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\begin{document}

\title{Differential presentations of arterial thromboembolic events between
venous thromboembolism and atrial fibrillation patients}



\author[1]{Yu-Sheng Lin}%
\author[2]{Ming-Shyan Lin}%
\author[3]{Chien-Chia Wu}%
\author[4]{Yung-Lung Chen}%
\author[1]{Jung-Jung  Chang}%
\author[3]{Pao-Hsien Chu}%
\author[5]{Gregory Lip}%
\author[4]{Mien-Cheng Chen}%
\affil[1]{Chiayi Chang Gung Memorial Hospital}%
\affil[2]{Chang Gung Memorial Hospital Chiayi Branch}%
\affil[3]{Chang Gung Memorial Hospital}%
\affil[4]{Chang Gung Memorial Hospital Kaohsiung Branch}%
\affil[5]{University of Liverpool}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Atrial fibrillation (AF) and venous thromboembolism (VTE)
share several risk factors related to arterial thromboembolism. No study
has reported the differential contribution to arterial thromboembolic
events and mortality between these two conditions in the same
population. Methods: We included AF and VTE national cohorts derived
from Taiwan National Health Insurance Research Database between 2001 and
2013. The eligible population was 314,861 patients in the AF cohort and
41,102 patients in the VTE cohort. The primary outcome was arterial
thromboembolic events, including ischemic stroke, extracranial arterial
thromboembolism (ECATE) and myocardial infarction (MI). Secondary
outcomes were all-cause mortality and cardiovascular death. Results:
After a 1:1 propensity matching, 32,688 patients in either group were
analyzed. The risk of arterial thromboembolic events was lower in the
VTE cohort than that in the AF cohort (subdistribution hazard ratio
{[}SHR{]}, 0.60; 95\% confidence interval {[}CI{]}, 0.57--0.62)). The
risk of ischemic stroke (SHR, 0.44; 95\% CI, 0.42--0.46) and MI (SHR,
0.80; 95\% CI, 0.72--0.89) were lower in the VTE cohort, while the risk
of ECATE (SHR, 1.23; 95\% CI, 1.14--1.33; particularly lower
extremities) was higher in the VTE cohort. All-cause mortality rate was
higher in the VTE cohort (HR, 1.18; 95\% CI, 1.15--1.21) while the risk
of cardiovascular death was lower in the VTE cohort (HR, 0.96; 95\% CI,
0.93--0.995). Conclusions: Patients with AF had higher risks of arterial
thromboembolic events compared to patients with VTE, despite having risk
factors in common. The VTE cohort had higher risks of all-cause
mortality and ECATE, particularly lower extremity events, compared to AF
patients. These differential manifestations of thromboembolism sequelae
in AF and VTE merit further investigation.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Atrial fibrillation (AF) is associated with an increased risk of stroke,
systemic thromboembolic events, and
mortality.\textsuperscript{1}Long-term anticoagulation therapy,
particularly with direct oral anticoagulants (DOACs), significantly
reduces the risk of stroke and mortality.\textsuperscript{2} In terms of
venous thromboembolism (VTE), including deep venous thrombosis (DVT) and
pulmonary embolism(PE), the duration of anticoagulation therapy to
prevent recurrences takes into
consideration~the~risk~of~recurrent~VTE~and~the~risk~of~bleeding.\textsuperscript{3}

AF and VTE have many pathophysiological and clinical risk factors in
common. For example, the pathogenesis of thromboembolism in AF has been
associated with a prothrombotic state by fulfilling Virchow's triad for
thrombogenesis, with abnormal blood flow (stasis), vessel wall
abnormalities (structural heart disease) and abnormal blood constituents
(coagulation factors).\textsuperscript{4} The pathogenesis of VTE also
has similar predisposing factors.\textsuperscript{3,5} Patients with AF
and/or VTE have many cardiovascular risk factors, such as hypertension,
smoking, hyperlipidemia, diabetes, and obesity \textsuperscript{6-8} and
malignancy.\textsuperscript{9} VTE has also been reported to be
associated with several cardiovascular diseases, including peripheral
artery disease and myocardial infarction (MI)\textsuperscript{10,11} as
well as non-cardiovascular factors, such as
malignancy.\textsuperscript{12,13} Indeed, one community registry study
reported that AF and VTE independently contributed to each
other.\textsuperscript{14}Thus, venous and arterial thrombosis may be
different sides of the same coin.\textsuperscript{15}

