Journal of Thrombosis and Haemostasis, 13: 1254–1263

DOI: 10.1111/jth.12982

ORIGINAL ARTICLE

Prevalence and risk factors of retinal vein occlusion: the Gutenberg Health Study K. A. PONTO,*† H. ELBAZ,*‡§ T. PETO,‡ D. LAUBERT-REH,*¶ H. BINDER,** P. S. WILD,†¶†† K . L A C K N E R , ‡ ‡ N . P F E I F F E R * and A . M I R S H A H I * § § *Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz; †Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; ‡NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; §Department of Ophthalmology, University of Marburg, Marburg; ¶Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center of the Johannes Gutenberg-University Mainz; **Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University Mainz; ††DZHK (German Center for Cardiovascular Research), Partner Site RhineMain; ‡‡Institute for Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz; and §§Dardenne Eye Hospital, Bonn-Bad Godesberg, Mainz, Germany

To cite this article: Ponto KA, Elbaz H, Peto T, Laubert-Reh D, Binder H, Wild PS, Lackner K, Pfeiffer N, Mirshahi A. Prevalence and risk factors of retinal vein occlusion: the Gutenberg Health Study. J Thromb Haemost 2015; 13: 1254–63.

Summary. Objective: To determine the age- and sex-specific prevalence and determinants of retinal vein occlusions (RVOs) in a large population-based German cohort. Methods: The investigation included 15 010 participants (aged 35–74 years) from the Gutenberg Health Study. We determined the prevalence of RVO (central retinal vein occlusion [CRVO] and branch retinal vein occlusion [BRVO]) for the local population by assessing fundus photographs of 12 954 (86.3%; 49.8% women and 50.2% men) participants. Further, we analyzed the associations of RVO with cardiovascular, anthropometric, and ophthalmic parameters. Results: The weighted prevalences of RVO, CRVO, and BRVO were 0.40%, 0.08%, and 0.32%, respectively. Men were 1.7 times more frequently affected by RVO than were women. Prevalence of RVO was 0.2% in participants aged 35– 44 and 45–54 years, respectively, 0.48% in those aged 55–64 years, and 0.92% in those aged 65–74 years. Of persons with RVO, 91.5% had one or more cardiovascular risk factor or disease vs. 75.9% of persons without RVO. BRVO was associated with arterial hypertension (odds ratio 2.69, 95% confidence interval 1.27–5.70) and atrial fibrillation (3.37, 1.24–9.12) and CRVO with higher age (7.02, 1.63–30.19) and a family Correspondence: Alireza Mirshahi, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr 1, 55131 Mainz, Germany. Tel.: +49 6131 17 7287; fax: +49 6131 17 47 3339. E-mail: [email protected] Received 8 December 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 22 March 2015

history of stroke (4.64, 1.18–18.25). Median visual acuity (base 10 logarithm of minimum angle of resolution) was 0.2 in persons with RVO vs. 0.05 in those without. Conclusion: The prevalence of RVO in this German population was 0.4%, and men were 1.7 times more frequently affected than women. CRVO was associated with higher age and a family history of stroke, and BRVO was associated with arterial hypertension and atrial fibrillation. Keywords: population; prevalence; retinal disease; retinal vein occlusion; risk factors.

Introduction Retinal vein occlusions (RVOs) are the most common retinal vascular disease second to diabetic retinopathy [1] and a major cause of vision loss [2]. RVO is an obstruction of the retinal venous system that may involve the central retinal vein (central retinal vein occlusion [CRVO]) or a branch retinal vein (branch retinal vein occlusion [BRVO]) [3]. In the vast majority of cases, BRVO occurs at arteriovenous crossing sites where the artery is positioned anterior to the vein [4]. Untreated RVO often results in vision impairment and significant ocular complications in a substantial proportion of patients [5,6]. Some patients with CRVO develop macular edema, and approximately 5–15% of eyes with BRVO develop macular edema over 1 year [7]. As the population ages, the burden of RVO is likely to increase. RVO goes along with many ophthalmic and systemic risk factors; cardiovascular disease and certain coagulopathies have © 2015 International Society on Thrombosis and Haemostasis

Prevalence and risk factors of RVO 1255

been identified as risk factors for RVO [7]. In a registrybased cohort study, CRVO was associated with an increase in mortality, which was attributed to cardiovascular disorders and diabetes [8]. Associations with thrombophilic disorders have been found, especially for young patients [9–13]. Ophthalmic risk factors are ocular hypertension, glaucoma, increased ocular perfusion pressure, and changes in the retinal arteries [14]. A hemiretinal vein occlusion (HRVO) refers to a proximal occlusion that affects half of the retinal drainage as opposed to the smaller portion affected by a BRVO. The Eye Disease Case-Control Study has identified different risk factors for BRVO and CRVO development [15,16]. An increased risk for BRVO was found, for example, in hypertensive individuals and in those with cardiovascular disease, CRVO was also associated with diabetes mellitus and open-angle glaucoma. To assess the need and frequency for new ophthalmological interventions such as intravitreous anti–vascular endothelial growth factor drug injections, data from population-based studies are desirable to obtain knowledge on the prevalence of RVO and its subtypes as well as on associations of RVOs with systemic diseases and ophthalmic parameters. The purpose of this study was to determine the age- and sex-specific prevalence of all phenotypes of RVOs, as well as their anthropometric, ocular, and cardiovascular determinants, in a large population-based study in Germany. Methods Study participants

Approximately 15 010 participants aged between 35 and 74 years living in the city of Mainz or the district of Mainz-Bingen were recruited for the Gutenberg Health Study (GHS). The study participants were selected randomly from the compulsory registry offices. Persons who refused to visit the study center were asked to respond to some questions about demographics and their reasons for non-participation. The GHS is a prospective, single-center, population-based cohort study designed to examine diseases of the eye, the cardiovascular system, mental health, the immune system, and incident cancer [17,18]. Main objectives of the ophthalmological branch of the study are to convey the prevalence and incidence of common ophthalmological risk factors and diseases and to investigate biological correlations and their genetic background. Details of the study protocol and the investigation methods are discussed elsewhere [17,19–22]. The random sample is stratified 1:1 for sex and residence (urban vs. rural) and in equal strata across four age decades. Primary end points of the study were myocardial infarction and cardiovascular death. The study protocol of GHS was approved by the Ethics Committee of the state Rhineland-Palatinate, Germany, and the local data safety commissioner. All persons gave their written © 2015 International Society on Thrombosis and Haemostasis

informed consent prior to their inclusion in the study. The present research adhered to the tenets of the Declaration of Helsinki. Fundus images, grading, and cardiovascular risk factors

