Repeated intravitreal injections of antivascular endothelial growth factor in patients with neovascular age-related macular degeneration may increase the risk of ischemic optic neuropathy

DOI: https://doi.org/10.21203/rs.2.1753/v1

Abstract

Background Previous case reports presented the occurrence of ischemic optic neuropathy (ION) following intravitreal injections of antivascular endothelial growth factor (anti-VEGF). However, no previous studies have investigated the impact of injection numbers on the risk of ION. The aim of our study was to investigate whether repeated intravitreal injections of anti-VEGF would increase the risk of subsequent ION in patients with neovascular age-related macular degeneration (AMD). Methods A population-based, retrospective cohort study using the Taiwan National Health Insurance Research Database was conducted from 2007 to 2013. Neovascular AMD patients receiving intravitreal injections of anti-VEGF during the period were enrolled in the study cohort. Enrollees were divided into three groups according to categorized levels of injection number (first level: < 10 times, second level: 10–15 times, third level: > 15 times). Kaplan-Meier curves were generated to compare the cumulative hazard of subsequent ION among the three groups. Cox regression analyzes were used to estimate crude and adjusted hazard ratios (HRs) for ION development with respect to different levels of injection numbers. Confounders included for adjustment were age, sex, and comorbidities (diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). Results In total, the study cohort had 77210 patients. Of these, 26520, 38010, and 12680 were in the first, second, and third level groups, respectively. The Kaplan-Meier method revealed that the cumulative hazards of ION were significantly higher in those who had a higher injection number. After adjusting for confounders, the adjusted HRs for ION in the second and third levels of injection number were 1.91 (95% confidence interval [CI], 1.32–2.76), and 2.20 (95% CI, 1.42–3.43), respectively, compared with the first level. Conclusions Among patients with neovascular AMD, those who receive a higher number of anti-VEGF injections are at a significantly higher risk of developing ION when compared with individuals who receive a lower number of injections.

Background

Neovascular age-related macular degeneration (AMD) is characterized by the proliferation of abnormal blood vessels (neovasculatures) in the choroid and can cause severe vision loss. Inhibition of vascular endothelial growth factor (VEGF) leads to marked decreases in neovascularization of both the choroid and retina [1-4]. Thus, intravitreal injection of anti-VEGF has been widely performed to treat neovascular AMD.

Ischemic optic neuropathy (ION), resulting from an insufficient blood supply, is the most common acute optic neuropathy in older patients [5, 6]. ION is classified as anterior or posterior ION according to the affected segment of the optic nerve. Both segments are further categorized into arteritic (related to vasculitis), and nonarteritic (not related to vasculitis). Of these, the nonarteritic anterior ION (NAION) is the most common type. Risk factors for NAION include a crowded optic disk, diabetes, hypertension, hyperlipidemia, and ischemic heart disease [7-11]. Diminished ocular blood perfusion due to elevated intraocular pressure (IOP) or glaucoma could also precipitate the occurrence of ION [12-17].

Although intravitreal injection of anti-VEGF is effective in treating neovascular AMD, it may have some possible complications such as endophthalmitis, intraocular inflammation, IOP elevation, and ocular hemorrhage [18]. Besides, one rare ocular adverse effect is ION [19-21]. The underlying pathogenesis of the association between anti-VEGF and the risk of subsequent ION is still not fully known. One potential mechanism may be the transient IOP elevation after intravitreal injection of anti-VEGF. If this is the case, then increasing the numbers of injections may increase the risk of developing ION. To the best of our knowledge, no previous studies have investigated the impact of injection numbers on the risk of ION. The lack of evidence-based studies results from the rare occurrence of ION. Besides, systemic diseases such as diabetes, hypertension, hyperlipidemia, ischemic heart disease, as well as glaucoma, may confound the association between anti-VEGF and ION, and thus had to be adjusted.

We conducted this study based on the Taiwan National Health Insurance Research Database (NHIRD) to elucidate the association between intravitreal injection of anti-VEGF and subsequent ION. Our hypothesis is that a higher number of intravitreal injections of anti-VEGF will increase the risk of subsequent ION among neovascular AMD patients. We used the whole population database and therefore had large numbers of patients as well as a high level of statistical power. The completeness of the database ensures that the diagnoses of each patient available, and the diagnoses were according to the generally accepted International Classification of Diagnoses, Ninth Revision, Clinical Modification (ICD-9-CM) Codes.

