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 of the patients were older than 75 years. These results were compatible with a previous hospital-based study regarding anti-VEGF use among neovascular AMD patients in Taiwan . It is noteworthy that the distribution of comorbidities was higher in our study cohort than in those without AMD in another population-based study in Taiwan . In addition, Table 1 revealed significant differences in age, sex, and comorbidities according to the number of injections. Therefore, the group differences in these variables were adjusted in our subsequent Cox regression analyses.
The Kaplan-Meier curves with the log-rank test (Fig. 1) and Cox regression analyses (Table 2) in our study revealed that a higher number of injections was associated with a higher risk of subsequent ION. Very few case reports have described the onset of ION following the intravitreal injection of anti-VEGF. Hosseini et al. reported a 72-year-old woman with NAION occurring 1 week after the second intravitreal injection of anti-VEGF under the indication of active subfoveal choroidal neovascularization . 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 . 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 . Although the elevated IOP that occurs during intravitreal injection might have a compression effect on the optic nerve head, the three patients with ION did not have an elevated IOP. It is possible that the IOP elevation was temporary and was not detected, or it is possible that other pathogeneses, 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 . Ameri et al. found that a sudden decrease in the effective VEGF concentration might be responsible for the closure of normal capillaries . Therefore, anti-VEGF may diminish the blood perfusion to the optic nerve head and cause ION. Additionally, VEGF has been reported to have both neurotrophic and neuroprotective effects . In a diabetic rat model following intravitreal anti-VEGF injection, the rate of apoptosis increased in retinal ganglion cells . It is possible that the optic nerve head is also directly disturbed by anti-VEGF and that the influence is additive after repeated injections. Therefore, repeated injections of anti-VEGF may lead to a higher risk of ION.
One limitation of our study is the lack of visual acuity and IOP values in our NHIRD. In addition, we retrieved patients receiving anti-VEGF injections through the procedure codes, but we could not differentiate what kind of anti-VEGF the patients received. These are the inherent drawbacks of our database. Further clinical studies are necessary in order to include these information.
Another limitation of our study is that we lacked controls with similar demographics. More studies regarding the comparison of ION risk between those with anti-VEGF and matched controls (without anti-VEGF) are warranted. In our study, patients who underwent fewer than 10 injections (the first-level group) were regarded as the reference group. However, the first-level, second-level, and third-level groups did not have similar baseline characteristics. Patients in the groups with higher numbers of intravitreal anti-VEGF injections were significantly older and had a significantly higher prevalence in hypertension, hyperlipidemia, and ischemic heart disease. These systemic factors may have affected the incidence of ION. Additionally, older people tend to have more comorbidities including diabetes, hypertension, and ischemic heart disease, which may coexist with ION. These confounding effects potentially complicated our analyses. We tried as possible as we could to adjust these factors in the Cox regression. However, from the perspective of epidemiology, not all confounders were measurable and could be adjusted with statistical methods. Therefore, randomized control trials are still needed to address this issue.
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 have been approved by a standard protocol of examinations. Therefore, the diagnoses in our database have a high degree of accuracy. It is noteworthy that in the diagnosis of neovascular AMD, OCT plays an important role. Although the brand or type of OCT machine is not exactly the same in every hospital or clinic, these machines are all useful for detecting the neovasculature and fluid. Some newer modalities, such as spectrum domain OCT, swept source OCT, enhanced depth OCT, and OCT angiography can provide earlier detection of the choroidal neovasculature and can be applied in additional research.
We cannot conclude a causal relationship between repeated anti-VEGF injections and ION. Most likely, the observation that a higher incidence of ION in patients receiving more anti-VEGF injections only reflects a greater need for anti-VEGF in those patients who tend to have ION. At present, all analyses were based on our database, and we derived a positive association between repeated anti-VEGF injections and ION. The underlying mechanism of the association is still not fully understood. Further basic research, animal models, and possibly large-scale prospective cohort studies are needed to unravel the pathogenesis.