www.nature.

com/scientificreports

OPEN Combined use of anticoagulant

and antiplatelet on outcome
after stroke in patients
with nonvalvular atrial fibrillation
and systemic atherosclerosis
JoonNyung Heo 1,2, Hyungwoo Lee 1,2, Il Hyung Lee 1,2, In Hwan Lim 1,2, Soon‑Ho Hong 1,2,
Joonggyeong Shin 1, Hyo Suk Nam 1 & Young Dae Kim 1*

This study aimed to investigate whether there was a difference in one-year outcome after stroke
between patients treated with antiplatelet and anticoagulation (OAC + antiplatelet) and those with
anticoagulation only (OAC), when comorbid atherosclerotic disease was present with non-valvular
atrial fibrillation (NVAF). This was a retrospective study using a prospective cohort of consecutive
patients with ischemic stroke. Patients with NVAF and comorbid atherosclerotic disease were
assigned to the OAC + antiplatelet or OAC group based on discharge medication. All-cause mortality,
recurrent ischemic stroke, hemorrhagic stroke, myocardial infarction, and bleeding events within
1 year after the index stroke were compared. Of the 445 patients included in this study, 149 (33.5%)
were treated with OAC + antiplatelet. There were no significant differences in all outcomes between
groups. After inverse probability of treatment weighting, OAC + antiplatelet was associated with a
lower risk of all-cause mortality (hazard ratio 0.48; 95% confidence interval 0.23–0.98; P = 0.045) and
myocardial infarction (0% vs. 3.0%, P < 0.001). The risk of hemorrhagic stroke was not significantly
different (P = 0.123). OAC + antiplatelet was associated with a decreased risk of all-cause mortality and
myocardial infarction but an increased risk of ischemic stroke among patients with NVAF and systemic
atherosclerotic diseases.

Nonvalvular atrial fibrillation (NVAF) is the most common cardioembolic source of ischemic ­stroke1. It sub-
stantially increases the risk of the stroke, and the outcome after stroke caused by NVAF is worse than any other
stroke ­etiology2. For preventing systemic embolism including ischemic stroke, the use of an oral anticoagulant
(OAC) such as vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) is strongly recommended
for patients with ­NVAF3.
Systemic atherosclerosis in the brain, heart, and peripheral artery can co-exist in patients with N ­ VAF4–7.
Furthermore, the co-existence of any systemic atherosclerosis in patients with stroke with NVAF carries an even
higher risk of vascular events in the same or different vascular beds, suggesting the need for optimum antithrom-
­ atients5. Addition of antiplatelet with OAC could be an option for the management of
botic strategies for these p
these patients, while these regimens could lead to an increased risk of ­bleeding3,8. Recent studies suggested that
low-dose rivaroxaban combined with aspirin could improve cardiovascular outcomes among patients with coro-
nary arterial occlusive disease (CAOD) or peripheral arterial occlusive diseases (PAOD)9,10, which suggests that
the use of OAC with antiplatelet might be beneficial for the management of atherosclerotic disease with stroke
and NVAF. However, there is limited information on the optimal management of stroke with NVAF and comor-
bid systemic atherosclerosis, including intracranial or extracranial artery stenosis as well as CAOD or PAOD.
This study aimed to investigate whether the combined use of antiplatelet and OAC could affect outcomes
within 1 year after index stroke among patients with NVAF and systemic atherosclerosis.

1
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea. 2Department of Radiology,
Yonsei University College of Medicine, Seoul, South Korea. *email: [email protected]

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 1

Vol.:(0123456789)
 www.nature.com/scientificreports/

Results
Study population
Among the 6912 patients with ischemic stroke or TIA, 1353 patients who were previously or newly diagnosed
with NVAF were selected. After excluding 51 (3.8%) patients being dead during hospitalization, 60 (4.4%) for
loss of follow-up, 546 (40.3%) for not having any evidence of atherosclerotic disease, 223 (16.5%) for not having
anticoagulation prescribed, and 28 (2.0%) for active cancer, 445 patients were included in this study (Fig. 1).

