Anti-vascular endothelial growth factor in neovascular age-related macular degeneration – a systematic review of the impact of anti-VEGF on patient outcomes and healthcare systems

All 11 publications reported data on blindness, although the definition of blindness was not the same for all studies (Table 1). The study design also varied across the studies and included four population-based studies, four cohort-based studies, and three simulation-based studies with hypothetical cohorts.

Among the population-based studies, Bloch et al. and Skaat et al. estimated the evolution of incidence rates of legal blindness from AMD using national blindness registry data from Denmark and Israel [12, 22]. Both studies describe outcomes before and after anti-VEGF therapies were introduced in the local clinical practice, and both reported a nearly 50% drop in the incidence rate of legal blindness by AMD since anti-VEGF was introduced [12, 22]. Rostron et al. reported the incidence rate of UK Visual Impairment Certification due to nAMD in the Leeds metropolitan area [21]. The analysis shows that the incidence of new registrations in the area dropped by nearly 50% (from 225 per million population to 137 per million) after the introduction of anti-VEGF in the UK’s National Health Service (NHS). Borooah et al. used blind certifications recorded by the Royal National Institute of Blind People in South East Scotland to estimate the impact of anti-VEGF on blindness attributable to nAMD [15]. The study reports a 47% drop in the number of blind certification cases between 2006 (date of introduction of anti-VEGF therapy) and 2011.

For the cohort studies, Sloan et al. used US Medicare data to analyze vision loss or blindness in the first 2 years following a new diagnosis of nAMD and found a 46% reduction in vision loss or blindness [23]. Johnston et al. and Keenan et al. used electronic medical records from UK hospitals (14 individual sites and one NHS Trust, respectively) to estimate the impact of anti-VEGF on vision-related outcomes [13, 18]. The research done by Johnston et al. reported a significant reduction on the cumulative incidence of new blindness [13], whereas Keenan et al. reported a 49% reduction in patients eligible for full or partial certificate of visual impairment [18]. The study by Campbell et al. (conference abstract) reports data on two small cohorts of patients: one each before and after introduction of anti-VEGF [17]. The study demonstrated a 95% reduction in the incidence of legal blindness [17]. Due to the limited sample size and non-availability of full text, this result should be interpreted with caution.

The review also identified three simulation studies [16, 19, 20]. Based on US, UK, and Australian perspectives, each study simulated the evolution of a hypothetical cohort of nAMD patients and estimated the number of blindness cases potentially avoided due to the introduction of anti-VEGF in clinical practice [16, 19, 20]. Each study used local data to reflect the age and sex of the targeted population and other key variables (e.g. mortality, incidence/prevalence of nAMD) and estimated the impact attributed to anti-VEGF treatment by modeling the efficacy reported in the randomized clinical trial. Both Bressler et al. (US) and Mitchell et al. (Australia) estimated that the use of anti-VEGF could reduce the number of legal blindness cases due to nAMD by 70% [16, 20]. Minassian et al. (UK) assessed the impact of anti-VEGF treatment on the prevalence of sight loss attributable to nAMD against expected demographic changes and concluded that the potential benefit of anti-VEGF would be outweighed by the aging effect and that the overall rate of blindness could increase in the future [19]. There are differences in the modeling approaches used by Bressler et al., Mitchell et al., and Minassian et al. in their analysis. The authors consider different approaches to model changes in demographics, efficacy of the anti-VEGF, and coverage. Additionally, the baseline characteristics of the patients are different. The different assumptions and the different modeling approaches, in particular how demographic changes are modeled, could justify the different conclusions.

Cohort studies by Sloan et al. and Campbell et al. also reported the impact of anti-VEGF on other vision-related outcomes, such as degree of visual impairment [17, 23]. Sloan et al. reported that the odds of decreased vision (defined as decline from normal to moderate, moderate to severe, or severe to blindness, where moderate, severe, and blindness is defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification code) fell by 41% after introduction of anti-VEGF therapy (odds ratio, 0.59; 95% confidence interval, 0.52–0.68) [23]. Campbell et al. reported that moderate and mild impairment (defined as 20/80 and 20/40 in the better-seeing eye) was reduced by 78 and 70%, respectively, after introduction of anti-VEGF therapies [17]. The simulation studies by Bressler et al. and Mitchell et al. also estimated that visual impairment among patients with nAMD (defined as a letter score of 68 or lower, thus including blindness) could be reduced by 28 to 37% with the use of anti-VEGF [16, 20].