Fundus images were recorded with a non-mydriatic fundus camera in a darkened room and with the pupil’s natural width. Three photographs were taken of each eye: at 30° and 45° centered on the optic nerve and at 30° centered on the macula. The grading of the fundus photographs for the detection of retinal vein occlusion was carried out by a trained grader (H.E.) at the Moorfields Eye Hospital Reading Center, London, UK, and was adjudicated by an experienced clinician grader (T.P.). A BRVO was characterized by the presence of a localized area of retinal thickening or hemorrhages along retinal vessels with abnormal caliber or a congested vein at an arteriovenous crossing site. An old BRVO showed any combination of the following characteristics: a localized area of sheathing of the retinal blood vessels, arteriovenous collaterals, or laser marks involving a localized area of the retina close to the vascular arcades without signs of diabetic retinopathy in the same eye or the other eye. The criteria for detection of HRVO were the same as for BRVO except that the area involved comprised either the upper or the lower half of the retina. A CRVO was characterized by an hyperemia of the optic nerve head with scattered superficial and deep retinal hemorrhages in the four quadrants. Old occlusions were detected through the presence of arteriovenous collaterals, neovascularization at the optic disc, opticociliary shunts, or panretinal photocoagulation without signs of diabetic retinopathy in the other eye. We defined cardiovascular risk factors as follows. Smoking was dichotomized into non-smokers and smokers. Arterial hypertension was diagnosed if antihypertensive drugs were taken or if the mean systolic (and/or diastolic) blood pressure was ≥ 140 (≥ 90) mm Hg in the second and third standardized measurement after rest. Diabetes was diagnosed in individuals with a definite diagnosis and treatment by a physician, a blood glucose level ≥ 126 mg/dl after overnight fasting (≥ 8 h), or a level ≥ 200 mg/dL after a fasting period of < 8 h. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m². Dyslipidemia was defined as a definite diagnosis of dyslipidemia by a physician or a low-density lipoprotein/highdensity lipoprotein ratio of ≥ 3.5. Taking the participants’ histories from computer-assisted personal interviews, we also investigated whether sex, age, presence of peripheral arterial occlusive disease, atrial fibrillation, chronic heart failure, coronary heart disease, and family history of previous stroke or heart attack were associated with the diagnosis of RVO. Associations with the following ophthalmic parameters were analyzed: presence of glaucoma (self-reported

1256 K. A. Ponto et al

diagnosis and/or antiglaucoma medication or history of glaucoma surgery), intraocular pressure (noncontact tonometer), corneal thickness (non-contact Scheimpflugbased measurement), refraction, and visual acuity (automated refractor/keratometer with built-in Snellen charts). We calculated the mean spherical equivalent (sphere + ½ cylinder) of both eyes for participants without RVO and the spherical equivalent of the affected eye in those with RVO. Statistical analysis

Statistical analyses were performed using SPSS (Statistical Package for the Social Sciences, Version 21, Chicago, Illinois, USA). Prevalences are given as relative frequencies for the study population and the study sample. In the GHS, to determine the prevalence in the study population, data from the study sample were weighted for the age and sex distribution in the local population (region of Mainz/Mainz-Bingen). Weighting based on census data as of December 31, 2009, coinciding approximately with the midpoint of our recruitment phase. Because the distribution of missing values (fundus photographs missing or of insufficient quality) was not age and sex independent, weighting was done without these data. For univariable analyses, either the Mann–Whitney U test or t test was used. To assess the association between visual acuity of eyes affected by RVO vs. the contralateral eye, the Wilcoxon test was used. A univariable binary logistic regression was performed to first show a crude odds ratio. A confounder-adjusted odds ratio was calculated in the multivariable logistic regression model. In this model we determined whether the presence of RVO was associated with major cardiovascular diseases and risk factors (including age, sex), and the presence of glaucoma, and potential confounders (such as age and sex) that were prespecified in a statistical analysis plan. Variables with fewer than two in one group were excluded from multivariable analysis. Results Fundus photographs of sufficient quality of at least one eye were available in 12 954 (86.3%) of 15 010 GHS participants. Of those, 6456 (49.8%) were women and 6498 (50.2%) were men. Mean age was 55.0
11.1 years. Cardiovascular risk factors and diseases of these persons are summarized in Table 1. RVO was found in 62 eyes of 59 (0.5%) participants. Twelve of these participants (20.3%) had a unilateral CRVO vs. 47 participants (79.7%) having a BRVO (including one case of HRVO and two cases of bilateral BRVO). The prevalences of RVO are listed in Table 2. One female participant of the youngest age decade had an HRVO (weighted prevalence: 0.07%). Mean age of persons with RVO was 62.5
9.5 years vs. 55.0
11.1 years in persons without RVO. Males were

1.7 times more frequently affected by RVO (prevalence of RVO in men: 0.52%) than females (0.29%). There was no significant difference in age between persons with CRVO (66.2
9.4 years) and those with BRVO (61.6
9.5 years). Overall, 22 (37.3%) of 59 persons with RVO, 18 (38.3%) of 47 with BRVO and four (33.3%) of 12 persons with CRVO were women. Odds ratios, 95% confidence intervals, and P values of associations of RVO with age and sex are shown in Table 3. Three (5.1%) of 59 persons with RVO had glaucoma (two BRVO and one CRVO) vs. 287 (2.2%) cases of glaucoma in 12 890 participants without RVO (P = .139). Visual acuity (logMAR) was better in participants without RVO (median 0.05, range 0.30–2.00) vs. in those with RVO (0.20, 0.10–1.70; P < 0.001). Table 4 summarizes the visual acuity values of eyes affected by RVO vs. the unaffected eyes. In eyes affected by RVO, median visual acuity was 0.2 (range 0.1–1.7) vs. 0.1 (0.1–1.0) in the contralateral eyes (P < .001). In affected eyes of persons with BRVO and CRVO, visual acuity was 0.2 (0.1–1.7) and 0.35 (0–1.5) vs. 0.1 (0.1–1.0; P = 0.066) and 0.05 (0–0.4; P = 0.612) in the contralateral eyes, respectively (P = 0.066). Table 5 summarizes the associations with the other ophthalmic parameters. No significant differences regarding spherical equivalent, intraocular pressure, or central corneal thickness were noted. Fifty-four (91.5%) of 59 persons with RVO (one with CRVO and four with BRVO) had one or more known cardiovascular risk factor or diseases when they participated in the GHS vs. 9782 (75.9%) of persons without RVO (P = .005). Figure 1 compares the frequencies of cardiovascular diseases and risk factors between persons with CRVO and BRVO. Regarding arterial hypertension in participants with CRVO and BRVO, one (8.3%) vs. five (10.6%), two (16.7%) vs. 14 (29.8%), and six (50%)