Baseline characteristics
The median age was 75 (interquartile range, IQR 70.0–80.0) and 59.3% (n = 264) was male in the included 445
patients. Of these patients, 193 (43.4%) had cerebral atherosclerosis, 278 (62.5%) had CAOD, 13 (2.9%) had
PAOD, 74 (16.6%) had aortic arch atheroma, 62 (13.9%) had coronary stents, and 12 (2.7%) had cerebral artery
stents. There were 293 (65.8%) patients with atherosclerotic lesions in one arterial bed, 121 (27.2%) in two beds,
27 (6.1%) in three beds, and four (0.9%) in four beds (Fig. 2 and Supplementary Table 1).
There were 296 (66.5%) patients on OAC alone and 149 (33.5%) on OAC + antiplatelet. Among 296 patients
treated with OAC alone, 103 (34.8%) received VKA and 193 (65.2%) received DOAC. Among the 149 patients
who received OAC + antiplatelet, 96.6% (n = 144) received a single antiplatelet agent. Aspirin was the most fre-
quently prescribed antiplatelet (n = 65, 43.6%), followed by clopidogrel (n = 63, 42.3%), triflusal (n = 11, 7.4%),
cilostazol (n = 5, 3.4%), and a combination of the two antiplatelets (n = 5, 3.4%). VKA was prescribed more fre-
quently than DOAC for patients in the OAC + antiplatelet group (55.0% [82/149] for VKA and 45.0% [67/149]
for DOAC). Among the patients who received VKA, there were no differences between international normal-
ized ratio at discharge between the two groups (2.3 [IQR 1.9–2.7] for OAC alone group and 2.4 [IQR 1.9–2.8]
for OAC + antiplatelet group, P = 0.585). Among the 260 patients who received DOAC, insufficient dose of
DOAC was used in 10% (n = 26) and the proportion of patients who received insufficient dose was not different
between the two groups (10.4% [20/193] for OAC alone group and 9.0% [6/67] for OAC + antiplatelet group,
P = 0.925). Statin was prescribed at discharge in 97.3% (n = 433). In addition, the statin treatment was not differ-
ent between the two groups (98.0% [290/296] for OAC only group and 96.0% [143/149] for OAC + antiplatelet
group, P = 0.358). There were no significant differences of stroke subtypes based on Trial of Org 10,172 in Acute
Stroke Treatment between the two study groups (P = 0.137, Supplementary Table 2). More than two causes
subtype was the most common etiology for both groups. Transesophageal echocardiography was performed for
63.4% (n = 282) of the patients, which was not different between the two groups (65.2% [193/296] for OAC only
group and 59.7% [89/149] for OAC + antiplatelet group, P = 0.305). When we assessed the maintenance of the

Figure 1.  Flow chart of patients included in this study.

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 2

Vol:.(1234567890)
www.nature.com/scientificreports/

Figure 2.  Distribution of patients for each atherosclerotic disease. CAOD coronary artery occlusive disease,
PAOD peripheral artery occlusive disease.

antithrombotic regimen using medical chart review and/or electronic prescription code for drugs for 38 patients,
whose prescription information could be checked at the time of death during follow-up, the antithrombotic
regimen at discharge was maintained for 81.6% (n = 31) of patients.
Compared with OAC alone, patients receiving OAC + antiplatelet were more likely to have hypertension,
CAOD, and cerebral and coronary stents (Table 1). Multivariable logistic regression analysis adjusting these four
variables showed that CAOD (odds ratio [OR] 1.71; 95% confidence interval [CI] 1.09–2.69; P = 0.019), cerebral
stent (OR 5.31; 95% CI 1.51–18.60; P = 0.009), and coronary stent (OR 6.24; 95% CI 3.42–11.39; P < 0.001) were
independent determinants for the use of OAC + antiplatelet.

Unadjusted groups Adjusted groups

OAC + Antiplatelet OAC OAC + Antiplatelet OAC
(n = 149) (n = 296) D (%) (n = 152.2) (n = 284.5) D (%)
Age (> 75 years) 76 (51.0) 131 (44.3) 13.5 67.0 (44.0) 127.7 (44.9) 1.7
Sex (Male) 94 (63.1) 170 (57.4) 11.5 86.1 (56.5) 167.7 (59.0) 4.9
Hypertension 135 (90.6) 246 (83.1) 22.3 128.3 (84.3) 243.1 (85.5) 3.3
Diabetes 60 (40.3) 105 (35.5) 9.9 57.8 (38.0) 109.4 (38.4) 0.9
Dyslipidemia 65 (22.0) 33 (22.1) 0.5 37.8 (24.8) 63.9 (22.5) 5.6
CAOD 106 (71.1) 172 (58.1) 27.4 94.3 (62.) 178.2 (62.6) 1.3
PAOD 3 (2.0) 10 (3.4) 8.4 2.6 (1.7) 5.6 (2.0) 2.0
Current smoker 22 (14.8) 38 (12.8) 5.6 18.0 (11.8) 36.3 (12.8) 2.8
CHF 17 (11.4) 20 (6.8) 16.2 13.0 (8.5) 24.1 (8.5) 0.2
Cerebral stent 8 (5.4) 4 (1.4) 22.4 3.3 (2.2) 5.4 (1.9) 1.9
Coronary stent 44 (29.5) 18 (6.1) 64.2 19.9 (13.1) 33.7 (11.9) 3.7
Initial NIHSS (> 4) 74 (49.7) 146 (49.3) 0.7 77.5 (50.9) 141.1 (49.6) 2.7
Low GFR 6 (4.0) 7 (2.4) 9.4 4.9 (3.2) 10.3 (3.6) 2.3
Cerebral artery stenosis 70 (47.0) 123 (41.6) 10.9 67.2 (44.1) 120.6 (42.4) 3.5
Aortic atheroma 24 (16.1) 50 (16.9) 2.1 22.2 (14.6) 42.9 (15.1) 1.4
High dose statin 102 (68.5) 226 (76.4) 17.7 111.8 (73.4) 212.3 (74.6) 2.6

Table 1.  Comparison of baseline characteristics between patients who received a combination of antiplatelet
and anticoagulation and anticoagulation alone. Values are presented as number (%) for categorical variables
and median [interquartile range] for continuous variables. CAOD coronary artery occlusive disease, PAOD
peripheral artery occlusive disease, CHF chronic heart failure, NIHSS National Institutes of Health stroke scale,
GFR glomerular filtration rate.

