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ISSN : 1229-6457(Print)
ISSN : 2466-040X(Online)
The Korean Journal of Vision Science Vol.24 No.1 pp.33-42
DOI : https://doi.org/10.17337/JMBI.2022.24.1.33

Effect of Antiplatelet Drugs on the Development of Vitreous Hemorrhage in Patients with Atrial Fibrillation

Yoon-Jung Choy
Dept. of Optometry, Eulji University College of Health Sciences, Professor, Seongnam
* Address reprint requests to Yoon-Jung Choy (https://orcid.org/0000-0003-3246-9762) Dept. of Optometry, Eulji University, Seongnam
Tel: +82-31-740-7242, E-mail: yjchoy7@eulji.ac.kr
January 15, 2022 March 15, 2022 March 15, 2022

Abstract


Purpose : This study aimed to investigate the incidence and risk factors of vitreous hemorrhage in patients with atrial fibrillation (AF) using thrombolytic agents with long-term follow-up.



Methods : Patients diagnosed with AF between 2002 and 2006 were selected from the National Health Insurance Corporation database and followed-up from 2007 to 2013. To investigate the relationship between the use of antiplatelets (aspirin and cilostazol) and vitreous hemorrhage, patients were divided based on length of antiplatelet use (<1 year, 1~4 years, and ≥4 years).



Results : A total of 7,471 patients were enrolled. Ninety-eight patients developed vitreous hemorrhage, of which 25 patients were taking aspirin (<1 year: 9[36%] patients, 1~4 years: 9[36%] patients, and ≥4 years: 7[28%] patients). The hazard ratio for developing vitreous hemorrhage after taking aspirin for 1~4 years was 0.799 and for ≥4 years was 0.489. In addition, 13 patients who developed vitreous hemorrhage were taking cilostazol (<1 year: 7[53.8%] patients, 1~4 years: 4[30.8%] patients, and ≥4 years: 2[15.4%] patients). The hazard ratios for developing vitreous hemorrhage after taking cilostazol for 1~4 years and for ≥4 years were 0.757 and 1.202, respectively. The cumulative incidence of vitreous hemorrhage at 12-years follow-up was 4.6%.



Conclusion : Long-term follow-up of patients with AF revealed that the use of aspirin and cilostazol may increase the risk of vitreous hemorrhage. However, vitreous hemorrhage was found to be multifactorial because the frequency of diabetic mellitus and hypertension was high in patients with vitreous hemorrhage.


Aspirin , Atrial fibrillation , Cilostazol , Vitreous hemorrhage

심방세동 환자에서 항혈소판제 복용이 유리체 출혈에 미치는 영향

최 윤정
을지대학교 보건과학부 안경광학과, 교수, 성남

    Ⅰ. Introduction

    Atrial fibrillation (AF), the most common arrhythmia in developed countries, increases the rates of stroke and mortality up to fivefold.1-3) Oral anticoagulants such as warfarin and clopidogrel are used to reduce stroke and mortality.2,3) The regular use of anticoagulants has increased over the past few decades, as the benefits of systemic anticoagulant therapy are increasingly being recognized in the treatment of cardiovascular and cerebrovascular diseases.4) In addition, the risk of bleeding complications associated with anticoagulants has increased. The most serious complication of warfarin is bleeding, which has been reported to occur in 39% of warfarin-treated patients.5-7) Hemorrhagic complications include gastrointestinal bleeding, intracranial hemorrhage, and hemorrhage.6,7) Ocular hemorrhage refers to subconjunctival, anterior, vitreous, and retinal hemorrhages, which can be vision-threatening complications.8)

    Vitreous hemorrhage is known to be a major risk factor for severe vision loss, occurring in 7 out of 100,000 people.9) The most common causes of vitreous hemorrhage are proliferative diabetic retinopathy, posterior vitreous detachment with or without retinal tear, ocular trauma, retinal vein occlusion, and age-related macular degeneration.10-17) Several studies have reported that the use of anticoagulants such as aspirin, clopidogrel bisulfate, and warfarin sodium increases the frequency of vitreous hemorrhage.10,18,19) Among them, in the case of non-diabetic vitreous hemorrhage, it is reported that the visual acuity after surgery is sufficient to improve in more than 80% of cases.20-22) Therefore, to predict the visual prognosis of vitreous hemorrhage, it is important to elucidate the cause of bleeding.