Table 1 Cardiovascular risk factors and diseases in the study sample Cardiovascular risk factors and diseases Smoking Arterial hypertension Diabetes mellitus Dyslipidemia Obesity Family history for myocardial infarction Family history for stroke Medicated heart failure Myocardial infarction Coronary heart disease Peripheral artery disease Stroke Atrial fibrillation

Men, % (n)

Women, % (n)

21.1 54.5 9.3 36.7 26.3 15.3

(1368) (3539) (602) (2388) (1708) (996)

18.2 44.9 5.5 22.3 24.1 17.9

(1172) (2899) (355) (1442) (1558) (1158)

7.1 1.4 4.5 6.5 3.7 2.4 3.7

(462) (88) (293) (421) (237) (153) (243)

9.1 1.3 1.3 2.0 3.4 1.3 1.7

(590) (85) (86) (130) (203) (87) (111)

Fundus photographs (of sufficient quality) of at least one eye were available in 12 954 (86.3%) of 15 010 GHS participants. Of those, 6456 (49.8%) were women and 6498 (50.2%) were men. © 2015 International Society on Thrombosis and Haemostasis

Prevalence and risk factors of RVO 1257 Table 2 Prevalence of retinal vein occlusions (RVOs) according to sex and decades of age Decades of age (yrs)

RVO Total Male Female Central RVO Total Male Female Branch RVO Total Male Female

Prevalence, % (n)

All ages

35–44

45–54

55–64

65–74

Study Study Study Study Study Study

sample population sample population sample population

0.46 0.40 0.57 0.52 0.34 0.29

(59) (51.9) (37) (33.1) (22) (18.8)

0.18 0.20 0.30 0.33 0.07 0.07

(5) (7.7) (4) (6.3) (1) (1.3)

0.20 0.20 0.34 0.34 0.06 0.05

(7) (7.6) (6) (6.7) (1) (1.0)

0.50 0.48 0.58 0.60 0.41 0.37

0.92 0.92 1.01 1.01 0.83 0.84

(30) (23.4) (17) (12.1) (13) (11.3)

Study Study Study Study Study Study

sample population sample population sample population

0.1 0.08 0.12 0.10 0.06 0.05

(12) (10.3) (8) (6.7) (4) (3.5)

0.04 0.04 0.07 0.07 0 0

(1) (1.4) (1) (1.4)

0.03 0.03 0.06 0.05 0 0

(1) (1.1) (1) (1.1)

0 0 0 0 0 0

0.31 0.31 0.36 0.36 0.26 0.26

(10) (7.8) (6) (4.3) (4) (3.5)

Study Study Study Study Study Study

sample population sample population sample population

0.36 0.32 0.45 0.41 0.28 0.23

(47) (41.6) (29) (26.4) (18) (15.3)

0.14 0.17 0.22 0.26 0.07 0.07

(4) (6.3) (3) (5.0) (1) (1.3)

0.17 0.17 0.28 0.29 0.06 0.05

(6) (6.6) (5) (5.6) (1) (1.0)

0.50 0.48 0.58 0.60 0.41 0.37

0.62 0.61 0.66 0.65 0.57 0.58

(20) (15.6) (11) (7.8) (9) (7.8)

(17) (13.2) (10) (8.0) (7) (5.2)

(17) (13.2) (10) (8.0) (7) (5.2)

To determine the prevalence in the (study) population, data from the study sample were weighted for the age and sex distribution in the local population.

Table 3 Univariable analysis: Logistic regression model RVO

Age (Ref: ≥ 65 yrs) Sex (Ref: male) Smoking Glaucoma Coronary heart disease Arterial hypertension Atrial fibrillation Peripheral arterial occlusive disease Medicated heart failure Stroke Family history for myocardial infarction Family history for stroke Diabetes mellitus Dyslipidemia Obesity

CRVO

BRVO

OR

95% CI

P value

OR

95% CI

P value

OR

95% CI

2.91

1.74–4.87

< 0.001

10.34

2.80–38.25

< 0.001

2.14

1.19–3.86

0.011

1.65 0.56 2.30 0.97

0.97–2.80 0.25–1.23 0.72–7.39 0.87–1.08

0.063 0.146 0.161 0.543

1.96 0.83 3.91 0.96

0.59–6.52 0.18–3.78 0.50–30.34 0.73–1.27

0.271 0.807 0.193 0.798

1.58 0.49 1.91 0.97

0.88–2.85 0.20–1.25 0.46–7.91 0.87–1.09

0.128 0.135 0.372 0.582

3.59

1.94–6.65

< 0.001

3.04

0.82–11.24

0.095

3.75

1.86–7.55

< 0.001

6.51 1.01

3.18–13.32 1.00–1.03

< 0.001 0.084

7.23 0.97

1.58–33.10 0.75–1.25

0.011 0.814

6.33 1.02

2.82–14.21 1.00–1.03

< 0.001 0.041

1.29

0.18–9.36

0.577

6.80

0.87–52.92

0.067

N/A (no cases)

1.02 1.142

0.99–1.04 0.77–2.64

0.158 0.263

1.02 0.22–4.60

1.00–1.04 0.993

0.101 1.54

0.78–3.03

0.212

1.05

0.42–2.63

0.916

3.78

1.02-13.99

0.046

0.50

0.12–2.08

0.344

1.43 1.50 1.52

0.61–3.32 0.88–2.57 0.89–2.62

0.413 0.135 0.127

1.24 1.37 0.99

0.16–59.65 0.40–4.67 0.27–3.66

0.841 0.619 0.988

1.47 1.54 1.68

0.58–3.72 0.85–2.78 0.93–3.06

0.417 0.155 0.087

N/A (no cases) 1.01

P value

Odds ratios (ORs) refer to retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO) (reference: no retinal vein occlusion). CI, confidence interval. Results with P < 0.05 in bold letters.