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 3

Vol.:(0123456789)
 www.nature.com/scientificreports/

Comparison of outcomes in the original study population

During the 1-year follow-up (median, 365 days; IQR 321–365 days), all-composite outcome within 1 year
occurred in 93 (20.9%) patients. For each outcome, there were all-cause mortalities in 50 (11.2%), recurrent
ischemic stroke in 16 (2.9%) (3 [0.7%] fatal and 13 [2.9%] non-fatal), myocardial infarction in five (1.1%) (3
[0.7%] fatal and 2 [0.4%] non-fatal), hemorrhagic stroke in four (0.9%, all non-fatal), and bleeding events in 35
(7.9%) (1 [0.2%] fatal and 34 [7.6%] non-fatal) patients. There was no difference in the rates of all predetermined
outcomes between antithrombotic regimens (Table 2).

Comparison of outcomes in the matched population

After performing inverse probability of treatment weighting, the baseline characteristics were well balanced with
weighted sample sizes of 284.5 for the OAC group and 152.2 for OAC + antiplatelet group (Table 1 and Supple-
mentary Fig. 1). The Kaplan–Meier estimate showed that the all-composite outcome did not differ according to
antithrombotic regimen. However, OAC alone had a higher risk of death within 1 year compared to OAC + anti-
platelet (log-rank P = 0.045, Fig. 3). Cox regression analysis showed that all-cause mortality within 1 year was
significantly higher in patients who received OAC alone than in those who received OAC + antiplatelet (6.1% vs.
12.2%; hazard ratio, 0.48; 95% CI 0.23–0.98; P = 0.045). In the subgroup analysis, the effect of OAC + antiplatelet
treatment on all-cause mortality was overall consistent regardless of baseline characteristics, while there were
interactions between antithrombotic type and cerebral stent, coronary stent, or hypertension (Fig. 4). The use
of OAC + antiplatelet was also associated with a lower risk of cardiovascular death (1.5% vs. 4.3%, P = 0.087) or
myocardial infarction (0% vs. 0.6%, P < 0.001). However, recurrent ischemic stroke was more common in patients
who received OAC + antiplatelet (8.8% vs. 3.1%; hazard ratio, 2.76; 95% CI 1.03–7.40; P = 0.044) (Table 2), and
most recurrent ischemic strokes were non-fatal (Supplementary Table 3). Other predetermined outcomes, such
as hemorrhagic stroke and bleeding events, did not differ according to antithrombotic regimen.

Discussion
This study investigated whether one-year outcome could differ according to antithrombotic strategy after index
ischemic stroke among patients with NVAF and systemic atherosclerosis. Although the combined use of OAC
and antiplatelet therapy had no beneficial effect in the original population and there was no difference in all-
composite outcomes in the matched population, inverse probability of treatment weighting analysis showed
that the risk of all-cause mortality or myocardial infarction was lower in patients with combined use of OAC
and antiplatelet when patients had NVAF and systemic atherosclerosis. These trends were consistently observed
in various subgroups, except in patients with cerebral or coronary stents or hypertension. However, the risk of
recurrent ischemic stroke was higher in patients receiving antiplatelet therapy along with OAC.
Comorbid atherosclerosis is not rare among patients with NVAF. Co-existing atherosclerotic diseases can
be observed in either the carotid artery (up to 64%)11, coronary artery (17–38%)12, or peripheral artery disease
(6.7%)12. In this study, CAOD was the most prevalent site of atherosclerosis (63%) followed by cerebral athero-
sclerosis (43%). Furthermore, approximately one-third of the patients had atherosclerotic disease with two or
more arterial beds. In addition, if any atherosclerotic diseases are present, cerebro-cardiovascular outcomes could
be worse among patients with atrial ­fibrillation5,13,14. Therefore, there are concerns regarding the management
of patients with NVAF and systemic atherosclerosis.
Considering the higher risk of cardiovascular events among patients with NVAF with coexisting atheroscle-
rosis, a more potent therapeutic strategy is required. Currently, data on the optimal antithrombotic strategy for
this specific population are limited. Because antiplatelets can inhibit platelet aggregation and prevent thrombus

Unadjusted groups Adjusted groups

OAC + Antiplatelet OAC OAC + Antiplatelet OAC
(n = 149) (n = 296) Hazard ratio P-value (n = 152.2) (n = 284.5) Hazard ratio P-value
All-composite
31 (20.8) 62 (20.9) 0.93 [0.60;1.45] 0.750 29.6 (19.4) 60.2 (21.1) 0.91 [0.55;1.50] 0.709
outcome
All-cause mortality 13 (8.7) 37 (12.5) 0.63 [0.33;1.20] 0.159 9.3 (6.1) 34.6 (12.2) 0.48 [0.23;0.98] 0.045
Cardiovascular
4 (2.7) 13 (4.4) 0.60 [0.19;1.83] 0.365 2.3 (1.5) 12.1 (4.3) 0.34 [0.10;1.17] 0.087
death
Ischemic stroke
10 (6.7) 9 (3.0) 2.19 [0.89;5.38] 0.089 13.5 (8.8) 8.9 (3.1) 2.76 [1.03;7.40] 0.044
(fatal, nonfatal)
Myocardial
infarction (fatal, 0 (0.0) 7 (2.4) 0.00 [0.00;Inf] 0.998 0.0 (0.0) 8.4 (3.0) 0.00 [0.00;0.00] < 0.001
nonfatal)
Hemorrhagic
stroke (fatal, 3 (2.0) 1 (0.3) 5.99 [0.62;57.60] 0.121 3.8 (2.5) 1.2 (0.4) 6.12 [0.61;60.91] 0.123
nonfatal)
Bleeding (fatal,
13 (8.7) 21 (7.1) 1.12 [0.55;2.27] 0.760 11.9 (7.8) 21.4 (7.5) 1.01 [0.46;2.21] 0.982
nonfatal)

