Association between retinal vein occlusion and an increased risk of acute myocardial infarction: A nationwide population-based follow-up study
Association between retinal vein occlusion and an increased risk of acute myocardial infarction: A nationwide population-based follow-up study
Yu-Yen Chen 0 1
Shwu-Jiuan Sheu 0 1
Hsiao-Yun Hu 1
Dachen Chu 1
Pesus Chou 1
0 School of Medicine, National Yang-Ming University , Taipei, Taiwan , 2 Department of Ophthalmology, National Yang-Ming University Hospital , Yilan City, Yilan County , Taiwan , 3 Community Medicine Research Center and Institute of Public Health, National Yang-Ming University , Taipei, Taiwan , 4 Department of Ophthalmology, Kaohsiung Veterans General Hospital , Kaohsiung, Taiwan , 5 Department of Education and Research, Taipei City Hospital , Taipei, Taiwan, 6 Deputy Superintendent , Taipei City Hospital , Taipei , Taiwan
1 Editor: Stephane Germain, Centre National de la Recherche Scientifique , FRANCE
Data Availability Statement: Data are available
from the National Health Insurance Research
Database (NHIRD) published by Taiwan National
Health Insurance (NHI) Bureau. The data utilized in
this study cannot be made available in the
manuscript, the supplemental files, or in a public
repository due to the ªPersonal Information
Protection Actº executed by Taiwan's government,
starting from 2012. Requests for data can be sent
as a formal proposal to the NHIRD (http://nhird.
nhri.org.tw) or by email to wt.gro.irhn@drihn.
To investigate a possible association between retinal vein occlusion (RVO) and an increased risk of developing acute myocardial infarction (AMI).
A population-based retrospective cohort study using the entire population of the Taiwan
National Health Insurance Research Database (NHIRD) from 1st January, 2001 to 31st
A total of 37921 subjects with RVO were enrolled in the RVO group, and 113763 subjects
without RVO were enrolled in the comparison group. The comparison group consisted of
randomly selected individuals who were propensity score (PS)-matched with the RVO
group at a ratio of 1:3, based on age, gender, obesity, stroke, hyperviscosity syndrome,
glaucoma, and the use of antithrombotic drugs. A log-rank test was used to compare the
cumulative hazard of AMI between the two groups. A multivariate Cox regression analysis
was used to estimate the adjusted hazard ratios (HRs) of AMI, adjusted for PS, diabetes,
hypertension, hyperlipidemia, congestive heart failure, and chronic renal failure.
The mean age of the cohort was 62.4±13.2 years. RVO patients had significantly higher pro
portions of diabetes, hypertension, hyperlipidemia, congestive heart failure, and chronic
renal failure than the comparisons. The mean follow-up period was 5.52 years in the RVO
group and 5.55 years in the comparison group (p = 0.16). A log-rank test comparing the
cumulative hazard curves of AMI for the two groups revealed a significant difference
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
(p<0.0001). In the multivariate Cox regression after adjustment for PS and confounders, the
RVO group had a significantly higher risk of AMI (adjusted HR = 1.21; 95% CI: 1.13 to 1.30).
When the RVO group was divided into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) and analyzed separately, both groups had significantly higher adjusted HRs for developing AMI than the comparison group. Moreover, the CRVO group had a significantly higher risk of AMI than the BRVO group.
People with RVO are at significantly greater risk of developing AMI than individuals without RVO.
Retinal vein occlusion (RVO) results from thrombosis in the retinal vein, due to compression
by a nearby atherosclerotic artery or increased blood viscosity. [1±4] Risk factors of RVO
include hypertension, diabetes, hyperlipidemia, and older age. [5±10] All of these factors are
also risk factors of acute myocardial infarction (AMI). Because RVO and AMI share a
common pathogenesis of atherosclerosis and similar risk factors, these conditions might be
Previous hospital-based studies investigating the relationships between RVO and the risk of
developing AMI revealed inconsistent results. [5,10±14] Recently, follow-up studies based on
healthcare claims databases were conducted to solve the problem but were also inconclusive.
Hu et al utilized the Taiwan National Health Insurance Database (NHIRD) and found that
RVO did not independently increase the risk of developing AMI during the 3-year follow-up
period.  Werther et al analyzed claims data in the US (including Medicare and Medicaid)
and showed that RVO was not significantly associated with AMI development during the
4-year follow-up period.  However, in South Korea, Rim et al used a database of a
nationwide sample cohort and showed that RVO increased the risk of developing AMI [hazard ratio
(HR) = 1.25; 95% confidence interval (CI): 1.02 to 1.52] during the 11-year follow-up period.
 The inconsistent results of previous studies may be due to the insufficient statistical
power, non-equivalent study designs, as well as different diagnostic classification methods.