vs. 18 (38.3%) participants with CRVO vs. BRVO were unaware of their hypertension, had uncontrolled/insufficiently treated hypertension, and had well-controlled © 2015 International Society on Thrombosis and Haemostasis

arterial hypertension, respectively. Of all participants included into analyses, 3.1% (407 of 12 954) had atrial fibrillation. Of these, nine (2.2%) had a RVO (two

1258 K. A. Ponto et al Table 4 Visual acuity in eyes affected by central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO) vs. in the contralateral eyes Visual acuity (logMAR) Proportion (%) Participants with central retinal vein occlusion (n = 12) Participants with branch retinal vein occlusion (n = 47)

≥ 1.0

0.5– 0.9

0.3– 0.48

0.18– 0.2

≤ 0.1

Affected eyes Contraleteral eyes

33.3 0

8.3 0

16.7 8.3

16.7 16.7

25.0 75.0

Affected eyes Contraleteral eyes

6.4 2.1

14.9 2.1

12.8 10.6

21.3 27.7

44.7 57.4

[22.2%] with CRVO and seven [77.8%] with BRVO). Overall, eight (88.9%) of nine persons with RVO and atrial fibrillation had anticoagulation therapy (P = .114). One (50%) of two persons with atrial fibrillation and CRVO (P = .679) and all persons with BRVO and atrial fibrillation (seven of seven; P = 0.045) had anticoagulation therapy. Participants with RVO had higher mean systolic and diastolic blood pressures than did those without: 143.2
22.2 mm Hg vs. 131.6
17.4 mm Hg (P < 0.001) and 86.6
14.7 mm Hg vs. 82.5
9.6 mm Hg (P = .038), respectively. BMI and waist-to-hip ratio were higher in persons with RVO vs. in those without: 28.7
4.6 kg/cm2 vs. 27.3
5.0 kg/cm2 (P = 0.04) and 0.97
0.09 vs. 0.92
0.09 (P < 0.001), respectively. Table 3 summarizes the univariable associations of RVO, CRVO, and BRVO with risk factors and confounding variables (crude odds ratios). The results of the multivariable analysis (confounder-adjusted odds ratios) are summarized in Table 6.

The analysis of the association between RVO and intake of statins and/or anticoagulant/antiplatelet medication revealed that statins were taken by 13 (22%) of 59 persons with RVO and by only 1580 (12.3%) of persons without RVO (P = .025). Antiplatelet/anticoagulant drugs were taken by 19 (32.2%) of participants with RVO and by 1488 (11.5%) participants without RVO (P < .001). Discussion The GHS provides detailed data on prevalence and determinants of RVO in a large cohort and assesses the youngest and largest cohort worldwide on this topic. To the best of our knowledge, the GHS is the first populationbased study to report on the prevalence of RVO in Germany and the only study that included persons aged younger than 40 years. Thus, the GHS provides data on the prevalence and associations of RVO particularly in these age groups. Prevalence of BRVO and CRVO

The prevalence of RVO, CRVO, BRVO, and HRVO in the population was 0.40%, 0.8%, 0.32%, and 0.1%, respectively. Men tended to be more frequently affected than women. In the GHS, we found a higher prevalence of BRVO with increasing age, and CRVO was foremost detected in older age decades. There is broad consensus that the prevalence of RVO is strongly associated with increasing age [23–28]. This has to be kept in mind when comparing the results of the present younger cohort with those from other population-based studies looking at populations older than 40 years. In a pooled analysis including data from 68 751 participants from 15 epidemiological studies from the United States, Europe, Asia, and Australia, the age- and sex-standardized prevalence (per 10 000 persons) was 37.7 for BRVO and 6.5 for

Table 5 Spherical equivalent, intraocular pressure, and central corneal thickness in participants with and without retinal vein occlusion

n Spherical equivalent Median (range)* (in diopters) P value (Mann– Whitney U test) Intraocular pressure mean
SD (in mm Hg) P value (t-test) Central corneal thickness mean
SD (in lm) P value (t-test)

No retinal vein occlusion 12 895 0.6 (21.5–12)

Retinal vein occlusion 59

0.3 (6.8–5.1)

0.101

14.21
2.79

0.2 (6.8–1.1)

Branch retinal vein occlusion 47

0.7 (3.8–5.1)

0.208

14.50
3.05

0.477

553.7
35.3 0.492

Central retinal vein occlusion 12

14.48
4.20

14.51
2.73

0.974

556.3
28.7

554.9
16.4 0.855

556.6
31.2

*In cases with RVO, the spherical equivalent (SE) of the affected eye was used for the analyses. In the other cases, the mean SE of both eyes was used. © 2015 International Society on Thrombosis and Haemostasis

Prevalence and risk factors of RVO 1259

90 80

CRVO BRVO

Relative frequency [%]

70 60 50 40 30 20 10

Pe

rip

he

ra

la

rte

Ar

te

ria

lh A yp ria rter ert e C l oc ial f ns or c i i on lu bril on Fa m M ary sive lati ily o ed ic hea dis n hi at ea st r ed t d s or y he ise e fo ar as rm tf e ai Fa yo lu m car re ily d S hi ial trok st in e o f D ry arc ia fo tio ba r s n te tro s k D me e ys ll i l i p tu id s em O ia be Sm sit y ok in g

0

Fig. 1. Frequency of cardiovascular diseases and risk factors between persons with central retinal vein occlusion (CRVO; n = 12) and branch retinal vein occlusion (BRVO; n = 47). The relative frequency of arterial hypertension was 75% and 78.7%, of atrial fibrillation 16.7% and 14.9%, of peripheral arterial occlusive disease 8.3% and 8.5%, of coronary heart disease 8.3% and 10.6%, of (medicated) heart failure 8.3% and 0%, of stroke 0% and 4.3%, of a family history for myocardial infarction 16.7% and 23.4%, of a family history for stroke 25% and 23.4%, of diabetes mellitus 8.3% and 10.6%, of dyslipidemia in 33.3% and 38.3%, of obesity 25% and 36.2%, and of smoking 16.7% and 10.6% in CRVO and BRVO respectively.