Methods

Data source

The NHIRD was derived from the Taiwan National Health Insurance Program, which covers more than 99% of Taiwan’s 23 million residents. The NHIRD consists of diagnoses, medical prescriptions, surgical procedures, insurance registry, and is released for scientific research after personal identification numbers have been encrypted. This study was approved by the institutional review board of National Yang-Ming University Hospital (2015A018).

 

Study subjects

We conducted a retrospective cohort study from January 1, 2007, to December 31, 2013. First, we selected patients from the NHIRD who were diagnosed with neovascular AMD (ICD-9-CM code 362.52) during the study period, which required confirmation by fundoscopy, fluorescein angiography, and/or optical coherence tomography. Patients diagnosed with neovascular AMD before the end of 2006 were excluded to ensure that all enrolled patients had new-onset neovascular AMD. Among them, those who received intravitreal anti-VEGF injections for the treatment of neovascular AMD were included in the study cohort. According to the number of anti-VEGF injections, patients in the study cohort were further divided into three groups (first level: < 10 times, second level: 10–15 times, third level: > 15 times).

 

Outcome variable

Patients in the study cohort were followed to identify the onset of ION (ICD-9-CM codes 377.41). Those with ION before the injection of anti-VEGF were excluded to ensure that all events of ION were new-onset.

 

Demographic variables and comorbidities

Demographic variables such as age and sex were extracted from the database. Age was categorized into three levels: the first (< 60 years), the second (60–75 years), and the third (≥ 75 years) level. Risk factors of ION such as diabetes (ICD-9-CM Codes 250), hypertension (ICD-9-CM Codes 401–405), hyperlipidemia (ICD-9-CM Codes 272), ischemic heart disease (ICD-9-CM Codes 410–414), and glaucoma (ICD-9-CM Codes 365) may confound the relationship between anti-VEGF and ION. Therefore, these comorbidities were identified in the medical records and included as covariates in our analyses.

 

Statistical analysis

Characteristics of the study cohort were presented according to age, sex, and comorbidities (e.g., diabetes, hypertension, hyperlipidemia, ischemic heart disease, and glaucoma). Group differences (first level: < 10 times, second level: 10–15 times, third level: > 15 times) in these variables were analyzed by ANOVA tests (for continuous variables) and chi-square tests (for categorical variables). Then, the study cohort was followed until the occurrence of ION, dropout from the database, or the end of 2013, whichever came first. Survival analysis using the Kaplan-Meier method with the log-rank test was applied to describe and compare cumulative hazard curves of ION, according to different levels of injection number.

Subsequently, all these variables (age, sex, number of intravitreal anti-VEGF injection, and comorbidities) were included in the Cox regression analyzes. Unadjusted hazard ratios (HRs) for ION were computed according to each variable in univariate analyzes. Then, adjusted HRs for ION were derived from multivariate analyzes. Comorbidities were regarded as time-dependent variables. All statistical operations were performed using SAS statistical package, version 9.2 (SAS Institute, Cary, NC, USA).

 

Results

Demographic and clinical characteristics of the study sample

In total, 77210 patients were enrolled in the study cohort. Of them, 26520 were in the first level group, 38010 were in the second level group, and 12680 were in the third level group. Table 1 presents their demographic and clinical characteristics. The mean age in the study cohort was 67.4 years. The male to female ratio was 1.7:1. The prevalence of comorbidities was 35.6% for diabetes, 64.6% for hypertension, 44.3% for hyperlipidemia, and 29.8% for ischemic heart disease. Besides, 16.5% of the study cohort had glaucoma. The mean number of injections among the study cohort was 12.0, with a standard deviation (SD) of 2.9. Almost 50% of the patients had injection numbers in the range of 10 to 15. Significantly differences were found across the three groups (first level: < 10 times, second level: 10–15 times, third level: > 15 times) in age, gender, and comorbidities. The follow-up period of the study cohort was 3.50 ± 1.86 (mean ± SD) years, and did not differ significantly among the three groups. Of 77210 patients, 180 (0.23%) had a subsequent occurrence of ION, including 40 (0.15%) in the first level, 100 (0.26%) in the second level, and 40 (0.32%) in the third level group.