    In Korea, studies on the prevalence and incidence of vitreous hemorrhage in patients receiving antiplatelet drugs are insufficient. Therefore, this study identified patients with AF from the National Health Insurance Corporation and analyzed the incidence and risk factors of vitreous hemorrhage in patients with AF taking antiplatelet drugs.

    Ⅱ. Materials and Methods

    This study was approved by the Institutional Review Board of Nowon Eulji University Hospital (IRB number: EMCS 2017-02-006-002).

    A total of 819,948 patients aged >15 years were selected from the National Health Insurance Corporation database. Inclusion criteria were as follows: patients diagnosed with an International Statistical Classification of Diseases, Tenth Revision (ICD-10) code for AF (code: I48) at least once during admission and those at least twice during outpatient diagnosis between 2002 and 2006.

    Patients with AF (ICD-10 code: I48) who developed vitreous hemorrhage (ICD-10 code: H431 or H450) between January 2007 and December 2013, regardless of any outpatient visit and hospitalization, were censored. Patients with AF and at-least one vitreous hemorrhage occurrence, regardless of outpatient hospitalization, were classified as the target group, and patients with AF and without vitreous hemorrhage were classified as the control group. All patients were analyzed statistically.

    Patients’ age, sex, and time to vitreous hemorrhage onset after the diagnosis of AF were reviewed.

    To investigate the relationship between AF and other systemic disease complications, the occurrence of hypertension (ICD-10 codes: I10, I109, I11, I110, I119, I12, I120, I129, I13, I130, I131, I132, I139, I15, I150, I151, I152, I158, and I159) and diabetic mellitus (ICD-10 codes: E10, E100-109, E11, and E110-149) was assessed. Hypertension and diabetes mellitus occurred before vitreous hemorrhage.

    To determine the relationship between antiplatelet use and vitreous hemorrhage, patients with AF were divided based on duration of aspirin (code 1110xxAxx) and cilostazol (code 1332xxAxx) use (≤ 1 year, 1-4 years, and ≥4 years). In addition, we extracted the time of antiplatelet drug intake from patients before the occurrence of vitreous hemorrhage.

    Statistical analysis was performed using the SAS version 9.2 (SAS Institute, Cary, NC, US) and SPSS 28 software (version 18; SPSS Inc., Chicago, IL, USA). A p-value of <0.050 was considered statistically significant. We used the data of patients with AF from the National Health Insurance Corporation database to compare the target group with vitreous hemorrhage and the control group without vitreous hemorrhage and to analyze the duration of use of each antiplatelet drug until the occurrence of vitreous hemorrhage.

    Patient’s identification information (such as name, resident registration number, and record number) was removed, and patient data were managed with study number.

    Ⅲ. Results

    This study selected 7,471 patients diagnosed with AF (3,875 men and 3,596 women) between 2002 and 2006 from the National Health Insurance Corporation database. A total of 7,373 of 7,471 patients died during the follow-up period or did not develop vitreous hemorrhage till the end of the follow-up period and 98 patients developed vitreous hemorrhage. Among the 98 patients with AF and vitreous hemorrhage, 56 (1.4%) were men and 42 (1.2%) were women. Among 7,373 patients with AF and without vitreous hemorrhage, 3,819 (98.6%) were men and 3,554 (98.8%) were women (p=0.310). Among the 98 patients with vitreous hemorrhage, 10 patients were ≤50 years old and 88 patients were ≥50 years old. The incidence of vitreous hemorrhage was lower than the expected frequency in patients aged <50 years, whereas that was higher than the expected frequency in patients aged ≥50 years. However, the frequency of vitreous hemorrhage in patients aged ≥70 years was lower than the expected frequency.

    Among 98 patients with vitreous hemorrhage, 72 patients with hypertension and 52 patients with diabetes mellitus were statistically significant with those without vitreous hemorrhage, respectively. The time to onset of vitreous hemorrhage after AF diagnosis was 4,300.47±8.23 days (Table 1).