CRVO [29]. Laouri et al. [7]compared the data of one pooled analysis and seven population-based studies to assess the prevalence of RVO. According to this systematic review, the prevalence of RVO is relatively constant across all countries: in populations older than 40 years, it ranges from 0.3% to 2.1%, with highest values in Japan and Australia and lowest values in the United States, Europe, and Singapore. In all studies, the prevalence of BRVO was higher than that of CRVO, ranging from three (Singapore [26]) to 10 (China [24]) times higher. Data from EUREYE and Rotterdam Eye Study were included in the pooled analysis [29]. In this pooled analysis, the prevalence of any RVO was 0.8% in EUREYE and 0.6% in the Rotterdam Eye Study. The prevalence for BRVO and CRVO in these two studies was 0.6% vs. 0.5% and 0.2% vs. 0.1%, respectively. In the Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health studies, the prevalence of RVO was 0.30% [18]. All other population-based studies found higher prevalences of RVO than the GHS [5]. The prevalence of © 2015 International Society on Thrombosis and Haemostasis

RVO in the GHS was 0.40% and thus 1.5–2 times lower than in those other European studies. This was most probably due to the fact that these studies were focused on diseases of the aging European populations and therefore included older participants (Rotterdam Eye Study ≥ 55 years and EUREYE ≥ 65 years), only. In contrast, participants aged 35–74 years at inclusion were investigated in the GHS. There are three limitations that might have led to an underestimation of the prevalence of RVO. First, cases of RVO could have been missed on fundus photographs, especially in cases of a reperfusion in non-ischemic RVO. Second, in the present study, the prevalence of RVO based on the grading of the non-mydriatic fundus photographs only. Unfortunately, the symptoms of the participants were not documented. Therefore, it is unclear how many had a previous diagnosis of RVO and how many were additionally diagnosed. As persons with CRVO (and HRVO or larger BRVO) experience a severe deterioration of visual acuity, it can be assumed that most of these persons had a previous diagnosis of RVO. Nevertheless, it might be that some BRVOs in peripheral branches of the retinal veins were not detected with the non-mydriatic fundus camera and therefore were overlooked in the present study. Third, a selection bias might have been present, as persons with severe RVO might not be willing to participate in the study since they are severely hampered by deteriorated visual acuity/blindness and/or neovascularization glaucoma. Cardiovascular risk factors and diseases in RVO

More than 90% of GHS participants with RVO had one or more known cardiovascular risk factor or disease. In the univariable analyses, mean systolic and diastolic blood pressures, as well as BMI and waist-to-hip ratio, were higher in persons with RVO vs. in those without. In BRVO, a high proportion of participants were unaware of their arterial hypertension or were without (sufficient) antihypertensive therapy. The multivariable analysis revealed a positive association of CRVO with age and a positive family history for stroke. BRVO was highly associated with arterial hypertension and atrial fibrillation. The associations of BRVO with arterial hypertension were in line with those found in other studies [14, 30–35]. The role of diabetes mellitus remains controversial in the literature [35–37]. For example in the Beaver Dam Eye Study, BRVO was associated with diabetes mellitus (odds ratio 2.43) [27]. In contrast, the population-based Central India Eye and Medical Study did not find any associations of RVO with diabetes or blood glucose levels [38]. As this study we did not detect an association with diabetes mellitus in the GHS. The association of RVO with atrial fibrillation is clinically relevant as the pathophysiological background might be atherosclerosis, a thrombotic event, or a

1260 K. A. Ponto et al Table 6 Multivariable analysis: Logistic regression model RVO

Age (Ref: ≥ 65 yrs) Sex (Ref: male) Smoking Glaucoma Coronary heart disease Arterial hypertension Atrial fibrillation Peripheral arterial occlusive disease Medicated heart failure Stroke Family history for myocardial infarction Family history for stroke Diabetes mellitus Dyslipidemia Obesity

CRVO

BRVO

OR

95% CI

P value

OR

95% CI

P value

OR

95% CI

P value

1.91 1.50 0.82 1.82 0.79

1.06–3.44 0.85–2.65 0.36–1.84 0.56–5.98 0.27–2.34

0.031 0.159 0.627 0.322 0.667

7.02 2.40 1.76 1.98 0.64

1.63–30.19 0.61–9.40 0.35–8.79 0.22–17.69 0.07–5.83

0.009 0.210 0.491 0.542 0.693

1.37 1.34 0.68 1.62 0.79

0.70–2.69 0.72–2.51 0.26–1.75 0.38–6.86 0.23–2.76

0.358 0.359 0.420 0.511 0.714

2.73 3.72 1.81

1.39–5.39 1.57–8.84 0.63–5.18

0.004 0.003 0.269

2.66 2.78 1.97

0.53–13.39 0.47–16.30 0.24–16.30

0.237 0.258 0.531

2.69 3.37 1.70

1.27–5.70 1.24–9.12 0.51–5.71

0.010 0.017 0.393

0.56

0.07–4.35

0.577

2.95

0.28–31.56

0.370

N/A (no cases)

1.08 1.12

0.25–4.66 0.56–2.26

0.913 0.752

N/A (no cases) 0.44

1.57 0.05–3.55

0.36–6.81 0.438

0.550 1.31

0.62–2.78

0.470

1.05

0.41–2.68

0.918

4.64

1.18–18.25

0.028

0.48

0.12–2.01

0.315

0.72 1.10 1.14

0.28–1.89 0.62–1.93 0.63–2.06

0.510 0.749 0.658

0.61 1.04 0.51

0.07–5.14 0.29–3.67 0.11–2.47

0.653 0.953 0.406

0.76 1.11 1.35

0.26–2.22 0.59–2.10 0.71–2.58

0.612 0.748 0.361

Odds ratios (ORs) refer to retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO) (reference: no retinal vein occlusion). CI, confidence interval. Results with P < 0.05 in bold letters.

combination of both. It has been shown that patients with RVO have an almost twofold higher risk for cerebrovascular events than controls without RVO [39]. Only sparse data are available regarding the association between RVO and atrial fibrillation [40–42]. It has been shown that in patients with atrial fibrillation, a history of RVO is associated with an increased risk of stroke [40]. This is in line with the conclusion of studies that have focused on the link between venous thromboembolism and atherosclerosis: the separate nature of arterial and venous disorders has been challenged, and future studies are needed to clarify the background of this association, to assess its extent, and to evaluate its implications for clinical practice [43]. One limitation that has to be addressed is the fact that coagulation parameters (including genetic analyses) were not available for the whole cohort. To further investigate this topic, we are now recruiting a ‘disease cohort’ of consecutive patients with acute RVO in the GHS. In these patients, further risk factors will be assessed in detail. Associations with medical therapy