 

Kaplan-Meier curves and log-rank test

Figure 1 illustrates the Kaplan-Meier curves of ION corresponding to each level of injection number. According to the log-rank test, the difference in cumulative hazards was significant (p < 0.01).

ION risk

Table 2 displays HRs for ION with regard to age, sex, injection number, and comorbidities. In the univariate Cox regression analysis, the second level (10–15 times) and the third level (≥ 15 times) of injection number yielded an unadjusted HR for ION of 1.75 (95% confidence interval [CI], 1.21–2.53) and 1.99 (95% CI, 1.28–3.08), respectively, compared with the first level (< 10 times) of injection number. Adjusted HRs obtained by comparing the second and third levels with the first level of injection number were 1.91 (95% CI, 1.32–2.76) and 2.20 (95% CI, 1.42–3.43), respectively. Diabetes significantly increased the risk for ION in both the univariate and multivariate analyzes. However, age, sex, hypertension, hyperlipidemia, and ischemic heart disease were not significant risk factors for ION in both the univariate and multivariate analyzes. Glaucoma increased the risk for ION in the univariate analysis, but the statistical significance was only marginal (unadjusted HR = 1.43; 95% CI, 1.01–2.03) and was not significant in the multivariate analysis (adjusted HR = 1.35; 95% CI, 0.95–1.92).

Discussion

This study is the first to reveal the increased risk of ION after repeated injections of anti-VEGF among neovascular AMD patients. In our population-based study, utilizing Taiwan’s NHIRD with a long (7-year) study period, we found that among patients with neovascular AMD, the risk of ION significantly increased in those who received more anti-VEGF injections, after adjusting for confounders.

AMD is a multifactorial disease, and advanced age is a main predisposing factor. In our study, the study cohort had a mean age of 67.4 years, and nearly one-third was older than 75 years. These results were compatible with a previous hospital-based study regarding anti-VEGF use among neovascular AMD in Taiwan [22]. It is noteworthy that the distribution of comorbidities in our study was higher than in those without AMD in another population-based study in Taiwan [23]. Besides, table 1 revealed significant differences in age, gender, and comorbidities by number of injections. Therefore, the group differences in these variables were adjusted in our following Cox regression analyses.

The Kaplan-Meier curves with the log-rank test (Fig. 1) and Cox regression analyzes (Table 2) in our study revealed that a higher number of injections were associated with a higher risk of subsequent ION. Very few case reports have described the onset of ION following intravitreal injection of anti-VEGF. Hosseini et al. reported a 72-year-old woman with NAION occurring one week after the second intravitreal injection of anti-VEGF under the indication of active subfoveal choroidal neovascularization [19]. In their 2009 case report, Ganssauge et al. presented a 51-year-old man with pseudoxanthoma elasticum who received an intravitreal injection for choroidal neovascularization secondary to angioid streaks. Two weeks later, NAION was observed [20]. Huang et al. described a case of a 38-year-old woman with diabetic retinopathy. Three weeks after intravitreal injection of anti-VEGF, anterior ION occurred [21]. Although the elevated IOP during intravitreal injection might have a compression effect on the optic nerve head, the three cases of ION did not have elevated IOP. It is possible that the IOP elevation was temporary and not detected or other pathogenesis such as anti-VEGF itself precipitated ION.

Previous studies have shown that VEGF plays a role in modulating both vascular tone and blood flow autoregulation [24]. Ameri et al. found that a sudden drop in effective VEGF concentration might be responsible for the closure of normal capillaries [25]. Therefore, anti-VEGF may diminish the blood perfusion to the optic nerve head and cause ION. Besides, VEGF has been reported to have both neurotrophic and neuroprotective effects [26]. In a diabetic rat model after intravitreal anti-VEGF injection, apoptosis in retinal ganglion cells increased [27]. Maybe the optic nerve head was also directly disturbed by anti-VEGF, and the influence was additive after repeated injections. Therefore, repeated injections of anti-VEGF lead to a higher risk of ION.