Of note, the duration of prescribing anticoagulation is quite different
between AF and VTE in current practice. Long-term anticoagulation should
be prescribed for AF patients \textsuperscript{2,16} whereas more
limited-duration of anticoagulation is sometimes prescribed for VTE
patients unless there are high risk features for
recurrence.\textsuperscript{3,17}

We hypothesized that AF and VTE, despite sharing many pathophysiological
and clinical risk factors, would have differential contribution to
arterial thromboembolic events and mortality in the same population.
Accordingly, we tested this hypothesis in a nationwide cohort study of
VTE and AF patients from the Taiwan National Health Insurance Database.

\textbf{Methods}

The data of this national retrospective cohort study was retrieved from
the Taiwan National Health Insurance Research Database (NHIRD) released
by the Taiwan National Health Research Institutes. The National Health
Insurance system is a mandatory universal health insurance program that
offers comprehensive medical care coverage to nearly all Taiwan
residents since the inception of the program in March 1995. In the
NHIRD, the patients' original identification numbers are encrypted and
the encrypting procedure is consistent, so that linking claims belonging
to the same enrollee is feasible and can be followed longitudinally. The
available health care information included complete outpatient visits,
hospitalization, and diseases, which were registered using International
Classification of Diseases, Ninth Revision, Clinical Modification
(ICD-9-CM) codes.\textsuperscript{18} In addition, medication
prescriptions are also recorded. Patients with newly diagnosis of AF and
VTE were included in this study. The study was approved by the
Institutional Review Board of Chang Gung Memorial Hospital
(201900915B1).

\textbf{Identification of patients with VTE and AF}

This study included national AF and VTE cohorts. Patients with AF were
identified with [?]2 times outpatient visits or in a discharge diagnosis
using the ICD-9 CM diagnostic code of 427.31 between 2001 and 2013.
Patients with VTE were identified using the discharge diagnosis
(ICD-9-CM: 453 for DVT and 415.1 for PE) with use of anticoagulation
during admission between 2001 and December 31, 2013. In the AF cohort,
we excluded patients who were under age of 20 years old and were
diagnosed as VTE historically or in follow-up period. In the VTE cohort,
we excluded patients who were under age of 20 years old and were
diagnosed as AF in the follow-up period. In order to compare the
differences of clinical outcomes after developing AF and VTE, we
excluded those who died at the index admission in both cohorts. Finally,
314,861 AF patients without VTE and 41,102 VTE patients without AF were
included in this study (Figure 1).

\textbf{Covariates}

Covariates were age, sex, eighteen comorbidities, Charlson Comorbidity
Index score, four historical events, and fourteen kinds of medications
(Table 1). Comorbidities were recognized with at least two clinic visits
or anyone inpatient record in the previous year before the index date.
Historical events were detected using anyone inpatient diagnosis before
the index date which could be tracked up to year 1997. The use of
medication was extracted within 3 months after index date. All the
information about medications were extracted from the claims data of
outpatient visits or the refill for chronic illness in the pharmacy by
using the Anatomical Therapeutic Chemical codes or the Taiwan NHI
reimbursement code.

\textbf{Outcomes}

The primary outcome was arterial thromboembolic events, including
ischemic stroke, myocardial infarction (MI) and extracranial arterial
thromboembolism (ECATE). Extracranial arterial thromboembolism included
arterial thromboembolic occlusion of an extremity or extracranial vital
organ, including kidney, intestine, and spleen. The occurrence of
ischemic stroke and MI was defined as the principal discharge diagnosis
of hospitalization. The occurrence of ECATE was defined as the principal
or secondary diagnoses of hospitalization. Secondary outcomes were
all-cause mortality and cardiovascular death. All-cause mortality was
defined as withdrawal from the NHI program.\textsuperscript{19} The
definition of cardiovascular (CV) death was the criteria of the
Standardized Definitions for Cardiovascular and Stroke Endpoint Events
in Clinical Trials by the FDA in the United States. Each patient was
followed from the discharge date of index admission to the date of event
occurrence, date of death, or December 31, 2013.