We observed a high proportion of persons with RVO taking statins and/or antiplatelet/anticoagulant drugs in our study. It might be assumed that these medications were given because of cardiovascular risk profile of these individuals or following the diagnosis of RVO [44,45]. Unfortunately, we were not able to answer this question. Statins are known to improve the ultrastructure and

function of the retinal pigment epithelium, Bruch0 s membrane, and photoreceptors and thus may be a promising pharmacologic tool for the treatment of ischemic retinal diseases [46–50]. HRVOs in the GHS

In the GHS, only one case of HRVO was detected. It has been shown that the site of the HRVO is located in a branch retinal vein in 90% of the eyes―as it was the case in the GHS―and in 10%, it is located in one of the dual intraneural trunks of the central retinal vein [51]. Other population-based studies found a low prevalence of HRVO; for example, in the Blue Mountains Eye Study, three cases (5.1%) were documented [23]. Due to the low frequency, no association analyses were performed in the GHS. Previous studies could not find differences of risk factors between HRVO and CRVO [52,53]. Association of RVO with ophthalmic parameters

As RVO is a sight-threatening disease, visual acuity was better in participants without RVO than in those with RVO. One-third of eyes with CRVO had a visual acuity of logMAR 1.0 or worse. In CRVO and BRVO, visual acuity was 0.1 or better in almost one-fourth and one-half of the participants, respectively. This is in line with the results from other studies [7,38]. In the present cohort, only two persons with BRVO and one with CRVO had a history of glaucoma. This appears to be in contrast with © 2015 International Society on Thrombosis and Haemostasis

Prevalence and risk factors of RVO 1261

previous findings which suggest that persons with increased intraocular pressure and/or glaucoma were found to have a higher prevalence of RVO than persons with no history of elevated intraocular pressure [54–59]. The Beaver Dam Eye Study investigated in detail the association between glaucoma parameters and RVO [27,60,61]: in this study, incident CRVO was associated with glaucoma. On the other hand, BRVO was positively associated with ocular perfusion pressure but not with glaucoma, intraocular pressure, or ocular hypertension. In the GHS, individuals with RVO had a higher spherical equivalent than those without RVO, although this difference was not statistically significant. An association between hyperopia and RVO has been shown previously [62–64], but the relationship remains controversial [65]. In the present study, no differences in intraocular pressure or central corneal thickness between persons with and without RVO were noted. The same was found by Azar et al. [54]. In summary, the present study emphasizes RVO as an important cause of (mostly unilateral) visual loss. Being associated with cardiovascular risk factors, RVO prevalence increased with older age in the GHS cohort. CRVO are associated with higher age and a family history of stroke, whereas BRVO is linked to arterial hypertension and atrial fibrillation. Future efforts will address the assessment of ophthalmic parameters and of cardiovascular risk factors and events after a 5-year follow-up period. Addendum K. A. Ponto, P. S. Wild, N. Pfeiffer, A. Mirshahi, and T. Peto were responsible for concept and design. H. Elbaz and T. Peto were responsible for data collection and analysis. K. A. Ponto, D. Laubert-Reh, H. Binder, and T. Peto were responsible for analysis and/or interpretation of data. K. A. Ponto and A. Mirshahi wrote the manuscript. K. A. Ponto, H. Elbaz, T. Peto, D. LaubertReh, H. Binder, P. S. Wild, K. Lackner, N. Pfeiffer, and A. Mirshahi critically revised the intellectual content and K. A. Ponto, H. Elbaz, T. Peto, D. Laubert-Reh, H. Binder, P. S. Wild, K. Lackner, N. Pfeiffer, and A. Mirshahi gave final approval of the version to be published. Acknowledgements We are indebted to all study participants and all members of the Gutenberg Health Study, who are involved in the planning and conduct of this study. The Gutenberg Health Study is funded through the Government of Rhineland-Palatinate (‘Stiftung Rheinland-Pfalz f€ ur Innovation’, contract AZ 961-386261/733), the research programs ‘Wissen schafft Zukunft’ and ‘Center for Translational Vascular Biology (CTVB)’ as well as the Center for Thrombosis and Hemostasis (CTH) of the Johannes Gutenberg-University of Mainz, and its contract with © 2015 International Society on Thrombosis and Haemostasis

Boehringer Ingelheim, PHILIPS Medical Systems, Bayer Health Care, including an unrestricted grant for the Gutenberg Health Study. P. S. Wild and K. A. Ponto are funded by the Federal Ministry of Education and Research (BMBF 01EO1003). P. S. Wild is principal investigator of the German Center for Cardiovascular Research (DZHK).T. Peta was funded by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript.

Disclosure of Conflict of Interests N. Pfeiffer reports that his institution received funds from Bayer HealthCare, Novartis, Alcon, MSD, Ivantis, Santen and Pfizer. Consultancy fees/payment for lectures including service on speakers bureaus were received from MSD, Alcon, Ivantis, Allergan, Santen and Novartis. K. A. Ponto reports grants from Bayer HealthCare during the conduct of the study. A. Mirshahi reports grants from Bayer HealthCare and Novartis, during the conduct of the study. P. S. Wild reports grants from Boehringer Ingelheim and PHILIPS Medical Systems, outside the submitted work. References 1 Ehlers JP, Fekrat S. Retinal vein occlusion: beyond the acute event. Surv Ophthalmol 2011; 56: 281–99. 2 Suner IJ, Margolis J, Ruiz K, Tran I, Lee P. Direct medical costs and resource use for treating central and branch retinal vein occlusion in commercially insured working-age and medicare populations. Retina 2014; 34: 2250–8. 3 Rehak M, Wiedemann P. Retinal vein thrombosis: pathogenesis and management. J Thromb Haemost 2010; 8: 1886–94. 4 Christoffersen NL, Larsen M. Pathophysiology and hemodynamics of branch retinal vein occlusion. Ophthalmology 1999; 106: 2054–62. 5 McIntosh RL, Rogers SL, Lim L, Cheung N, Wang JJ, Mitchell P, Kowalski JW, Nguyen HP, Wong TY. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010; 117: e15. 6 Rogers SL, McIntosh RL, Lim L, Mitchell P, Cheung N, Kowalski JW, Nguyen HP, Wang JJ, Wong TY. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010; 117: e5. 7 Laouri M, Chen E, Looman M, Gallagher M. The burden of disease of retinal vein occlusion: review of the literature.Eye (Lond) 2011; 25: 981–8. 8 Bertelsen M, Linneberg A, Christoffersen N, Vorum H, Gade E, Larsen M. Mortality in patients with central retinal vein occlusion. Ophthalmology 2014; 121: 637–42. 9 Kuhli C, Hattenbach LO, Scharrer I, Koch F, Ohrloff C. High prevalence of resistance to APC in young patients with retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2002; 240: 163–8. 10 Kuhli C, Jochmans K, Scharrer I, Luchtenberg M, Hattenbach LO. Retinal vein occlusion associated with antithrombin deficiency secondary to a novel G9840C missense mutation. Arch Ophthalmol 2006; 124: 1165–9.