Our study has the strengths of a large sample size, an extended study period, a statistical analysis that adjusted for confounders, and validated diagnoses. In our health care system, the National Health Administration (NHA) frequently checks the cross-consistency of claims and chart data. The NHA also confirmed diagnoses that were approved by a standard protocol of examinations. Therefore, the diagnoses in our database have a high degree of accuracy.

The limitation of our study is that we cannot conclude a causal relationship between repeated anti-VEGF injection and ION. All analyzes were based on our database, and we derived a positive association between repeated anti-VEGF injection and ION. The underlying mechanism of the association is still not fully elucidated. Further basic research, animal models, and maybe large-scale prospective cohort studies are needed to unravel the pathogenesis.

At present, our study reminds ophthalmologists to check the optic nerve changes following the anti-VEGF injection among neovascular AMD patients, especially those who received a higher number of injections. The risk of ION should also be considered when deciding anti-VEGF injections as treatment for neovascular AMD.

Abbreviations

AMD: age-related macular degeneration; VEGF: vascular endothelial growth factor; ION: Ischemic optic neuropathy; NAION: nonarteritic anterior ION; IOP: intraocular pressure; NHIRD: National Health Insurance Research Database; ICD-9-CM Codes: International Classification of Diagnoses, Ninth Revision, Clinical Modification Codes; HRs: hazard ratios; CI: confidence interval; NHA: National Health Administration

Declarations

Ethics approval

This study was approved by the ethical committee of Yang-Ming University Hospital (2015A018).

 

Consent for publication

Not applicable.

 

Availability of data and materials

The dataset analyzed during the current study are available from the Collaboration Center of Health Information Application, Ministry of Health and Welfare, Taiwan: [email protected], adderss:4F., No.488, sec. 6.Zhongxiao E. RD., Nangang Dist., Taipei City 115, Taiwan.

 

Completing interests

The authors declare that they have no competing interests.

 

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

 

Authors’ contributions

Conceptualization: YYC, PC, YFH, HJC, YCW, CCL, LYH, HHC; Formal analysis: YYC, PC, and HJC; Investigation: YYC, YCW, HHC, and CCL; Methodology: YYC, LYH, and HHC; Validation: YYC, PC, and YFH; Writing the original draft: YYC, and PC. 

 

Acknowledgements

Not applicable.

 