\textbf{Ascertainment of VTE, AF, ischemic stroke and ECATE}

The validation of AF has been assessed and presented in our previous
reports, with a high positive predictive value (PPV) of
89\%.\textsuperscript{20} The accuracy of VTE was reliable in the Taiwan
insurance claim system and some published studies also used the same
diagnosis method.\textsuperscript{10,21} Ischemic stroke was also
validated with high PPVs.\textsuperscript{22}In terms of ECATE, a
validation study was conducted at our medical center, randomly sampling
100 hospitalizations for systemic thromboembolism who were selected
using the same criteria as mentioned in this study. After experienced
physicians (YSL and VCCW) reviewed the medical records and all imaging
results, including vascular duplex, computed tomography angiography and
intervention reports, the PPV of systemic thromboembolism was 88\% (data
not shown).

\textbf{Statistics}

There would be substantial difference in the baseline characteristics
between study groups (i.e., VTE and AF cohorts). Therefore, we performed
1:1 ratio propensity score matching to make the covariates balanced
between groups. The propensity score was the predicted probability to be
in the one group (i.e., VTE) given the values of covariates using the
multivariable logistic regression without considering interaction
effects. The variables selected to calculate propensity score were
listed in Table 1 where the follow-up year was replaced with the index
date (Table 1). The matching was processed using a greedy nearest
neighbor algorithm with a caliper of 0.2 times of the standard deviation
of the logit of propensity score, with random matching order and without
replacement. The quality of matching was checked using the absolute
value of standardized difference (STD) between the groups, where a value
less than 0.1 was considered negligible difference. We additionally
performed three propensity score matchings to compare the PE-only cohort
with the DVT-only cohort, the DVT-only cohort with the AF cohort and the
PE-only cohort with the AF cohort, respectively.

As to the time to fatal outcomes (i.e., all-cause mortality and
cardiovascular death), the risks between the groups were compared by the
Cox proportional hazard model. The incidences of time to non-fatal
outcomes (e.g., ischemic stroke or MI) between groups were compared by
the Fine and Gray subdistribution hazard model which considered
all-cause mortality a competing risk. The within-pair clustering of
outcomes after propensity score matching was accounted for by using a
robust standard error.\textsuperscript{23} A two-sided \emph{P} value
\textless{}0.05 was considered statistically significant. Statistical
analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

\textbf{Results}

\textbf{Baseline characteristics}

This study enrolled 314,861 AF patients (mean age of 71.2\selectlanguage{ngerman}± 13.5 years)
and 41,102 VTE patients (mean age of 64.3 ± 16.4 years). These two
cohorts were different in age distribution, whereby the VTE cohort was
predominantly age \textless{} 65 years while the AF cohort was
predominantly age \selectlanguage{english}[?] 75 years (Table 1). The AF cohort had significantly
greater prevalence of hypertension, ischemic heart disease, chronic
obstructive pulmonary disease (COPD), hyperthyroidism and heart failure,
while VTE cohort had higher prevalence of peripheral artery disease,
cancer and auto-immune disease. In terms of medications, angiotensin
converting enzyme inhibitors/angiotensin receptor blockers, beta
blockers and digoxin were more frequently prescribed in the AF
population. In addition, the available follow-up period in AF cohort
were longer than that in VTE cohort (AF cohort vs VTE cohort: 4.2 +- 3.4
vs 3.8 +- 3.5 years, standardized difference: -0.12).

After matching, 32,688 patients in either cohort were well balanced in
baseline characteristics, including follow-up period (Table 1). In
patients with DVT-only versus AF, the AF cohorts had higher incidence of
ischemic heart disease, heart failure and COPD while DVT-only cohort had
higher incidence of cancer, auto-immune disease and peripheral artery
disease. (Supplemental table 1) In patients with PE-only versus AF, the
PE-only cohort had a higher incidence of cancer. ( Supplemental table 2)
In terms of the PE-only versus DVT-only cohorts, the PE-only cohort had
higher incidence of ischemic heart disease, heart failure and COPD while
DVT-only cohort had higher prevalence of cancer and peripheral artery
disease.( Supplemental table 3)