The objective of our study is to investigate whether patients with RVO have a higher risk of
developing AMI than controls using the ªwhole populationº NHIRD in Taiwan, not ªsample
dataº as reported in previous studies. Thus, we will have sufficient statistical power. Besides,
during the study period, NHIRD adopted the International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9-CM) Codes, which are generally acknowledged
worldwide. Therefore, the results of our study were compared with the results of previous studies.
Furthermore, given the completeness of the NHIRD, we can have a long-term study period
and can derived the risk ratio of developing AMI after controlling and adjusting for the impact
Materials and methods
Taiwan's National Health Insurance (NHI) program, which was launched in 1995, currently
covers the health care services of greater than 99% of Taiwan's 23 million residents.  The
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National Health Insurance Research Database (NHIRD), which is maintained by the National
Health Research Institutes of Taiwan, is a collection of all registration file data and claims data
for all ambulatory and in-hospital patients in Taiwan. The identification of all patients in the
database is encrypted before the data are released for research purpose.  Therefore,
according to the rules of the Instituitional Review Board, writthen informed consent was waived.
[19±20] Based on the healthcare claims of the entire population, we sought to compare the
incidence rate of AMI in subjects with and without RVO during the 13-year period. This study
was approved by the ethical committee of Yang-Ming University Hospital (2015A018).
Inclusion and exclusion criteria
Using the Taiwan NHIRD from 1996 to 2013, we performed a retrospective cohort study. We
first selected patients with RVO during January 1, 2001 to December 31, 2013. The diagnostic
codes of RVO included central retinal vein occlusion (CRVO; ICD-9-CM codes 362.35) and
branch retinal vein occlusion (BRVO; ICD-9-CM codes 362.36). Patients with RVO diagnoses
from January 1, 1996 to December 31, 2000 were excluded to eliminate patients with previous,
chronic RVO. The date of the first RVO claim was defined as the index date. We also randomly
selected individuals who had never received a diagnosis of RVO as a comparison group. To
eliminate the bias caused by the group differences, the RVO group and the comparison group
were 1:3 matched using propensity score (PS) matching method,  in terms of age, gender,
index year (the year of index date), use of antithrombotic drugs, obesity, stroke, hyperviscosity
syndrome, and glaucoma. Both the RVO and comparison groups were tracked during the
follow-up period to identify the occurrence of AMI (ICD-9-CM codes 410). Patients who
received a diagnosis of AMI before the index date were excluded to ensure that patients with
only newly diagnosed AMI were included.
The demographic/clinical characteristics of the RVO and comparison groups were compared
by chi-square test for categorical variables and two-sample t-test for continuous variables. A
log-rank test was performed to describe and compare the cumulative hazard curves of AMI
between the two groups. A multivariate Cox proportional hazard model was used to estimate
the adjusted HRs for the occurrence of AMI. Covariates adjusted in the regression analysis
were PS and relevant comorbidities, including diabetes, hypertension, hyperlipidemia,
congestive heart failure, and chronic renal failure.  To eliminate the effect of the immortal time
bias, these comorbidities were regarded as time-dependent variables. 
Furthermore, we divided the RVO group into BRVO and CRVO groups and compared the
demographic/clinical characteristics between them. Finally we separately compared the HRs
for AMI among the BRVO, CRVO and comparison groups. All statistical operations were
performed using SAS statistical package, version 9.3 (SAS Institute, Cary, NC, USA).
The study population
This study included 37921 patients with RVO and 113763 PS-matched comparisons. Among
the patients with RVO, 11855 (31.3%) were diagnosed with CRVO, and 26066 (68.7%) were
diagnosed with BRVO. Table 1 shows a summary of the characteristics of the RVO and the
comparison groups. Because the two groups were well-matched on PS derived from age,
gender, use of antithrombotic drugs, obesity, stroke, hyperviscosity syndrome, and glaucoma, no
differences in theses variables and PS were found between the two groups. The mean age of
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RVO: Retinal vein occlusion; PS: propensity score; CHD: coronary heart disease; AMI: acute myocardial infarction
the overall cohort was 62.4 years, with a standard deviation of 13.2 years. Greater than 60
percent of the subjects were over 60 years old. Males constituted a slightly higher proportion than
females (51.1% vs. 48.9%). The mean follow-up period was 5.52 years in the RVO group and
5.55 years in the comparison group, without significant differences (p = 0.16). Comparing the
prevalence of comorbidities in the RVO group with the comparison group, we identified
significant differences in the prevalence of diabetes, hypertension, hyperlipidemia, congestive
heart failure, and chronic renal failure (all p <0.0001). During the 13-year study period, AMI
occurred in 1240 (3.22%) patients in the RVO group and in 2616 (2.3%) in the comparison
Cumulative hazard curves and log-rank test
Fig 1 illustrates the cumulative incidence curves of AMI in the RVO group and the comparison
group. These two curves were moving apart from each other from the very beginning until the
end of the study period. According to the log rank test, the RVO group had a significantly
higher cumulative hazard of AMI than the comparison group (p-value<0.0001)
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Fig 1. Cumulative hazard curves for AMI among the RVO and comparison groups. The black line
represents the RVO group, and the gray line represents the comparison group. RVO: retinal vein occlusion.
