Journal Search Engine
Search Advanced Search Adode Reader(link)
Download PDF Export Citaion korean bibliography PMC previewer
ISSN : 1229-6457(Print)
ISSN : 2466-040X(Online)
The Korean Journal of Vision Science Vol.21 No.4 pp.489-496

Analysis of Duration of Aspirin Administration and Incidence of Subconjunctival Hemorrhage in Patients with Atrial Fibrillation

Yoon-Jung Choy1)*, Yoon-Soo Choy2)
1)Dept. of Optometry, Eulji University College of Health Sciences, Professor, Seongnam
2)Eulji Foundation External Cooperation Task Force Team, Eulji University, Lecturer, Seongnam
Address reprint requests to Yoon-Jung Choy Dept. of Optometry, Eulji University, Seongnam TEL: +82-31-740-7242, E-mail:
September 20, 2019 December 14, 2019 December 26, 2019


Purpose :

The purpose of this study was to investigate the incidence and risk factors of subconjunctival hemorrhage (SCH) in long-term follow-up of patients with atrial fibrillation (AF) using thrombolytic agents.

Methods :

Patients with AF in the National Health Insurance Corporation database from 2002 to 2006 were followed up from 2007 to 2013. To evaluate the relationship between aspirin use and SCH, we analyzed the duration of aspirin and the incidence of SCH in patients with AF.

Results :

A total of 7,471 AF patients were selected, 893 of whom were SCH. In 289 patients with SCH, 90(31.1%) patients had taken aspirin for <1 year: 97(33.6%) for 1~4 years: 102(35.3%) for >4 years. Hazards ratio of developing SCH after taking aspirin for 1~4 and >4 years was 0.856(95% confidence interval (CI), .642-1.14, p=.287), and 0.699(95% CI, .526-.929, p=.014), respectively. When taking aspirin for more than 4 years, the risk was significantly lower than when taking less than 1 year(p =.014). The cumulative incidence rate of SCH was 45%, 37% and 35% for aspirin users of <1 year, 1~4 years, and >4 years, respectively, in the 11th year of taking aspirin.

Conclusion :

The incidence of SCH was higher in older AF patients, but the occurrence risk of SCH and cumulative incidence rate due to prolonged usage of aspirin were not high. However, when there is recurrent and persistent SCH, further evaluation of the patient’s systemic disorder and side effects of prescription drugs is needed.

심박세동 환자에서 아스피린 투여기간과 결막하출혈 발생률의 분석

최 윤정1)*, 최 윤수2)
1)을지대학교 보건과학부 안경광학과, 교수, 성남
2)을지대학교 대외협력팀, 강사, 성남

    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, hypertension11-14) 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 studies11-14) 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.


    Y-JC designed the study; Y-JC and YSC conducted the study; Y-JC and YSC were involved in data collection and management, analysis and interpretation of data; Y-JC and YSC prepared, reviewed, and approved the manuscript.



    Kaplan-Meier survival plots of probabilities of subconjunctival hemorrhage incidence.


    Weighted prevalences and frequencies of atrial fibrillation patients with subconjunctival hemorrhage and without subconjunctival hemorrhage in the Korean population during 7-year study period(2007~2013)

    Age distribution of patients with and without subconjunctival hemorrhage in atrial fibrillation

    Oral antiplatelet drug treatment in atrial fibrillation patients and multivariate relative risk of occurrence of subconjunctival hemorrhage


    1. Fuster V, Ryden LE et al.: 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 57(11), e101-198, 2011.
    2. Gomez-Outes A, Lagunar-Ruiz J et al.: Causes of Death in Anticoagulated Patients With Atrial Fibrillation. J Am Coll Cardiol. 68(23), 2508-2521, 2016.
    3. El-Sanhouri AA, Foster RE et al.: Retinal tears after posterior vitreous detachment and vitreous hemorrhage in patients on systemic anticoagulants. Eye 25(8), 1016-1019, 2011.
    4. Levine MN, Raskob G et al.: Hemorrhagic complications of anticoagulant treatment. Chest 108(Suppl 4), S276-S290, 1995.
    5. Fang MC, Chang Y et al.: Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 141(10), 745-752, 2004.
    6. Palareti G, Leali N et al.: Bleeding complications of oral anticoagulant treatment: an inceptioncohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 348(9025), 423-428, 1996.
    7. Biyik I, Mercan I et al.: Ocular bleeding related to warfarin anticoagulation in patients with mechanical heart valve and atrial fibrillation. J Int Med Res. 35(1), 143-149, 2007.
    8. Witmer MT, Cohen SM: Oral anticoagulation and the risk of vitreous hemorrhage and retinal tears in eyes with acute posterior vitreous detachment. Retina 33(3), 621-626, 2013.
    9. Jun JH, Hwang JC: Association of rivaroxaban anticoagulation and spontaneous vitreous hemorrhage. JAMA Ophthalmol. 133(10), 1184- 1186, 2015.
    10. Lindgren G, Lindblom B: Causes of vitreous hemorrhage. Curr Opin Ophthalmol. 7(3), 13-19, 1996.
    11. Mimura T, Usui T et al.: Recent causes of subconjunctival hemorrhage. Ophthalmologica 224(3), 133-137, 2010.
    12. Fukuyama J, Hayasaka S et al.: Causes of subconjunctival hemorrhage. Ophthalmologica 200(2), 63-67, 1990.
    13. Mimura T, Yamagami S et al.: Location and extent of subconjunctival hemorrhage. Ophthalmologica 224(2), 90-95, 2010.
    14. Hu DN, Mou CH et al.: Incidence of Non-Traumatic Subconjunctival Hemorrhage in a Nationwide Study in Taiwan from 2000 to 2011. PLoS One 10(7), e0132762, 2015.
    15. Tarlan B, Kiratli H: Subconjunctival hemorrhage: risk factors and potential indicators. Clin Ophthalmol. 7, 1163-1170, 2013.
    16. Kumar N, Jivan S et al.: Sub-Tenon's anesthesia with aspirin, warfarin, and clopidogrel. J Cataract Refract Surg. 32(6), 1022-1025, 2006.
    17. Leiker LL, Mehta BH et al.: Risk factors and complications of subconjunctival hemorrhages in patients taking warfarin. Optometry 80(5), 227-231, 2009.
    18. Bodack MI: A warfarin-induced subconjunctival hemorrhage. Optometry 78(3), 113-118, 2007.
    19. Kobayashi H: Evaluation of the need to discontinue antiplatelet and anticoagulant medications before cataract surgery. J Cataract Refract Surg. 36(7), 1115-1119, 2010.
    20. Stuart MJ, Gross SJ et al.: Effects of acetylsalicylicacid ingestion on maternal and neonatal hemostasis. N Engl J Med. 307(15), 909-912, 1982.