\textbf{Outcomes between VTE and AF cohorts}

The~outcomes~between~VTE~and~AF~cohort~obtained~After~propensity~matching
are shown in Supplemental table 4 and Figure 2. The risk of the arterial
thromboembolic events was lower in the VTE cohort (subdistribution
hazard ratio {[}SHR{]}, 0.60; 95\% confidence interval {[}CI{]},
0.57--0.62) (Figure 2A), as were the risks of ischemic stroke (SHR,
0.44; 95\% CI, 0.42--0.46) (Figure 2B) and MI (SHR, 0.80; 95\% CI,
0.72--0.89). The risk of ECATE (SHR, 1.23; 95\% CI, 1.14--1.33) (Figure
2C) and all-cause mortality rate (HR, 1.18; 95\% CI, 1.15--1.21) was
higher in VTE cohort (Figure 2E), although the latter had lower CV death
(HR, 0.96; 95\% CI, 0.93--0.995) (Figure 2D).

In subgroup analysis of the cause of death after propensity matching,
the percentage of CV death was significant higher in AF cohort than in
VTE cohort (VTE cohort versus AF cohort: 56.4\% versus 66.6\%,
P\textless{}0.001). (Supplemental table 5) The percentages of death
related to cancer and infection other than pneumonia among the causes of
non-CV death were significantly higher in the VTE cohort than in the AF
cohort.

\textbf{Outcomes between DVT-only and AF cohorts}

After propensity matching, there was no substantial difference in the
baseline characteristics between the DVT-only and AF cohorts
(Supplemental table 1). Clinical outcomes between DVT-only and AF
cohorts are shown in Supplemental table 6.

The incidence of arterial thromboembolic event was lower in the DVT-only
cohort than that in the AF cohort (SHR, 0.62; 95\% CI, 0.59--0.65)
(Figure 3A). The risks of ischemic stroke (SHR, 0.45; 95\% CI,
0.43--0.48) (Figure 3B) and MI (SHR, 0.76; 95\% CI, 0.67--0.86) were
lower, while the risk of ECATE was higher, in the DVT-only cohort (SHR,
1.31; 95\% CI, 1.20--1.43) (Figure 3C). All-cause mortality rates were
higher in the DVT-only cohort (HR, 1.14; 95\% CI, 1.11--1.17), while the
rate of CV death was lower (HR, 0.89; 95\% CI, 0.85--0.92) (Figure 3D
and Figure 3E).

\textbf{Outcomes between PE-only and AF cohorts}

After propensity matching, there was no substantial difference in the
baseline characteristics between the PE alone and AF cohorts
(Supplemental table 2). Clinical outcomes between PE-only and AF cohorts
were shown in Supplemental table 7. The incidence of the arterial
thromboembolic event was lower in the PE-only cohort than that in AF
cohort (SHR, 0.52; 95\% CI, 0.48--0.56) (Figure 4A). The risk of
ischemic stroke was lower in the PE-only cohort (SHR, 0.41; 95\% CI,
0.37--0.45) (Figure 4B) with no differences in ECATE (Figure 4C) and MI
event rates (Supplemental table 7). The PE-only cohort had higher
all-cause mortality (HR, 1.26; 95\% CI, 1.20--1.32) and CV death (HR,
1.14; 95\% CI, 1.07--1.22) than the AF cohort (Figure 4D and Figure 4E).

\textbf{Outcomes between PE-only and DVT-only cohorts}

After propensity matching, there was no substantial difference in the
baseline characteristics between the PE-only and DVT-only cohorts
(Supplemental table 3). Clinical outcomes between PE-only and DVT-only
cohorts were shown in Supplemental table 8. The arterial thromboembolic
event was lower in the PE-only cohort than in the DVT-only cohort (SHR,
0.80; 95\% CI, 0.73--0.88) (Figure 5A). The risks of ischemic stroke
(SHR, 0.82; 95\% CI, 0.74--0.92) and ECATE, including lower extremity
events, (SHR, 0.69; 95\% CI, 0.58--0.82) were lower in the PE-only
cohort than in the DVT-only cohort (Figure 5B and Figure 5C). The risks
of all-cause mortality (HR, 1.08; 95\% CI, 1.03--1.13) and CV death (HR,
1.28; 95\% CI, 1.19--1.37) were higher in the PE-only cohort compared to
the DVT-only cohort (Figure 5D and Figure 5E).