References

  1. Vedula SS, Krzystolik MG: Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. The Cochrane database of systematic reviews 2008(2):Cd005139.
  2. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS: Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005, 112(6):1035-1047.
  3. Bashshur ZF, Haddad ZA, Schakal A, Jaafar RF, Saab M, Noureddin BN: Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. American journal of ophthalmology 2008, 145(2):249-256.
  4. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY: Ranibizumab for neovascular age-related macular degeneration. The New England journal of medicine 2006, 355(14):1419-1431.
  5. Hayreh SS: Ischemic optic neuropathies - where are we now? Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2013, 251(8):1873-1884.
  6. Biousse V, Newman NJ: Ischemic Optic Neuropathies. The New England journal of medicine 2015, 372(25):2428-2436.
  7. Burde RM: Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. American journal of ophthalmology 1993, 116(6):759-764.
  8. Hayreh SS, Joos KM, Podhajsky PA, Long CR: Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. American journal of ophthalmology 1994, 118(6):766-780.
  9. Jacobson DM, Vierkant RA, Belongia EA: Nonarteritic anterior ischemic optic neuropathy. A case-control study of potential risk factors. Archives of ophthalmology (Chicago, Ill : 1960) 1997, 115(11):1403-1407.
  10. Chang YS, Weng SF, Chang C, Wang JJ, Su SB, Huang CC, Wang JY, Jan RL: Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Following End-Stage Renal Disease. Medicine 2016, 95(12):e3174.
  11. Hayreh SS, Zimmerman MB: Nonarteritic anterior ischemic optic neuropathy: clinical characteristics in diabetic patients versus nondiabetic patients. Ophthalmology 2008, 115(10):1818-1825.
  12. Hayreh SS: Anterior ischemic optic neuropathy. IV. Occurrence after cataract extraction. Archives of ophthalmology (Chicago, Ill : 1960) 1980, 98(8):1410-1416.
  13. Hurmeric V, Bayer A, Durukan AH, Mutlu FM: Nonarteritic ischemic optic neuropathy developed after capsular block syndrome. Indian journal of ophthalmology 2014, 62(3):346-348.
  14. McCulley TJ, Lam BL, Feuer WJ: Nonarteritic anterior ischemic optic neuropathy and surgery of the anterior segment: temporal relationship analysis. American journal of ophthalmology 2003, 136(6):1171-1172.
  15. Choudhari NS, George R, Kankaria V, Sunil GT: Anterior ischemic optic neuropathy precipitated by acute primary angle closure. Indian journal of ophthalmology 2010, 58(5):437-440.
  16. Kuriyan AE, Lam BL: Non-arteritic anterior ischemic optic neuropathy secondary to acute primary-angle closure. Clinical ophthalmology (Auckland, NZ) 2013, 7:1233-1238.
  17. Kim KN, Kim CS, Lee SB, Lee YH: Delayed non-arteritic anterior ischemic optic neuropathy following acute primary angle closure. Korean journal of ophthalmology : KJO 2015, 29(3):209-211.
  18. Falavarjani KG, Nguyen QD: Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (London, England) 2013, 27(7):787-794.
  19. Hosseini H, Razeghinejad MR: Anterior ischemic optic neuropathy after intravitreal injection of bevacizumab. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2009, 29(2):160-161.
  20. Ganssauge M, Wilhelm H, Bartz-Schmidt KU, Aisenbrey S: Non-arteritic anterior ischemic optic neuropathy (NA-AION) after intravitreal injection of bevacizumab (Avastin) for treatment of angoid streaks in pseudoxanthoma elasticum. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2009, 247(12):1707-1710.
  21. Huang JY, Ozaki H, Hayashi H, Uchio E: Anterior ischemic optic neuropathy following intravitreal bevacizumab. Japanese journal of ophthalmology 2010, 54(3):252-254.
  22. Chang YS, Lee WJ, Lim CC, Wang SH, Hsu SM, Chen YC, Cheng CY, Teng YT, Huang YH, Lai CC et al: Real-world use of ranibizumab for neovascular age-related macular degeneration in Taiwan. Scientific reports 2018, 8(1):7486.
  23. Tsai DC, Chen SJ, Huang CC, Yuan MK, Leu HB: Age-Related Macular Degeneration and Risk of Degenerative Dementia among the Elderly in Taiwan: A Population-Based Cohort Study. Ophthalmology 2015, 122(11):2327-2335.e2322.
  24. Hayreh SS: Blood flow in the optic nerve head and factors that may influence it. Progress in retinal and eye research 2001, 20(5):595-624.
  25. Ameri H, Chader GJ, Kim JG, Sadda SR, Rao NA, Humayun MS: The effects of intravitreous bevacizumab on retinal neovascular membrane and normal capillaries in rabbits. Investigative ophthalmology & visual science 2007, 48(12):5708-5715.
  26. Nicoletti JN, Shah SK, McCloskey DP, Goodman JH, Elkady A, Atassi H, Hylton D, Rudge JS, Scharfman HE, Croll SD: Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus. Neuroscience 2008, 151(1):232-241.
  27. Park HY, Kim JH, Park CK: Neuronal cell death in the inner retina and the influence of vascular endothelial growth factor inhibition in a diabetic rat model. The American journal of pathology 2014, 184(6):1752-1762.