    The relationship between anticoagulant use and vitreous hemorrhage was investigated after adjusting for age,23,24) sex,25) hypertension,23,24,26,27), and diabetic mellitus,23,24) the known confounding factors for ocular hemorrhage.

    A total of 1,793 patients were taking aspirin. Twenty-five of 98 patients with vitreous hemorrhage were taking aspirin (<1 year: 9[36%] patients, 1~4 years: 9[36%] patients, and ≥4 years:　7[28%] patients). A total of 1,768 patients did not develop vitreous hemorrhage despite taking aspirin (<1 year: 575[32.5%] patients, 1~4 years: 621[35.1%] patients, and ≥4 years: 572[32.4%] patients). No statistically significant difference was noted in the number of patients taking and not taking aspirin (p=0.886). In total, 101 patients were taking cilostazol. Thirteen of 98 patients who developed vitreous hemorrhage were taking cilostazol (<1 year:　 7[53.8%] patients, 1~4 years:　4[30.8%] patients, and ≥4 years:　2[15.4%] patients). A total of 88 patients did not develop vitreous hemorrhage despite taking cilostazol (<1 year:　46[52.3%] patients, 1~4 years:　33[37.5%] patients, and ≥4 years:　9[10.2%] patients).

    Considering patients taking aspirin for <1 year as the reference category (Ref), the hazard ratio (HR) for developing vitreous hemorrhage among patients taking aspirin for 1~4 years was found to be 0.799 (95% CI, 0.317~2.014, p=0.634), and that among patients taking aspirin for ≥4 years was found to be 0.489 (95% CI, 0.182~1.319, p=0.158). Both of them did not show a significant differences with the HR of taking ≤1 year, respectively. In addition, considering patients taking cilostazol for <1 year as the Ref, the HR for developing vitreous hemorrhage among patients taking cilostazol for 1~4 years was found to be 0.757 (95% CI, 0.221~2.589, p=0.657) and that among patients taking cilostazol for ≥4 years was found to be 1.202 (95% CI, 0.249~5.802, p=0.819). There were no significant difference with the HR of taking the drug for ≤1 year, respectively (Table 2).

    The yearly incidence of vitreous hemorrhage in the target patient group was approximately 0.18~0.93%. Therefore, the cumulative survival rates without vitreous hemorrhage at 5, 10, and 12-years follow-up timepoints were 98.29, 96.18, and 95.47%, respectively (Fig. 1).

    Ⅳ. Discussion

    The cause of bleeding in vitreous hemorrhage is difficult to determine because of insufficient diagnostic evidence. In patients with vitreous hemorrhage, age, presence of systemic diseases (such as hypertension, diabetic mellitus, cardiovascular disease), and presence of systemic problems (such as taking antiplatelet drugs) should be considered.28) In Korea, few studies have investigated the relationship between vitreous hemorrhage and use of anticoagulants, especially according to the type of antiplatelet drugs. Although short-term studies on the causes of vitreous hemorrhage have been conducted abroad,4,8,18,19,29,30) no long-term follow-up studies, such as this study, have been conducted.

    Among the recently studied antiplatelet drugs, aspirin,4,18,19) rivaroxaban,19,29,30) apixaban,29,30) and dabigatran29,30) are known to be related to vitreous hemorrhage. The risk of thromboembolism in patients with AF increases by 3-5% every year from the age of 65 years, even in the absence of history of stroke, and therefore, antiplatelet drugs are the primary prevention therapy.31,32) Aspirin is the first-line drug for all vascular diseases and is known to be effective against AF.31,32) Although cilostazol is used as a second-line drug for peripheral vascular diseases, one study reported that cilostazol is an effective and safe alternative for patients with aspirin intolerance.33) Therefore, this study investigated the relationship of vitreous hemorrhage with aspirin (the first-line drug for thromboembolism) and cilostazol (an antiplatelet drug that has not been studied) use in patients with AF with long-term follow-up.