\par\null

\textbf{Discussion}

This retrospective 10-year nationwide cohort study enrolled two national
cohorts shows that the arterial thromboembolic events, ischemic stroke
and MI, were higher in matched patients with AF cohort than those with
VTE cohort. Second, the VTE cohort had higher incidence of ECATE than AF
cohort, particularly lower extremity thromboembolism. Third, the AF
cohort had higher incidence of CV death, but lower incidence of
all-cause mortality compared to the VTE cohort. (Figure 6 and
Supplemental table 9) In subgroup analyses comparing the DVT-only,
PE-only and AF cohorts, the AF patients had highest incidence of
ischemic stroke among the three cohorts and had similar incidence of MI
compared to patients with PE-only. Patients with DVT-only had highest
incidence of ECATE among the three cohorts, particularly lower extremity
thromboembolic event. In terms of mortality, patients with PE-only had
highest incidence of CV death and all-cause mortality. (Supplemental
table 9)

A national 20-year observational study demonstrated that patients with
VTE had a 1.26-1.31fold increased risk of subsequent arterial
thromboembolic events, including MI and stroke.
\textsuperscript{11}Schulman et al. also showed that VTE was associated
with a 1.28 fold increased risk of MI or stroke over a 10-year follow-up
period.\textsuperscript{24} Epidemiological studies and meta-analysis
have also recognized that AF is independently associated with a
five-fold increased risk of stroke\textsuperscript{1}, 1.47 fold
increased risk of MI \textsuperscript{25}, and a two-fold increased risk
of mortality.\textsuperscript{26}

Although VTE and AF contribute to similar arterial thromboembolic
events, we are unaware of any study that has compared the different
presentations of arterial thromboembolic events between VTE and AF
patients, from the same population cohort. Based on our study, AF
contributed to more arterial thromboembolic events while VTE contributed
to greater all-cause mortality. In terms of the causes of mortality,
more AF patients (66.6\%) died from cardiovascular death than VTE
patients (56.4\%) while more VTE patients (13.7\%) died from cancer than
AF patients (8.6\%) (Supplemental table 5). Our results were generally
consistent with other studies in terms of causes of death in VTE and AF
patients.\textsuperscript{27}

As mentioned above there are many parallels between the epidemiology of
risk factors and associated pathogenesis of thrombosis in AF and
VTE.\textsuperscript{4-6,8,28} Nonetheless, our study showed some
differential distributions of baseline characteristics between VTE and
AF cohorts. Of note, the prevalence of peripheral artery disease and
cancer was higher in VTE cohort than AF cohort. In contrast, the
prevalence of ischemic heart disease and heart failure was higher in AF
cohort than VTE cohort. Importantly, even after propensity matching, AF
cohort had higher risks of arterial thromboembolic event, ischemic
stroke and MI compared to the VTE cohort. VTE cohort had higher
all-cause mortality while AF cohort had higher CV mortality. Therefore,
VTE and AF patients have different risks in presentations related to
arterial thromboembolic events; thus, AF and VTE should not be
considered as a different side of exactly the same coin.

Long-term anticoagulation therapy to prevent arterial thromboembolism is
a well-established strategy in AF population\textsuperscript{2} and a
net clinical benefit more than 5 years with DOACs is still
evident.\textsuperscript{16} On the other hand, long-term
anticoagulation was not recommended in VTE population due to uncertain
net clinical benefit in the era of vitamin K antagonists (VKA, eg.
warfarin).\textsuperscript{17} However, some studies have shown that
extended treatment with DOAC for 6 months to 15 months resulted in less
recurrent VTE events than no treatment, and had less bleeding events
compared to VKA.\textsuperscript{29-32} Of note, extended low-dose
aspirin in VTE patients for up to 4 years results in a significant
reduction in the rate of major vascular events, with improved net
clinical benefit in the ASPIRE study.\textsuperscript{33}

Given the different presentations of arterial thromboembolic events
between AF and VTE cohorts over a 10-year follow-up period, further
studies of extended antithrombotic therapy in preventing arterial
thromboembolic events, particularly lower extremity thromboembolic
events, in VTE patients are warranted.