1262 K. A. Ponto et al 11 Kuhli C, Scharrer I, Koch F, Ohrloff C, Hattenbach LO. Factor XII deficiency: a thrombophilic risk factor for retinal vein occlusion. Am J Ophthalmol 2004; 137: 459–64. 12 Kuhli-Hattenbach C, Scharrer I, Luchtenberg M, Hattenbach LO. Coagulation disorders and the risk of retinal vein occlusion. Thromb Haemost 2010; 103: 299–305. 13 Lip PL, Blann AD, Jones AF, Lip GY. Abnormalities in haemorheological factors and lipoprotein (a) in retinal vascular occlusion: implications for increased vascular risk. Eye (Lond) 1998; 12: 245–51. 14 Kolar P. Risk factors for central and branch retinal vein occlusion: a meta-analysis of published clinical data. J Ophthalmol 2014; 2014: 724780. 15 Risk factors for branch retinal vein occlusion. The eye disease case-control study group. Am J Ophthalmol 1993; 116: 286–96. 16 Risk factors for central retinal vein occlusion. The eye disease case-control study group. Arch Ophthalmol 1996; 114: 545–54. 17 Mirshahi A, Ponto KA, Hohn R, Wild PS, Pfeiffer N. Ophthalmological aspects of the Gutenberg Health Study (GHS): an interdisciplinary prospective population-based cohort study. Ophthalmologe 2013; 110: 210–7. 18 Wild PS, Zeller T, Beutel M, Blettner M, Dugi KA, Lackner KJ, Pfeiffer N, Munzel T, Blankenberg S. The gutenberg health study. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012; 55: 824–9. 19 Hoffmann EM, Lamparter J, Mirshahi A, Elflein H, Hoehn R, Wolfram C, Lorenz K, Adler M, Wild PS, Schulz A, Mathes B, Blettner M, Pfeiffer N. Distribution of central corneal thickness and its association with ocular parameters in a large central European cohort: the Gutenberg health study. PLoS One 2013; 8: e66158. 20 Korb CA, Kottler UB, Wolfram C, Hoehn R, Schulz A, Zwiener I, Wild PS, Pfeiffer N, Mirshahi A. Prevalence of age-related macular degeneration in a large European cohort: results from the population-based Gutenberg Health Study. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1403–11. 21 Lamparter J, Raum P, Pfeiffer N, Peto T, Hohn R, Elflein H, Wild P, Schulz A, Schneider A, Mirshahi A. Prevalence and associations of diabetic retinopathy in a large cohort of prediabetic subjects: the Gutenberg Health Study. J Diabetes Complications 2014; 28: 482–7. 22 Mirshahi A, Ponto KA, Hoehn R, Zwiener I, Zeller T, Lackner K, Beutel ME, Pfeiffer N. Myopia and level of education: results from the gutenberg health study. Ophthalmology 2014; 121: 2047–52. 23 Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch Ophthalmol 1996; 114: 1243–7. 24 Liu W, Xu L, Jonas JB. Vein occlusion in Chinese subjects. Ophthalmology 2007; 114: 1795–6. 25 Yasuda M, Kiyohara Y, Arakawa S, Hata Y. Yonemoto K, Doi Y, Iida M, Ishibashi T. Prevalence and systemic risk factors for retinal vein occlusion in a general Japanese population: the Hisayama study. Invest Ophthalmol Vis Sci 2010; 51: 3205–9. 26 Lim LL, Cheung N, Wang JJ, Islam FM, Mitchell P, Saw SM, Aung T, Wong TY. Prevalence and risk factors of retinal vein occlusion in an Asian population. Br J Ophthalmol 2008; 92: 1316–9. 27 Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc 2000; 98: 133–41. 28 Cheung N, Klein R, Wang JJ, Cotch MF, Islam AF, Klein BE, Cushman M, Wong TY. Traditional and novel cardiovascular risk factors for retinal vein occlusion: the multiethnic study of atherosclerosis. Invest Ophthalmol Vis Sci 2008; 49: 4297–302. 29 Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY. The prevalence of