HRs for AMI analyzed using Cox models
AMI: acute myocardial infarction; HR: hazard ratio; CI: confidence interval; RVO: retinal vein occlusion;
CHD: coronary heart disease
Propensity score and all the other variables in the table were included for adjustment in the Cox multivariate
CRVO: central retinal vein occlusion; BRVO: branch retinal vein occlusion; PS: propensity score; CHD: coronary heart disease; AMI: acute myocardial
and chronic renal failure, had a significantly increased risk of AMI (all p<0.0001). For those
with both congestive heart failure and coronary heart disease (CHD, not AMI), the hazard of
AMI was significantly increased 4.19-fold compared with those without congestive heart
failure. For those with congestive heart failure but without CHD, the hazard for AMI was still
statistically higher than those without congestive heart failure (adjusted HR = 1.96 with 95% CI:
Comparison of characteristics between the CRVO and BRVO groups
In Table 3, we divided the RVO group into the CRVO group (with 11855 patients) and BRVO
group (with 26066 patients), and compared their demographic/clinical characteristics. The age
distribution in the CRVO group was younger than that in the BRVO group. The CRVO group
had a significantly higher proportions of hyperviscosity syndrome, glaucoma, and diabetes
than the BRVO group. However, the two groups were similar in the proportions of obesity,
stroke, and congestive heart failure. The two groups also had similar mean follow-up time
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Fig 2. Hazard ratios for AMI in the BRVO and CRVO groups compared with the comparison group.
AMI: acute myocardial infarction; BRVO: branch retinal vein occlusion; CRVO: central retinal vein occlusion.
(5.51 years in the CRVO group and 5.53 years in the BRVO group). The occurrence rate of
AMI is 3.60% in the CRVO group, significantly higher than that of 3.12% in the BRVO group
Comparison of the risk of AMI between the CRVO and BRVO groups
Fig 2 compares the adjusted HR for AMI among the comparison, CRVO, and BRVO groups.
Compared with the comparison group, the adjusted hazard ratio for AMI was 1.35 (95% CI:
1.22±1.49) in the CRVO group and 1.15 (95% CI: 1.06±1.25) in the BRVO group. When
patients with BRVO and CRVO were compared, the CRVO group still had a significantly
higher risk of developing AMI than the BRVO group (p-value = 0.01).
In this nationwide follow-up study using the complete population data from the Taiwan
NHIRD, the risk of developing AMI were compared between 37921 RVO patients and 113763
PS-matched comparisons. After adjusting for PS and possible confounders, the RVO group
had a significantly higher risk of developing AMI than the comparison group (adjusted
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HR = 1.21, 95% CI: 1.13±1.30). When RVO group was divided into CRVO and BRVO groups,
we found both of them had significantly higher adjusted HR for AMI than the comparison
group. And, the CRVO group had a significantly higher risk of developing AMI than the
BRVO group (p = 0.01).
RVO, including CRVO and BRVO, is one of the most common causes of visual
impairment, particularly in older people. [
] The pathogenesis of RVO has not been completely
described, but occlusion resulting from thrombosis is a well-accepted theory. RVO mainly
occurs at arteriovenous crossings where the retinal arteriole and venule share a common
adventitia sheath. If the arterial wall is sclerotic, it may compress the underlying vein, and the
turbulent blood flow in the vein will facilitate the formation of venous thrombosis and venous
] Similarly, the underlying mechanism of AMI involves a sclerotic artery
(coronary artery), which causes thrombus formation and venous obstruction. [
] We postulate
that RVO and AMI may be associated because the changes in retinal vessels may somehow
imply that changes have also occurred in coronary vessels.