\textbf{Limitations}

Our study has several limitations. First, we could not clearly identify
the prevalence of provoked and unprovoked VTE in our VTE cohort. Several
observational studies have reported that unprovoked VTE does not
contribute to the same risk as provoked VTE in terms of clinical
outcomes, including arterial thromboembolic events. However, a 20-year
national observational cohort study reported no significant differences
in arterial CV events between provoked and unprovoked
VTE.\textsuperscript{11} In addition, the distinction between
provoked/unprovoked PE is no longer supported by the 2019 ESC guidelines
for the diagnosis and management of acute pulmonary
embolism.\textsuperscript{34} Furthermore, clinical
presentations/manifestations and laboratory data were not available in
NHIRD and such information might affect the outcomes of VTE, especially
those with PE.\textsuperscript{34} In order to reduce the bias, we
excluded those died during hospitalization and within 3 months after
discharge. Second, differentiating subtypes of AF (paroxysmal,
sustained) cannot be performed because this information was not
available in our national database. Although the incidence of ischemic
stroke is considered to be generally lower in paroxysmal AF patients
than in patients with sustained AF,\textsuperscript{35} it should not
affect the outcomes between AF and VTE in such a large volume study.
Third, the duration of anticoagulation therapy was different between AF
versus VTE cohorts.\textsuperscript{2,34} We also did not compare the
outcomes between AF and VTE cohorts in individual different scenarios
with different durations of anticoagulation therapy.

\textbf{Conclusion}

Patients with AF had higher risks of arterial thromboembolic events
(ischemic stroke and MI) compared to patients with VTE, despite having
risk factors in common. The VTE cohort had higher risks of all-cause
mortality and ECATE, particularly lower extremity events, compared to AF
patients. These differential manifestations of thromboembolism sequelae
in AF and VTE merit further investigation.

\textbf{Acknowledgments}

We would like to thank Alfred Hsing-Fen Lin and Ben Yu-Lin Chou for the
statistical assistance during the completion of this manuscript.

\textbf{Sources of Funding}

None.

\textbf{Disclosures}

GYHL: Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer
Ingelheim, Novartis, Verseon and Daiichi-Sankyo. Speaker for Bayer,
BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees
are directly received personally.

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\textbf{Figure legends}

\textbf{Figure 1.} Flowchart for selection of the study patients

\textbf{Figure 2.} The cumulative incidence rate of arterial
thromboembolic event (A), ischemic stroke (B), extracranial arterial
thromboembolic events (C), cardiovascular death (D) and all-cause
mortality (E) after propensity score matching comparing patients with
venous thromboembolism and those with atrial fibrillation.

\textbf{Figure 3.} The cumulative incidence rate of arterial
thromboembolic event (A), ischemic stroke (B), extracranial arterial
thromboembolic events (C), cardiovascular death (D) and all-cause
mortality (E) after propensity score matching comparing patients with
deep vein thrombosis alone and those with atrial fibrillation.

\textbf{Figure 4.} The cumulative incidence rate of arterial
thromboembolic event (A), ischemic stroke (B), extracranial arterial
thromboembolic events (C), cardiovascular death (D) and all-cause
mortality (E) after propensity score matching comparing patients with
pulmonary embolism alone and those with atrial fibrillation.

\textbf{Figure 5:} The cumulative incidence rate of arterial
thromboembolic event (A), ischemic stroke (B), extracranial arterial
thromboembolic events (C), cardiovascular death (D) and all-cause
mortality (E) after propensity score matching comparing patients with
pulmonary embolism alone and those with deep vein thrombosis alone.

\textbf{Figure 6.} The incidence of arterial thromboembolic events and
mortality between VTE and AF cohorts. The incidence of ischemic stroke
and myocardial infarction were lower in VTE cohort than AF cohort but
ECATE, particularly in low extremity, was lower in AF cohort than VTE
cohort. In terms of mortality, CV death was lower in VTE cohorts than AF
cohort while all-cause mortality and non-CV death were lower in AF
cohort than VTE cohort. Abbreviation: AF: atrial fibrillation, CV:
cardiovascular; ECATE: extracranial arterial thromboembolic event; VTE:
venous thromboembolism.

\textbf{Hosted file}

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