonk, NY, USA) and SAS soware
(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: 2014-416-32M). 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 8years. A study
owchart is presented in Fig.1, and baseline characteristics are shown in Table1. e mean age of participants
was 72years, 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 4.6years, 85 patients had
at least one serious bleeding event, for a cumulative incidence of 8.6% (95% condence 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 ≥ 75years (n = 557), the long-term cumulative incidence of serious bleeding was signicantly higher at
13.4% (95% CI 12.9–14.0%) compared with patients aged < 75years, 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 (Table2). 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
Figure1. 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 (Table1).
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 dier between groups, and there was no signicant dierence 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 (TableS2). In
the multivariable Cox analysis (Table3), signicant predictors of bleeding were age ≥ 75years (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 dier according to level of education, subtype of index
Table 1. Baseline characteristics stratied 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 signicant results as the multi-
variable Cox analysis.
Mortality. A total of 404 patients died during follow-up, with a signicantly 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 dierence in mortality appeared aer 3–3.5years (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
Figure2. 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
Figure3. Cumulative incidences without serious bleedings during long-term follow-up, stratied 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 Unspecied GI
78 SAH Unspecied GI
78 SAH Upper GI
88 Other Upper GI Lower GI
88 Upper GI Upper GI Upper GI
91 Unspecied GI Unspecied 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 aer ACS. HR hazard
ratio, CI condence interval, ACS acute coronary syndrome.
Predictor HR CI p
Age ≥ 75years 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
Figure4. Cumulative survival aer ACS, stratied by bleeding.
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analysis (Supplement TableS3) 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 signicantly 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 4.6years and 3.0% within 1year. In patients
aged ≥ 75years, the long-term incidence (13.4%) was more than twice that among patients age < 75years (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 (4.9years), 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 dierence may reect 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 7–8years 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 5years)
even though those authors used a denition 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 etal., with
a follow-up time of approximately 2years, found a post-discharge incidence of 7.4% for bleeding-related re-
hospitalization. Bleeding events were identied through a diagnosis registry using ICD codes similar to ours. In
contrast, the diagnoses were not validated against the medical records for conrmation, which may have led to
an overestimation of clinically relevant events because registry-based diagnoses oen include a broader deni-
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 dierences in bleeding denitions make comparison dicult.
ICH is more strictly dened and therefore more easily compared across dierent studies. In our study, the
cumulative incidence of ICH within 1year 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 denitions and cohorts, our results are
consistent10,15 or the values are lower25,26. Brinkert etal. found a post-discharge 1-year bleeding rate of 2.6%, and
the bleeding rate was signicantly lower in patients treated with PCI. Patients treated medically only are oen
older with more comorbidity, which can explain the dierences between the groups. Gray etal. found a 1-year
incidence of serious bleeding of 3.2% in the total cohort, but among patients older than 75years, 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 denition 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 dierence (i.e., there was no review of the medical records for conrmation)25.
STEMI patients have previously been reported to have a lower incidence of major bleeding compared to
NSTEMI patients25,27, a dierence related to a lower mean age and a lower risk prole overall among STEMI
patients. In contrast to these previous reports, we found no dierence 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 dierence 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 identiable 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 12month of hospital
discharge29. A previous study found a more than doubled risk of GI bleeding aer 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 conrm some of the previously recognized predictors of bleeding: age, lower baseline
Hb, previous hypertension, and previous heart failure16,29,33. We could not conrm kidney failure or previous
stroke/transient ischemic attack to be associated with increased bleeding risk34,35. In previous studies, kidney
failure has predicted bleeding aer ACS (HRs 1.3–1.9)35,36, and in a study of patients with kidney failure (not
post-ACS), bleeding risk signicantly 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 identied 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 conrm 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-discharge29,40–42. 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 signicant 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 3years post-discharge but then
increased in patients with a bleeding event. Surprisingly, higher BMI (≥ 30kg/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 4.6years in a population-based ACS cohort, the cumulative incidence of re-hospi-
talization for serious bleeding was 8.6%. Patients aged ≥ 75years had a more than doubled incidence of serious
bleeding compared with patients < 75years. 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 signicant predictor of increased mortality. To decrease bleeding
risk aer 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 denition that did not require laboratory values,
which is not directly comparable to standard bleeding denitions in randomized trials. e denition 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 eect 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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