Table 2.  Hazard ratios for the prescription of combination of oral anticoagulant with antiplatelet on outcomes.
Values are represented as numbers (%) for incidence and hazard ratios [95% confidence intervals]. Only the
first occurrence of each outcome during the 1 year follow-up period was included. Inf infinite, MI myocardial
infarction.

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 4

Vol:.(1234567890)
www.nature.com/scientificreports/

A B C
1.00 1.00 1.00

Survival probability
0.75 P = 0.709 0.75 P = 0.045 0.75 P < 0.001

0.50 0.50 0.50

0.25 0.25 0.25

0.00 0.00 0.00

0 100 200 300 0 100 200 300 0 100 200 300
Time (days) Time (days) Time (days)

Anticoaguation 292 241 216 205 186 292 251 229 219 202 292 251 228 217 201
Antiplatelet +
Anticoagulation 147 123 109 104 98 147 132 119 116 112 147 132 119 116 112

Numbers at risk Numbers at risk Numbers at risk

D E F
1.00 1.00 1.00
Survival probability

0.75 P = 0.044 0.75 P = 0.123 0.75 P = 0.982

0.50 0.50 0.50

0.25 0.25 0.25

0.00 0.00 0.00

0 100 200 300 0 100 200 300 0 100 200 300
Time (days) Time (days) Time (days)

Anticoaguation 292 249 226 217 200 292 251 228 218 201 292 242 219 208 188
Antiplatelet + 147 129 114 111 106 147 129 116 113 109 147 125 113 108 102
Anticoagulation
Numbers at risk Numbers at risk Numbers at risk

Antiplatelet + Anticoagulation
Anticoagulation

Figure 3.  Kaplan–Meier survival curves of (A) all-composite outcome, (B) all-cause mortality, (C) myocardial
infarction, (D) ischemic stroke, (E) hemorrhagic stroke, and (F) bleeding event by antithrombotic regimens in
the matched population.

formation under conditions of elevated shear stress and high velocity, adding antiplatelet to OAC could be
beneficial for patients with atherothrombotic diseases. However, the combined use of antiplatelet and OAC for
patients with NVAF is challenging because previous retrospective studies and subsequent meta-analyses dem-
onstrated that the benefit of antiplatelet with OAC for preventing ischemic events was not clearly observed or
only noted in a specific s­ ituation8. In our study, the beneficial effect of the combined use of OAC and antiplatelet
was not observed in the original study population, whereas the benefit of these regimens was noted in terms of
all-cause mortality and myocardial infarction after balancing the baseline characteristics using inverse prob-
ability of treatment weighting. This suggests that patient characteristics or comorbidities may affect the efficacy
of medication, and an optimum selection of patients who are supposed to benefit from OAC + antiplatelet would
be necessary. In this context, further investigation on the population that would benefit from the combined use
of OAC and antiplatelet is warranted.
However, ischemic stroke recurrence was higher for those who were prescribed OAC + antiplatelet, although
most recurrent ischemic strokes on OAC + antiplatelet therapy during follow-up did not seem to be severe or
fatal in our study. This implies that the combined use of an antithrombotic regimen would be less effective for
the prevention of recurrent ischemic stroke than the use of OAC alone. The stroke risk and severity in patients
with NVAF is affected by the intensity of VKA or dosage of ­DOAC15,16. Physicians might be reluctant to use the