Another explanation for the association between RVO and AMI is that they have common
risk factors. As noted in Table 1 in our study, the RVO group exhibits a greater proportion of
systemic comorbidities, such as diabetes, hypertension, hyperlipidemia, congestive heart
failure, and chronic renal failure, than the comparison group. The result is consistent with the
results from previous studies. [9,10,12,16,25,27±31] Notably, these systemic comorbidities are
also risk factors for AMI, thus potentially explaining why patients with RVO are predisposed
As shown in Fig 1, the cumulative hazard of AMI in the RVO group was significantly higher
than the comparison group. The result is compatible with the results of the population-based
studies in the US and South Korea. [16,17] Hu's study in Taiwan, with a follow-up time of 3
years, also revealed a higher cumulative incidence of AMI in the RVO group.  With a
much larger sample size and a much longer follow-up period, our study further confirms the
Shih et al analyzed claims data from 10,081 patients with RVO aged 70 years in Taiwan and
reported that patients with RVO had higher risks of subsequent myocardial infarction (HR =
1.29, 95% CI: 1.15±1.44).  Our study, analyzing data of the whole population, not only the
elderly, also revealed a significantly higher adjusted HR for the patients with RVO than the
individuals without RVO. Bertelsen et al reviewed the registries of 439 photographically
verified patients with CRVO from four referral centers in Denmark and found that patients with
RVO had a 1.9-fold increased risk of developing ischemic heart disease compared with the
control cohort (HR = 1.9, 95% CI: 1.32±2.75).  However, in another study by Bertelsen
et al utilizing the same data source, BRVO was not significantly associated with subsequent
myocardial infarction (MI). [
] In our study, as shown in Fig 2, both the BRVO and CRVO
groups have a significantly higher risk of developing AMI than the comparison group. In
addition, the risk in patients with CRVO is significantly higher than the risk in BRVO patients.
Thus, BRVO and CRVO may not have the same risk factors. [
] To the best of our
knowledge, our study is the first to report a significantly higher risk of AMI in the CRVO group
compared with the BRVO group.
One strength of our study is the use of the complete population database, precluding
possible selection bias, and providing stronger statistical power. Another strength of our study is
the accuracy of the diagnoses. In our healthcare system, patients must receive a standard
protocol of examinations to confirm the diagnoses or the National Health Insurance
Administration will not pay the fees for treatment. Previous studies also validated the accuracy of the
diagnoses in the database. [32±34] Therefore, the diagnoses in our study, including RVO,
AMI, and comorbidities, were thoroughly verified.
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Another strength is the controlling and adjustment for possible confounders using PS
matching method and PS analysis. In brief, PS is computed through mathematical algorithms
from confounders that have impact on RVO, which means PS represents the overall impact of
these confounders. Therefore, if the RVO and comparison groups are well-matched on PS (PS
matching method), these confounders would be evenly distributed in the RVO and
comparison groups, thus the PS matching method reduces the selection bias. PS analysis means that PS
as well as other confounders are regarded as covariates in the regression adjustment, thus we
can derive a more accurate relationship between RVO and AMI.
The limitation of our study is that some patients with asymptomatic RVO may not seek
medication. Thus, subjects with undetected RVO were classified as the comparison group and
not the RVO group. Such a misclassification bias would weaken the effect of RVO on the
development of AMI. Even so, RVO patients in our study had a higher hazard of AMI.
Therefore, our observation of an increased AMI risk in the RVO group is a real phenomenon.
It is a limitation that our database does not include tobacco use, which is a risk factor of
RVO and AMI. However, we have included a wide range of variables to make our RVO and
comparison groups balanced. Kolar P, [
] in a review article, has demonstrated that age,
gender, obesity, stroke, hyperviscosity syndrome, and glaucoma are risk factors of RVO. In our
study through PS matching method, these variables, as well as the use of antithrombotic drugs,
have been well-matched and controlled between the RVO and comparison groups. Besides,
risk factors that may confound the relationship between RVO and AMI, such as diabetes,
hypertension, hyperlipidemia, congestive heart failure, and chronic renal failure, [
been adjusted under the multivariate regression adjustment.
Our study has clinical implications and public health implications. Clinically, our study
reminds ophthalmologists to pay more attention to the risk of AMI when they are treating
patients with RVO. In particular, patients with RVO who have risk factors for AMI, such as
diabetes and hypertension, if are not under proper treatment, should be referred to physicians
for early diagnosis and treatment to prevent the occurrence of AMI. From the public health
perspective, policy makers are encouraged to enforce the surveillance for AMI risks in patients
Conceptualization: Yu-Yen Chen, Shwu-Jiuan Sheu, Dachen Chu, Pesus Chou.
Formal analysis: Yu-Yen Chen, Shwu-Jiuan Sheu, Hsiao-Yun Hu, Pesus Chou.
Investigation: Yu-Yen Chen.
Methodology: Yu-Yen Chen, Shwu-Jiuan Sheu, Hsiao-Yun Hu, Dachen Chu, Pesus Chou.
Validation: Yu-Yen Chen, Shwu-Jiuan Sheu, Hsiao-Yun Hu, Dachen Chu, Pesus Chou.
Writing ± original draft: Yu-Yen Chen, Pesus Chou.
Writing ± review & editing: Yu-Yen Chen, Pesus Chou.
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