30

31

32

33

34

35

36

37

38

39

40

41

42

43 44

45

46

47

48

retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117: 313–9. e1. Bertelsen M, Linneberg A, Rosenberg T, Christoffersen N, Vorum H, Gade E, Larsen M. Comorbidity in patients with branch retinal vein occlusion: case-control study. BMJ 2012; 345: e7885. Christoffersen N, Gade E, Knudsen L, Juel K, Larsen M. Mortality in patients with branch retinal vein occlusion. Ophthalmology 2007; 114: 1186–9. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001; 131: 61–77. Lee JY, Yoon YH, Kim HK, Yoon HS, Kang SW, Kim JG, Park KH, Jo YJ. Baseline characteristics and risk factors of retinal vein occlusion: a study by the Korean RVO Study Group. J Korean Med Sci 2013; 28: 136–44. Martin SC, Butcher A, Martin N, Farmer J, Dobson PM, Bartlett WA, Jones AF. Cardiovascular risk assessment in patients with retinal vein occlusion. Br J Ophthalmol 2002; 86: 774–6. Newman-Casey PA, Stem M, Talwar N, Musch DC, Besirli CG, Stein JD. Risk factors associated with developing branch retinal vein occlusion among enrollees in a United States managed care plan. Ophthalmology 2014; 121: 1939–48. Johnston RL, Brucker AJ, Steinmann W, Hoffman ME, Holmes JH. Risk factors of branch retinal vein occlusion. Arch Ophthalmol 1985; 103: 1831–2. O’Mahoney PR, Wong DT, Ray JG. Retinal vein occlusion and traditional risk factors for atherosclerosis. Arch Ophthalmol 2008; 126: 692–9. Jonas JB, Nangia V, Khare A, Sinha A, Lambat S. Prevalence and associations of retinal vein occlusions: the Central India Eye and Medical Study. Retina 2013; 33: 152–9. Werther W, Chu L, Holekamp N, Do DV, Rubio RG. Myocardial infarction and cerebrovascular accident in patients with retinal vein occlusion. Arch Ophthalmol 2011; 129: 326–31. Christiansen CB, Lip GY, Lamberts M, Gislason G, Torp-Pedersen C, Olesen JB. Retinal vein and artery occlusions: a risk factor for stroke in atrial fibrillation. J Thromb Haemost 2013; 11: 1485–92. Kittisupamongkol W. Atrial fibrillation in patients diagnosed with retinal vein occlusion. Am J Ophthalmol 2009; 147: 1104; author reply - 5. Plunkett O, Lip PL, Lip GY. Atrial fibrillation and retinal vein or artery occlusion: looking beyond the eye. Br J Ophthalmol 2014; 98: 1141–3. Prandoni P. Venous thromboembolism and atherosclerosis: is there a link? J Thromb Haemost 2007; 5 (Suppl. 1): 270–5. Hayreh SS, Podhajsky PA, Zimmerman MB. Central and hemicentral retinal vein occlusion: role of anti-platelet aggregation agents and anticoagulants. Ophthalmology 2011; 118: 1603–11. Sartori MT, Barbar S, Dona A, Piermarocchi S, Pilotto E, Saggiorato G, Prandoni P. Risk factors, antithrombotic treatment and outcome in retinal vein occlusion: an age-related prospective cohort study. Eur J Haematol 2013; 90: 426–33. Barathi VA, Yeo SW, Guymer RH, Wong TY, Luu CD. Effects of simvastatin on retinal structure and function of a high-fat atherogenic mouse model of thickened Bruch’s membrane. Invest Ophthalmol Vis Sci 2014; 55: 460–8. Ko ML, Chen CF, Peng PH, Peng YH. Simvastatin upregulates Bcl-2 expression and protects retinal neurons from early ischemia/reperfusion injury in the rat retina. Exp Eye Res 2011; 93: 580–5. Krempler K, Schmeer CW, Isenmann S, Witte OW, Lowel S. Simvastatin improves retinal ganglion cell survival and spatial vision after acute retinal ischemia/reperfusion in mice. Invest Ophthalmol Vis Sci 2011; 52: 2606–18. © 2015 International Society on Thrombosis and Haemostasis

Prevalence and risk factors of RVO 1263 49 Medina RJ, O’Neill CL, Devine AB, Gardiner TA, Stitt AW. The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies. PLoS One 2008; 3: e2584. 50 Terai N, Spoerl E, Fischer S, Hornykewycz K, Haustein M, Haentzschel J, Pillunat LE. Statins affect ocular microcirculation in patients with hypercholesterolaemia. Acta Ophthalmol 2011; 89: e500–4. 51 Sanborn GE, Magargal LE. Characteristics of the hemispheric retinal vein occlusion. Ophthalmology 1984; 91: 1616–26. 52 Sperduto RD, Hiller R, Chew E, Seigel D, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J, Seddon JM, Yannuzzi LA. Risk factors for hemiretinal vein occlusion: comparison with risk factors for central and branch retinal vein occlusion: the eye disease case-control study. Ophthalmology 1998; 105: 765–71. 53 Appiah AP, Trempe CL. Differences in contributory factors among hemicentral, central, and branch retinal vein occlusions. Ophthalmology 1989; 96: 364–6. 54 Azar G, Voigt M, Al-Arabi Z, Lachkar Y. Primary open-angle glaucoma (POAG), retinal vein occlusions (RVO) and central corneal thickness (CCT): what is the relationship? J Fr Ophtalmol 2013; 36: 449–54. 55 Barnett EM, Fantin A, Wilson BS, Kass MA, Gordon MO. The incidence of retinal vein occlusion in the ocular hypertension treatment study. Ophthalmology 2010; 117: 484–8. 56 Beaumont PE, Kang HK. Cup-to-disc ratio, intraocular pressure, and primary open-angle glaucoma in retinal venous occlusion. Ophthalmology 2002; 109: 282–6.

© 2015 International Society on Thrombosis and Haemostasis

57 David R, Zangwill L, Badarna M, Yassur Y. Epidemiology of retinal vein occlusion and its association with glaucoma and increased intraocular pressure. Ophthalmologica 1988; 197: 69–74. 58 Hirota A, Mishima HK, Kiuchi Y. Incidence of retinal vein occlusion at the Glaucoma Clinic of Hiroshima University. Ophthalmologica 1997; 211: 288–91. 59 Prata TS, Rozenbaum I, de Moraes CG, Lima VC, Liebmann J, Ritch R. Retinal vascular occlusions occur more frequently in the more affected eye in exfoliation syndrome. Eye (Lond) 2010; 24: 658–62. 60 Klein BE, Meuer SM, Knudtson MD, Klein R. The relationship of optic disk cupping to retinal vein occlusion: the Beaver Dam Eye Study. Am J Ophthalmol 2006; 141: 859–62. 61 Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008; 126: 513–8. 62 Bandello F, Tavola A, Pierro L, Modorati G, Azzolini C, Brancato R. Axial length and refraction in retinal vein occlusions. Ophthalmologica 1998; 212: 133–5. 63 Simons BD, Brucker AJ. Branch retinal vein occlusion. Axial length and other risk factors. Retina 1997; 17: 191–5. 64 Timmerman EA, de Lavalette VW, van den Brom HJ. Axial length as a risk factor to branch retinal vein occlusion. Retina 1997; 17: 196–9. 65 Kir E, Tulin Berk A, Osman Saatci A, Kaynak S, Ergin MHAxial length and hyperopia in eyes with retinal vein occlusions. Int Ophthalmol 1997; 21: 209–11.