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 5

Vol.:(0123456789)
 www.nature.com/scientificreports/

Outcome Number (%) HR (P-value) P for interaction

Sex
Male 253.82(58.12) 0.53 (0.196)
Female 182.92(41.88) 0.42 (0.121) 0.753
Age
≤75 242.06(55.42) 0.22 (0.078)
0.255
>75 194.68(44.58) 0.65 (0.29)
Hypertension
Yes 371.4(85.04) 0.57 (0.128)
< 0.001
No 65.34(14.96) 0 (<0.001)
Diabetes
Yes 167.23(38.29) 0.26 (0.027)
0.152
No 269.51(61.71) 0.78 (0.594)
Dyslipidemia
Yes 101.67(23.28) 0.28 (0.141)
0.515
No 335.07(76.72) 0.53 (0.110)
CAOD
Yes 272.5(62.39) 0.75 (0.514)
0.154
No 164.24(37.61) 0.22 (0.040)
PAOD
Yes 8.24(1.89) 1.1 (0.949)
0.635
No 428.5(98.11) 0.47 (0.044)
Current smoker
Yes 54.31(12.44) 0.46 (0.367)
0.942
No 382.43(87.56) 0.49 (0.073)
CHF
Yes 37.13(8.5) 0.3 (0.173)
0.584
No 399.61(91.5) 0.51 (0.089)
Stent inserted
9
Yes 62.36(14.28) 1.15 x 10 (<0.001)
< 0.001
No 374.38(85.72) 0.38 (0.023)
DOAC
Yes 248.89(56.99) 0.4 (0.109)
0.746
No 187.85(43.01) 0.52 (0.173)
Initial NIHSS
>4 218.68(50.07) 0.55 (0.179)
≤4 218.06(49.93) 0.32 (0.074) 0.501
GFR
<30 15.23(3.49) NA (NA)
0.299
≥30 421.51(96.51) 0.48 (0.044)
Cerebral artery stenosis
Yes 187.78(43) 0.34 (0.015)
0.222
No 248.96(57) 0.85 (0.799)
Relevant artery stenosis
Yes 106.7(24.43) 0.26 (0.109)
0.443
No 330.04(75.57) 0.54 (0.121)
Aortic atheroma
Yes 65.11(14.91) 0.66 (0.662)
0.705
No 371.63(85.09) 0.46 (0.051)
Arterial beds
1 295.31(67.62) 0.4 (0.064)
2 125.14(28.65) 0.37 (0.228) 0.249
3 14.77(3.38) 0.22 (0.105)

0 1 2 3 4 5
Combination better Anticoagulation better

Figure 4.  Subgroup analysis of patients weighted with inverse probability of treatment weighting. Cox
proportional hazard ratios were obtained for each subgroup.Combination indicates combination of antiplatelet
and anticoagulation. The arterial bed count was defined as the number of atherosclerotic diseases a patient
had, which included cerebral artery stenosis, CAOD, PAOD, aortic atheroma, and coronary and cerebral stent
insertion history. CAOD coronary artery occlusive disease, PAOD peripheral artery occlusive disease, CHF
chronic heart failure, DOAC direct oral anticoagulants, NIHSS national institutes of health stroke scale, GFR
glomerular filtration rate, HR hazard ratio.

optimal dose of DOAC or to maintain the therapeutic intensity of VKA during follow-up because of concerns
regarding bleeding risk, although we could not investigate the intensity of OAC during follow-up. Furthermore,
considering that the risk of cardiovascular events increases with an increase in the burden of cerebral ­stenosis17,

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 6

Vol:.(1234567890)
www.nature.com/scientificreports/

the addition of antiplatelet with OAC might not be enough to prevent recurrent ischemic stroke. These findings
suggest that a more potent therapeutic approach is required to prevent recurrent strokes in this population. For
example, vascular risk factors such as hypertension, dyslipidemia, and diabetes are well-known determinants
of thromboembolism caused by atrial fibrillation and atherosclerotic d ­ iseases18–20, and strict control of vascular
risk factors during follow-up would be helpful.
When using OAC with antiplatelet, concerns on increase in the risk of bleeding complication are r­ aised21.
Concurrent use of antiplatelet with OAC increased the bleeding risk (especially at gastrointestinal or intracranial
site) compared to OAC ­alone8. However, in our study, even though cerebral hemorrhages seemed to be frequent
in case of OAC + antiplatelet, there was no significant difference in bleeding complications between OAC + anti-
platelet and OAC only. Bleeding complications were less likely to occur when using DOAC with antiplatelet,
rather than VKA with a­ ntiplatelet22 or using OAC with single rather than OAC with dual a­ ntiplatelet23. In our
patients using OAC + antiplatelet, a single antiplatelet agent was mostly used and many patients were treated with
DOAC. In addition, strict vascular risk factor control during follow-up was regularly monitored at our stroke
center. These might be related to our findings.
Our study has several limitations. In this study, we divided the study population according to the medication
on discharge. Although the medication during follow-up seemed to be well maintained after discharge, we could
not assess the compliance or intensity of antithrombotic agents completely. Even though inverse probability of
treatment weighting, a validated statistical method to assess the effect of different treatments using retrospective
­data24, was performed to eliminate selection bias for antithrombotic therapy, there could be other factors that we
did not consider. We only investigated 1 year outcomes after index stroke; therefore, this result did not imply any
benefit of long-term use of OAC + antiplatelet. Considering that the dataset was from a single center, as well as
the retrospective nature of the study, there could be selection bias in the dataset. Randomized controlled studies
should be performed to eliminate selection bias between the two groups.

Methods
Patients
This was a retrospective study using data from a hospital-based observational cohort study (Clinicaltrials.gov
NCT03510312) investigating the long-term prognosis of patients with ischemic stroke or transient ischemic
attack (TIA) who were admitted to the Severance Stroke Center located in Seoul, Republic of Korea. This cohort
included patients with acute cerebral infarction or TIA within 7 days of onset who were admitted between
January 1, 2012, and December 31, 2020. All patients underwent brain CT and/or magnetic resonance imaging
along with angiography, including CT angiography, magnetic resonance angiography, or digital subtraction
angiography. During hospitalization, all the patients were extensively and thoroughly evaluated to determine
their demographic data, medical history, clinical manifestations, vascular risk factors, and comorbidities. The
patients also underwent standard blood tests, 12-lead electrocardiography, and Holter monitoring. Nearly all
patients were admitted to the stroke unit and monitored continuously using electrocardiography during their stay
(median, 5 days; IQR 4–6 days). Echocardiography, including transesophageal echocardiography, was a routine
examination unless it could not be performed because of the patient’s condition or failure to obtain informed
consent. This study was approved by the Institutional Review Board of Yonsei University College of Medicine
(approval number: 4-2022-1098) with a waiver of informed consent owing to the retrospective nature of the
study. All methods in our study were performed in accordance with the tenets of the Declaration of Helsinki.