Tables

Table 1. Characteristics of the study cohort

Variable

Study cohort (n=77210)

First level

(n=26520)

Second level

(n=38010)

Third level

(n=12680)

p-value

Age, years

67.4±12.2

65.3±13.0

68.1±12.0

69.5±10.5

<0.0001

Age group, categorical

 

 

 

 

<0.0001

<60

20020 (25.9)

8840 (33.3)

8940 (23.5)

2240 (17.7)

 

60–75

32780 (42.5)

10400 (39.2)

16410 (43.2)

5970 (47.1)

 

³75

24410 (31.6)

7280 (27.5)

12660 (33.3)

4470 (35.2)

 

Sex

 

 

 

 

<0.0001

Male

48570 (62.9)

15480 (58.4)

24490 (64.4)

8600 (67.8)

 

Female

28640 (37.1)

11040 (41.6)

13520 (35.6)

4080 (32.2)

 

Number of injection, times

12.0±2.9

8.7±3.4

12.3±1.7

 

18.1±4.2

<0.0001

Number of injection, categorical

 

 

 

 

 

First level (<10)

26520 (34.4)

26520

0

0

 

Second level (10-15)

38010 (49.2)

0

38010

0

 

Third level (≥15)

12680 (16.4 )

0

0

12680

 

Diabetes

 

 

 

 

<0.0001

Yes

27490 (35.6)

10770 (40.6)

12510 (32.9)

4210 (33.2)

 

No

49720 (64.4)

15750 (59.4)

25500 (67.1)

8470 (66.8)

 

Hypertension

 

 

 

 

<0.0001

Yes

49900 (64.6)

16940 (63.9)

24420 (64.2)

8540 (67.3)

 

No

27310 (35.4)

9580 (36.1)

13590 (35.8)

4140 (32.7)

 

Hyperlipidemia

 

 

 

 

<0.0001

Yes

34200 (44.3)

11760 (44.3)

16480 (43.4)

5960 (47.0)

 

No

43010 (55.7)

14760 (55.7)

21530 (56.6)

6729 (53.0)

 

Ischemic heart disease

 

 

 

 

<0.0001

Yes

22990 (29.8)

7630 (28.8)

11350 (29.9)

4010 (31.6)

 

No

54220 (70.2)

18890 (71.2)

26660 (70.1)

8670 (68.4)

 

Glaucoma

 

 

 

 

<0.0001

Yes

12730 (16.5)

4570 (17.2)

5890 (15.5)

2270 (17.9)

 

No

64480 (83.5)

21950 (82.8)

32120 (84.5)

10410 (82.1)

 

Follow-up period, years

3.50±1.86

3.51±1.87

3.49±1.86

3.53±1.84

0.09

Incident ION

180 (0.23)

40 (0.15)

100 (0.26)

40 (0.32)

<0.01

ION ischemic optic neuropathy. Data are presented as mean±standard deviation or n (%).  

 

Table 2. Risk Factors for ION in the study cohort

Variables

Univariate analysis

 

Multivariate analysis

Unadjusted HR (95% CI)

 

p-value

 

Adjusted HR (95% CI)

 

p-value

Age group, years

             

  <60

Reference

     

Reference

   

60–75

1.02 (0.76–1.39)

 

0.86

 

1.01 (0.75–1.38)

 

0.91

  ³75

1.17 (0.86–1.61)

 

0.31

 

1.09 (0.76–1.58)

 

0.62

Sex (male vs. female)

0.84 (0.65–1.09)

 

0.19

 

0.82 (0.63–1.07)

 

0.14

Number of injection

 

 

 

 

 

 

 

First level (<10)

Reference

 

 

 

Reference

 

 

Second level (10-15)

1.75 (1.21–2.53)

 

<0.01

 

1.91 (1.32–2.76)

 

<0.001

Third level (≥15)

1.99 (1.28–3.08)

 

<0.01

 

2.20 (1.42–3.43)

 

<0.001

Diabetes

1.82 (1.36–2.44)

 

<0.0001

 

2.03 (1.46–2.81)

 

<0.0001

Hypertension

1.05 (0.83–1.35)

 

0.65

 

1.04 (0.85–1.30)

 

0.65

Hyperlipidemia

1.27 (0.95–1.70)

 

0.11

 

1.04 (0.75–1.43)

 

0.83

Ischemic heart disease

1.16 (0.85–1.58)

 

0.35

 

1.20 (0.86–1.67)

 

0.29

Glaucoma

1.43 (1.01–2.03)

 

<0.05

 

1.35 (0.95–1.92)

 

0.09

ION ischemic optic neuropathy; HR hazard ratio; CI confidence interval.

In the multivariable analysis, all other variables in the table were included for adjustment.