    'Ocular bleeding' includes subconjunctival hemorrhage, anterior chamber hemorrhage, vitreous hemorrhage, and retinal hemorrhage.34) According to Biyik et al.8) old age may lead to ocular bleeding in patients taking anticoagulants such as warfarin. Conversely, no correlation was found between ocular bleeding, sex, duration of warfarin treatment, concomitant aspirin use, and diabetes mellitus. Although not statistically significant, the incidence of vitreous hemorrhage increased from the age of ≥50 years and decreased from the age of ≥70 years in this study. A large population study investigated the average incidence of non-traumatic subconjunctival hemorrhage among subconjunctival hemorrhages included in the category of ocular bleeding24) and found that the incidence increased from the age of ≥60 years and decreased after the age of 80 years. Mimura et al.23) reported that the incidence of subconjunctival hemorrhage increases with age. However, Fukuyama et al.27) reported no association between age and subconjunctival hemorrhage.

    In this study, although the incidence of vitreous hemorrhage was higher in men than in women, no statistically significant sex difference was found. According to Fukuyama et al.27) sex is not a risk factor for ocular bleeding. In addition, Sam et al.35) reported that age and sex are not related to bleeding in aspirin users as well as nonusers.

    In this study, the incidence of vitreous hemorrhage was significantly higher in patients with hypertension and diabetes mellitus. According to Biyik et al.8) the incidence of ocular hemorrhage was significantly higher in patients with hypertension, but was not related to sex or diabetes.

    An examination of the relationship between aspirin use and vitreous hemorrhage revealed that the risk of vitreous hemorrhage was lower in the group taking aspirin for long-term asprin users than in short-term aspirin users. Thus, ophthalmic complications seem to develop immediately after taking a weak anticoagulant (e.g., aspirin) as well as over time, as the patient's body is adapted to the drug. According to a study by Riemann et al.4) vitreous hemorrhage occurs more frequently in patients taking anticoagulants such as aspirin; however, the occurrence of retinal tear or retinal detachment is reduced after the development of vitreous hemorrhage. Therefore, the side effects of ocular bleeding due to anticoagulants cannot be excluded. Witmer et al.18) investigated patients taking anticoagulants (aspirin, clopidogrel, and warfarin) and found that vitreous hemorrhage occurred as a result of acute posterior vitreous detachment. Although not statistically significant, the risk of vitreous hemorrhage was high among patients taking cilostazol for ≥4 years. Although no domestic or foreign papers have studied cilostazol, it is considered that aspirin and clopidogrel should be taken once a day and other antiplatelet drugs such as cilostazol should be taken at least twice a day.31) However, due to the small number of patients in this study, further studies are needed.

    The study has some limitations. First, information on retinal tears and posterior vitreous detachment, which are contributing factors for vitreous hemorrhage, was not available. Therefore, the incidence of vitreous hemorrhage because of antiplatelet use can be highly evaluated and may affect the interpretation of the analysis. Second, ocular hemorrhages such as anterior chamber hemorrhage and retinal hemorrhage were not considered; hence, additional research including ocular hemorrhages is required in the future. Third, patients with vitreous hemorrhage were limited to patients with AF. Although the subject of investigation in this study is limited to a representative of the whole, it has significance in that there has been no group study on the occurrence of vitreous hemorrhage according to the types of aspirin and cilostazol. This study is meaningful in that although the subject of the survey is limited to representing the whole, there has been no group study on vitreous hemorrhage in Korea so far. Although the sample size of this study was not small, caution should be exercised when generalizing the results to the entire population.

    Ⅴ. Conclusion

    In conclusion, long-term follow-up of patients with AF revealed that the use of aspirin and cilostazol may increase the risk of vitreous hemorrhage. However, vitreous hemorrhage was found to be multifactorial because the frequency of diabetic mellitus and hypertension was high in patients with vitreous hemorrhage. In a patient with persistent or unknown vitreous hemorrhage, further evaluation of the systemic condition or side effects of prescription drugs should be performed.

    Conflict of interest

    The author conclude that they have no interest in the products associated with this study.

    Figure

    KJVS-24-1-33_F1.gif

    Kaplan-Meier plots of survival without vitreous hemorrhage.

    Table

    Weighted prevalence and frequency of vitreous hemorrhage in patients with atrial fibrillation (AF) in Korea over 7 years (2007~2013)

    Oral antiplatelet drug use in patients with atrial fibrillation and multivariate relative risk of occurrence of vitreous hemorrhage

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