Clinical variables
For each patient, demographic data, vascular risk factors, and comorbidities including hypertension, diabetes
mellitus, dyslipidemia, CAOD, PAOD, and history of stroke were collected. Current smoking (one or more
cigarettes smoked during the last month) and alcohol consumption status were also assessed. Stroke severity
was assessed using the National Institutes of Health Stroke Scale (NIHSS). Premorbid disability was defined as
a modified Rankin Scale (mRS) score of 2–5 before the index stroke. Stroke subtypes were classified according
to the Trial of Org 10172 in the Acute Stroke Treatment c­ lassification25. Estimated glomerular filtration was cal-
culated using the CKD-EPI method. Data on statin medications prescribed upon discharge were also collected.
High-intensity statin therapy was defined as atorvastatin > 40 mg or rosuvastatin > 20 ­mg26.
Our study population was stratified according to the antithrombotic regimen prescribed upon discharge:
OAC alone versus combined OAC and antiplatelet. OAC consisted of VKA and DOAC, including dabigatran,
rivaroxaban, apixaban, and edoxaban. Antiplatelet agents included aspirin, clopidogrel, cilostazol, triflusal, prasu-
grel, ticlopidine, and aggrenox.

Systemic atherosclerotic lesion

The presence of atherosclerotic lesions in the arteries of the aorta, brain, heart, and peripheral arteries was inves-
tigated in each patient. This included one or more of the following atherosclerotic diseases: (1) cerebral athero-
sclerosis with > 50% stenosis based on the North American Symptomatic Carotid Endarterectomy Trial ­method27
for extracranial artery or Warfarin vs. Aspirin for Symptomatic Intracranial Disease ­method28 for intracranial
artery; (2) > 4 mm aortic atheroma at the ascending aorta or aortic arch on transesophageal echocardiography;
(3) previous history of CAOD or PAOD; and (4) coronary or carotid stent insertion. To prevent the misinterpre-
tation of embolic occlusion as cerebral atherosclerosis, we included only stenotic lesions after excluding arterial
culprit lesions in infarcted areas or complete occlusion of the cerebral artery. CAOD was defined as (1) previous
history of myocardial infarction or unstable angina and (2) coronary artery stenosis, either symptomatic or
asymptomatic, on documented catheter coronary angiography or multidetector coronary CT. The presence of
PAOD was defined when it was verified by sonographic evaluation or CT angiography. The burden of systemic

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 7

Vol.:(0123456789)
 www.nature.com/scientificreports/

atherosclerosis was calculated as the total number of atherosclerotic diseases including cerebral artery stenosis,
CAOD, PAOD, aortic atheroma, and coronary or cerebral stent insertion history.

Outcome measures
In our stroke center, stroke neurologists and research nurses regularly contacted patients or their caregivers
via regular face-to-face visits or telephone interviews with or without medical chart review to investigate the
development of vascular events, cancer, or risk factors newly detected during follow-up. Patients included in
this study were regularly followed-up at 3 months and 1 year after discharge.
When a patient died, we recorded the date and if possible, the cause of death was determined. Cardiovas-
cular death was defined as death resulting from myocardial infarction, sudden cardiac death, heart failure,
cardiovascular procedure, or ­stroke29. We also collected the data on the occurrence of recurrent ischemic stroke
(including TIA), hemorrhagic stroke, myocardial infarction, or bleeding events within 1 year after stroke and if
any, the date of events. Recurrent ischemic stroke was determined by a stroke specialist based on the clinical and
radiological findings. Hemorrhagic stroke included intracerebral, intraventricular, subarachnoid, and subdural
hemorrhages. Myocardial infarction was defined as the diagnosis of acute myocardial infarction based on clini-
cal symptoms, cardiac enzymes, electrocardiography, and imaging studies, such as coronary angiography. All
bleeding events were recorded, including hemorrhagic stroke, gastrointestinal bleeding, respiratory bleeding,
and muscular bleeding requiring transfusion or hospitalization. Fatal ischemic stroke, fatal hemorrhagic stroke,
fatal myocardial infarction, and fatal bleeding events were defined as death after severe respective disease without
any other obvious cause of death, which was decided by the ­physician16,28. The primary outcome of this study
was the all-composite outcome within 1 year of the index stroke. We compared these predetermined outcomes
within 1 year of the index stroke according to medication.

