Ⅰ. Introduction

AF (atrial fibrillation) is the most common arrhythmia in developed countries, with a 5-fold increase in stroke and mortality rates.^1,2) Oral anticoagulants such as warfarin and clopidogrel are used to reduce stroke and mortality risk.²⁾ With the increasing recognition of the benefits of systemic anticoagulation in the treatment of cardiovascular and cerebrovascular diseases, the regular use of anticoagulants has increased over the past several decades.³⁾ In addition, bleeding risk complications associated with anticoagulants are increasing.

The most serious complication of warfarin is bleeding, which is reported to occur in 39% of patients treated with warfarin.^4-6) Hemorrhagic complications include gastrointestinal bleeding, intracranial hemorrhage, nasal and dental hemorrhage, skin bruising, and ocular hemorrhage.^5,6) Ocular hemorrhage refers to subconjunctival, intracameral, vitreous, and retinal hemorrhage, which can be a complication that threatens vision.⁷⁾ Several studies have reported that the use of anticoagulants, such as aspirin, clopidogrel bisulfate, and warfarin sodium, increases the frequency of vitreous hemorrhage.^8-10)

SCH (subconjunctival hemorrhage) is a common ocular disease caused by rupture of the conjunctival vessels, and blood is drained into subconjunctival tissues and subconjunctival episcleral space.^11-13) The causes of SCH are diverse, and one of the most common causes is local trauma.¹⁴⁾ Nontraumatic or spontaneous SCH occurs due to spontaneous conjunctival vessel rupture.^11-13)

Although non-traumatic SCH is relatively common, its prevalence and incidence in patients using domestic anticoagulants has not been studied yet. According to Hu et al.¹⁴⁾ a small proportion of non-traumatic SCH are associated with antiplatelet therapy; systemic vascular disease such as arterial hypertension or diabetes mellitus of oter relevant disorders. They reported that among various medications, non-traumatic SCH was significantly associated with the use of aspirin, with an adjusted OR (odds ratio) at 1.09 (95% CI 1.05-1.13). In addition, since the study of non-traumatic SCH has not been conducted in Korea, the authors performed this study.

The purpose of this study was to analyse the incidence and risk factors of SCH in patients with AF receiving anticoagulation therapy by analysing the sample cohort of National Health Insurance Corporation.

Ⅱ. Subjects and Methods

The present study was approved by the Institutional Review Board (IRB number: EMCS 2017-02-006- 002) of Nowon Eulji Medical Center, Eulji University, Seoul, Korea.

A total of 819,948 patients aged >15 years were included in the cohort of the National Health Insurance Corporation. Research patients who billed for ICD-10 code from 2002 to 2006 at least once during admission and at least twice during outpatient diagnosis were selected as AF(code I48) patients.

The censoring condition was defined as the occurrence of SCH(code H113) among patients with AF(code I48) from January 2007 to December 2013 without any outpatient visit or hospitalization. Patients with AF without SCH were selected as the control group when SCH occurred only once without any outpatient visit or hospitalization, and statistical analysis was performed.

Patients’ age, sex, and duration of SCH after AF diagnosis were reviewed. We investigated the relationship between AF and other systemic diseases. ICD-10 codes of hypertension were I10, I109, I11, I110, I119, I12, I120, I129, I13, I130, I131, I132. I139, I15, I150, I151, I152, I158, and I159, and those of diabetes mellitus were E10, E100~E109, E11, and E110~E149. To investigate the relationship between anticoagulant use and SCH, the duration of aspirin (code1110xxAxx) use in the patients with AF was classified as ≤1 year, 1~4 years, and >4 years.

Statistical analysis was performed using SPSS (ver. 22, SPSS Inc., Chicago, IL) and a p-value <0.050 was considered statistically significant. Based on data from the National Health Insurance Corporation, we analysed the duration of anticoagulant therapy until SCH and compared these data between patients who had SCH and those who did not. To evaluate the relationship between anticoagulant use and SCH, we corrected the disturbance variable known by the existing papers. To investigate the relationship between anticoagulant and SCH, age,^13,14) which was known as a disturbance variable, was corrected by the existing papers. In addition, hypertension^11-14) and diabetes,^13,14) which are known as disturbance variable of SCH, were further corrected. We analysed the cumulative incidence rate of SCH in patients with aspirin-induced AF.

Patient's identification information, such as name, resident registration number, and record number were removed, and patients were assigned a study number.

Ⅲ. Result

A total of 7,471 patients(3,875 men and 3,596 women) diagnosed with AF from 2002 to 2006 were selected for this study. Of these, 6,578 patients did not develop SCH at the end of the follow-up period or died, whereas 893 patients developed SCH. Among the 893 patients with SCH, 508(13.1%) were men and 385(10.7%) were women. Among the 6,578 patients with AF without SCH, 3,367(86.9%) were men, and 3,211(89.3%) were women(p=.001). Among patients with SCH, 58 patients were aged <40 years and 835 patients were aged >40 years. The incidence of SCH was lower than the expected frequency in patients aged <40 years, whereas that in patients aged >40 years was higher than the expected frequency. In addition, the incidence of SCH was lower than the expected frequency in patients aged >70 years.

Among the patients with SCH, there were 574 patients with hypertension, which was statistically significantly higher than those without SCH, and there were 236 patients with diabetes mellitus, which did not show a statistically significant difference from that of patients without SCH(p=.778). The time taken until the occurrence of SCH was 3,665.906 ± 21.068 days(Table 1).