Statistical analysis
The baseline characteristics of the study participants were compared. Continuous variables were compared using
the Mann–Whitney U test, and categorical variables using Pearson’s chi-square test. To find out independent
factor for the use of antiplatelet along with OAC, variables significantly associated with OAC + antiplatelet group
was selected. Using these variables, multivariable logistic regression analysis was performed to finally derive the
odds ratio for each variable.
To adjust for substantial differences in baseline characteristics between the OAC alone and OAC + antiplatelet
groups, inverse probability of treatment weighting was performed. Propensity scores were estimated for all the
patients enrolled in this study using logistic regression. The selected confounders were older age (> 75 years),
sex, hypertension, diabetes, dyslipidemia, current smoking, congestive heart failure, high initial NIHSS score
(> 4), low estimated glomerular filtration rate (< 30 mL/min/1.73 ­m2), presence of aortic atheroma (> 4 mm),
CAOD, PAOD, cerebral atherosclerosis with > 50% stenosis, history of coronary stent insertion, history of cerebral
artery stent insertion, and prescription of high-dose statin on discharge. The inverse probability of treatment
weighting was calculated by weighting each case using inverse propensity score. Symmetrical trimming was
performed with an optimal cut-off to achieve the final d ­ ataset30. Subgroup analysis was performed according to
all variables used in this analysis.
A Kaplan–Meier estimate of survival with the log-rank test was used to compare the differences in event rates
of outcomes between the OAC alone and OAC + antiplatelet groups. Cox proportional hazard regression was
performed to compare the outcomes between the treatment groups. All P values were two-sided. R version 4.0
(R Core Team, Vienna, Austria) was used for statistical a­ nalysis31. Inverse probability of treatment weighting was
performed with the “PSWeight” package and survival analysis using the “survival” p ­ ackage32,33.

Data availability
The data supporting the findings of this study are available from the corresponding author on reasonable request.

Received: 4 April 2023; Accepted: 29 December 2023

References
1. Friberg, L. et al. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke 45, 2599–2605 (2014).
2. Lin, H. J. et al. Stroke severity in atrial fibrillation: The Framingham study. Stroke 27, 1760–1764. https://​doi.​org/​10.​1161/​01.​str.​
27.​10.​1760 (1996).
3. Kleindorfer, D. O. et al. 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline
from the American Heart Association/American Stroke Association. Stroke 52, e364–e467. https://​doi.​org/​10.​1161/​STR.​00000​
00000​000375 (2021).
4. Sun, W. et al. Clinical and imaging characteristics of cerebral infarction in patients with nonvalvular atrial fibrillation combined
with cerebral artery stenosis. J. Atheroscler. Thromb. 25, 720–732. https://​doi.​org/​10.​5551/​jat.​43240 (2018).
5. Lehtola, H. et al. Stroke recurrence in patients with atrial fibrillation: Concomitant carotid artery stenosis doubles the risk. Eur. J.
Neurol. 24, 719–725. https://​doi.​org/​10.​1111/​ene.​13280 (2017).
6. Zhou, G. et al. Cerebral arteriosclerosis stenosis predicts poor short-term prognosis in non-valvular atrial fibrillation related car-
dioembolic stroke treated by reperfusion therapy. Clin. Neurol. Neurosurg. 207, 106738. https://​doi.​org/​10.​1016/j.​cline​uro.​2021.​
106738 (2021).
7. Chang, Y. J., Ryu, S. J. & Lin, S. K. Carotid artery stenosis in ischemic stroke patients with nonvalvular atrial fibrillation. Cerebrovasc.
Dis. 13, 16–20. https://​doi.​org/​10.​1159/​00004​7740 (2002).
8. Dentali, F., Douketis, J. D., Lim, W. & Crowther, M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagu-
lant therapy alone among patients at risk for cardiovascular disease: A meta-analysis of randomized trials. Arch. Intern. Med. 167,
117–124. https://​doi.​org/​10.​1001/​archi​nte.​167.2.​117 (2007).

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 8

Vol:.(1234567890)
www.nature.com/scientificreports/

9. Eikelboom, J. W. et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N. Engl. J. Med. 377, 1319–1330. https://​
doi.​org/​10.​1056/​NEJMo​a1709​118 (2017).
10. Bonaca, M. P. et al. Rivaroxaban in peripheral artery disease after revascularization. N. Engl. J. Med. 382, 1994–2004. https://​doi.​
org/​10.​1056/​NEJMo​a2000​052 (2020).
11. Chen, L. Y. et al. Atrial fibrillation burden: Moving beyond atrial fibrillation as a binary entity: A scientific statement from the
American Heart Association. Circulation 137, e623–e644 (2018).
12. Investigators, A. Baseline characteristics of patients with atrial fibrillation: The AFFIRM Study. Am. Heart J. 143, 991–1001 (2002).
13. Zhu, J., Tan, X. & Zhou, J. Z. Peripheral artery disease and clinical outcomes in patients with atrial fibrillation: A systematic review
and meta-analysis. Clin. Cardiol. 44, 1050–1057. https://​doi.​org/​10.​1002/​clc.​23678 (2021).
14. Hillerson, D., Wool, T., Ogunbayo, G. O., Sorrell, V. L. & Leung, S. W. Incidental coronary artery calcification and stroke risk in
patients with atrial fibrillation. AJR. Am. J. Roentgenol. 215, 344 (2020).
15. Hylek, E. M. et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med.
349, 1019–1026 (2003).
16. Auer, E. et al. Stroke severity in patients with preceding direct oral anticoagulant therapy as compared to vitamin K antagonists.
J. Neurol. 266, 2263–2272. https://​doi.​org/​10.​1007/​s00415-​019-​09412-y (2019).
17. Park, J. H. et al. Atherosclerotic burden and vascular risk in stroke patients with atrial fibrillation. Stroke 52, 1662–1672. https://​
doi.​org/​10.​1161/​strok​eaha.​120.​032232 (2021).
18. Kodani, E. et al. Impact of blood pressure control on thromboembolism and major hemorrhage in patients with nonvalvular atrial
fibrillation: A subanalysis of the J-RHYTHM registry. J. Am. Heart Assoc. 5, e004075. https://​doi.​org/​10.​1161/​JAHA.​116.​004075
(2016).
19. Ding, W. Y., Protty, M. B., Davies, I. G. & Lip, G. Y. H. Relationship between lipoproteins, thrombosis, and atrial fibrillation.
Cardiovasc. Res. 118, 716–731. https://​doi.​org/​10.​1093/​cvr/​cvab0​17 (2021).
20. Echouffo-Tcheugui, J. B. et al. Care patterns and outcomes in atrial fibrillation patients with and without diabetes. J. Am. Coll.
Cardiol. 70, 1325–1335. https://​doi.​org/​10.​1016/j.​jacc.​2017.​07.​755 (2017).
21. Best, J. G. et al. Antithrombotic dilemmas in stroke medicine: New data, unsolved challenges. J. Neurol. Neurosurg. Psychiatry
https://​doi.​org/​10.​1136/​jnnp-​2020-​325249 (2022).
22. Douros, A. et al. Concomitant use of direct oral anticoagulants with antiplatelet agents and the risk of major bleeding in patients
with nonvalvular atrial fibrillation. Am. J. Med. 132, 191-199.e112. https://​doi.​org/​10.​1016/j.​amjmed.​2018.​10.​008 (2019).
23. Lou, B. et al. Meta-analysis comparing dual versus single antiplatelet therapy in combination with antithrombotic therapy in
patients with atrial fibrillation who underwent percutaneous coronary intervention with stent implantation. Am. J. Cardiol. 122,
604–611. https://​doi.​org/​10.​1016/j.​amjca​rd.​2018.​04.​050 (2018).
24. Deb, S. et al. A review of propensity-score methods and their use in cardiovascular research. Can. J. Cardiol. 32, 259–265. https://​
doi.​org/​10.​1016/j.​cjca.​2015.​05.​015 (2016).
25. Adams, H. P. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST.
Trial of Org 10172 in Acute Stroke Treatment. Stroke 24, 35–41. https://​doi.​org/​10.​1161/​01.​STR.​24.1.​35 (1993).
26. Grundy, S. M. et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the man-
agement of blood cholesterol: A report of the American College of Cardiology/American Heart Association task force on clinical
practice guidelines. Circulation 139, e1082–e1143. https://​doi.​org/​10.​1161/​CIR.​00000​00000​000625 (2019).
27. NACET Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N.
Engl. J. Med. 325, 445–453 (1991).
28. Chimowitz, M. I. et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N. Engl. J. Med. 352,
1305–1316. https://​doi.​org/​10.​1056/​NEJMo​a0430​33 (2005).
29. Hicks, K. A. et al. 2017 Cardiovascular and stroke endpoint definitions for clinical trials. Circulation 137, 961–972. https://​doi.​
org/​10.​1161/​CIRCU​LATIO​NAHA.​117.​033502 (2018).
30. Crump, R. K., Hotz, V. J., Imbens, G. W. & Mitnik, O. A. Dealing with limited overlap in estimation of average treatment effects.
Biometrika 96, 187–199. https://​doi.​org/​10.​1093/​biomet/​asn055 (2009).
31. Team, R. C. R: A Language and Environment for Statistical Computing. http://​www.R-​proje​ct.​org (2014).
32. Therneau, T. M. & Grambsch, P. M. Modeling Survival Data: Extending the Cox Model (Springer, 2000).
33. Zeng, S., Li, F., Wang, R. & Li, F. Propensity score weighting for covariate adjustment in randomized clinical trials. Stat. Med. 40,
842–858 (2021).

Acknowledgements
This study was supported by a faculty research grant of Yonsei University College of Medicine (6-2022-0170)
and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development
Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-00265497).

Author contributions
J.H. performed the analysis, wrote, and revised the main manuscript. H.L., I.H.L., I.H.L., and S.H.H. performed
a major role in data preparation. J.S. participated in data preparation and in part of statistical analysis. H.S.N.
revised the manuscript. Y.D.K. conceptualized the study, oversaw the analysis, wrote, and revised the main
manuscript.

Competing interests
The authors declare no competing interests.

Additional information
Supplementary Information The online version contains supplementary material available at https://​doi.​org/​
10.​1038/​s41598-​023-​51013-3.
Correspondence and requests for materials should be addressed to Y.D.K.
Reprints and permissions information is available at www.nature.com/reprints.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations.

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 9

Vol.:(0123456789)
 www.nature.com/scientificreports/

Open Access This article is licensed under a Creative Commons Attribution 4.0 International
License, which permits use, sharing, adaptation, distribution and reproduction in any medium or
format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons licence, and indicate if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

© The Author(s) 2024

Scientific Reports | (2024) 14:304 | https://doi.org/10.1038/s41598-023-51013-3 10

Vol:.(1234567890)