The age distribution of SCH was less frequent than expected frequency when the age was under 40. From age 40 and older, the incidence of SCH was higher than expected frequency. However, age over 70 had less frequent of SCH than expected frequency(Table 2).

The cumulative survival probability of unexplained total survival was 62.6%. In each year, SCH was found in approximately 2.2~5.7% of the patients at risk.

A total of 1,793 patients were taking aspirin. Among the patients with SCH, 289 patients had taken aspirin, with 90 patients(31.1%) having taken aspirin for <1 year, 97 patients(33.6%) for 1~4 years, and 102 patients(35.3%) for >4 years. The total number of patients who did not develop SCH after aspirin treatment was 1,504 patients, with 494 patients(32.8%) having taken aspirin for <1 year, 533 patients(35.4%) for 1~4 years, and 477 patients(31.7%) for >4 years.

There was no statistically significant difference between the number of aspirin users and nonaspirin users(p = .492).

The aspirin use duration of <1 year was defined as the reference category and analysed HR (hazards ratio). Results showed that the HR of occurrence of SCH after taking aspirin for 1~4 years was 0.856(95% confidence interval (CI), .642-1.14, p= .287). HR of taking aspirin for >4 years was 0.699 (95% CI, .526-.929; p=.014), which was significantly lower than 1 year(Table 3).

The cumulative incidence rate of subconjunctival hemorrhage was 45% for patients taking 1 year or less at the 11th year of taking the drug, and for 1 to 4 years was 37%, and 35% for more than 4 years(Fig. 1).

Ⅳ. Discussion

This study investigated the association of anticoagulant use(aspirin) with SCH in patients with AF. To the best of our knowledge, there have been no studies on the relationship between anticoagulants and SCH in Korea. Although there have been short-term studies^11-14) on the cause of SCH in other countries, there have been no longterm follow-up studies similar to the present investigation.

A large-scale population study reported that the average incidence of non-traumatic SCH was 65 per 10,000 persons per year. The number of individuals with non-traumatic SCH aged between 10 and 19 years was 25.5 per 10,000 persons, but it increased to 136.2 per 10,000 persons in those aged 60~69 years and decreased to 84 per 10,000 persons in those aged >80 years.¹⁴⁾ This study also showed that the incidence increased with age and decreased from 70 years of age.

Mimura et al.¹³⁾ and Tarlan et al.¹⁵⁾ also reported that the incidence of SCH increased with age. However, Fukuyama et al.¹²⁾ reported that age and SCH were not related. Hu et al.¹⁴⁾ reported that the incidence of non-traumatic SCH was significantly higher in women than in men. This was probably due to the large number of women with postpartum conditions and idiopathic thrombocytopenic purpura, but Fukuyama et al.¹²⁾ reported that sex was not a risk factor for SCH. In this study, SCH occurred more frequently in men than in women.

Hypertension has been reported to be common in patients with non-traumatic SCH.^12-15) It is thought that this is caused by blood vessel rupture due to the weakening of the conjunctival vessels in hypertensive patients, which led to the development of hemorrhage into subconjunctival space. Diabetes is also associated with non-traumatic SCH.^11-15) However, in this study, the distribution of diabetes mellitus in patients with AF was not significant. Moreover, diabetes was not found as a risk factor for SCH in the study of Hu et al.¹⁴⁾ After adjusting for age, sex, and use of medications, diabetic mellitus was no longer statistically significant with SCH.¹⁴⁾ When angiogenesis and vascular related complications occur in diabetic patients, it is thought to be significantly related to diabetes, and diabetes itself is not related with SCH.

The use of aspirin, clopidogrel, and warfarin in some papers has been described as a risk factor for the development of non-traumatic SCH.^11,14-20) However, these articles were either retrospective or case-based and were not long-term cohort studies, wherein the duration of aspirin administration was categorized and investigated in detail.

In this study, the relationship between aspirin use and SCH was investigated. The longer the aspirin treatment duration, the lower the risk of occurrence of SCH and the lower the cumulative incidence risk rate of SCH. Among various medications (clopidogrel and warfarin), non-traumatic SCH was significantly associated with the use of aspirin, with an adjusted OR at 1.09(95% CI 1.05-1.13).¹⁴⁾ This suggests that weak anticoagulants, such as aspirin, appear to cause ophthalmologic complications only shortly after taking the drug, and the patient's body also seems to have adapted to the drug over time.

This study has several limitations. First, there is no information about the degree of SCH. Thus, the incidence of aspirin-induced SCH may be underestimated and may influence the interpretation of the analysis. Second, we did not investigate ocular bleeding including vitreous, intracameral, and retinal hemorrhage; thus, further research is needed in this area. Third, patients with SCH analysed in this study were limited compared to those with AF. Although this study is meaningful, in that there has been study on SCH in our country until now, our patients are limited to represent the whole population. Thus, our study data may not be generalizable to the entire population, despite the fact that our study population was not small.

Ⅴ. Conclusion

In conclusion, the long-term follow-up of patients with AF revealed that the incidence of SCH was higher in older patients, and long-term aspirin use was associated with a lower occurrence risk of SCH and lower cumulative incidence rate. Our data suggest that the cause of results suggest that the cause of SCH is multifactorial. In patients with recurrent and persistent SCH, further evaluation of the systemic status or side effects of the prescription drugs may be needed.