Keenan et al. was the only study that reported on the impact of anti-VEGF therapy on the ability to drive [18]. In this study, the proportion of nAMD patients suitable for driving (defined as VA in the better eye ≥70 EDTRS letters) increased from 27% in 2008 (before anti-VEGF) to 51.4% in 2012 (P < 0.0001).

Our review identified five publications from four studies that explored the impact of anti-VEGF on patients’ VRQoL [25‐28]. The impact on VRQoL was assessed using the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) in three of the studies [26‐28] and the Impact of Vision Impairment (IVI) questionnaire in one study [25]. Key findings per study are provided in Table 2.

The NEI VFQ-25 contains one general health item, and 25 questions measuring dimensions of self-reported vision-targeted health status that are considered most important for individuals with any chronic eye disease such as nAMD [34]. Questions are categorized into eleven vision-related subscales on: general vision (one question), ocular pain (two questions), near-vision and distance-vision activities (three questions each), social functioning (two questions), mental health (four questions), role difficulties (two questions), dependency and driving (three questions each), and color vision and peripheral vision (one question each). Each subscale is transformed on a 0–100 scale, with higher scores indicating better subjective function. The NEI VFQ-25 composite score is calculated as the mean score of all vision-related subscales, and excluding the general health item [34].

The IVI questionnaire contains 28 items with three to four active response options that employed Likert scaling, ranging from not at all to a lot [35, 36]. Items 1 to 15 have an additional response: don’t do this for other reasons. These items form three specific subscales: Reading and Accessing Information, Mobility and Independence, and Emotional Well-being [35, 36].

All the studies using NEI-VFQ-25 reported an improvement in patients’ VRQoL after 12 months of treatment. The change in total composite score of NEI VFQ-25 from baseline to month 12 ranged from 0.7 to 4.4 [26‐28]. This improvement was associated with the improved vision in the treatment eyes. Inoue et al. and Zhu et al. showed improvement in the VRQoL of nAMD patients after a shorter period of treatment; mean change in total composite score on the NEI VFQ-25 was 3.5 at 3 months of treatment and 4.5 at 6 months of treatment. In general, all studies saw improvement in patients’ VRQoL after start of intravitreal treatment (NEI VFQ-25 scores improved at reported time points compared with baseline; P < 0.05 for all) [25, 27, 28].

Finger et al., Inoue et al., and Zhu et al. also assessed the impact of anti-VEGF treatment on patients’ mental health and emotional well-being. Both dimensions were improved from baseline to last follow-up at 12 months [25, 27, 28].

Our review identified six studies that assessed the impact of anti-VEGF therapies on VRQoL (Table 2) [23, 29‐33].

In the pilot study by Casten et al., depression in nAMD patients receiving anti-VEGF therapy was assessed using the Patient Health Questionnaire 9 (PHQ-9) [29]. PHQ-9 rates the severity of depressive symptoms based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for depression [37]. Scores range from 0 to 27; a score greater than 5 is clinically significant. In this report, the authors calculated the prevalence rate of depression to be 20% among patients receiving anti-VEGF treatments and reported that these were slightly lower than in previous studies conducted before the widespread use of anti-VEGF treatments. In addition, depressed patients were found to have a greater decline in vision despite treatment compared with non-depressed patients [37]. Interesting, depression was unrelated to changes in NEI-VFQ scores [37].

Lee et al. analyzed 107 Korean patients with nAMD treated with anti-VEGF using the Geriatric Depression Scale [38] and found a 26.2% prevalence of depression, which is consistent with published rates before anti-VEGF treatments became widely available [31]. It was further suggested that age is the most important factor associated with depression in AMD, with older age, being associated with more severe depression [31].

The incidence of a first diagnosis of depression was analyzed among Medicare beneficiaries in the United States in a retrospective study of patients diagnosed with nAMD [23]. Overall, only 2.0% of the patient population studied received first diagnosis of depression during the 2-year follow-up period and the study reported no significant differences in the incidence of depression in patients who received anti-VEGF treatments compared with those who did not. However, the study did find that patients receiving anti-VEGF therapy had a 19% lower probability of being admitted into a long-term care facility.

Two studies explored patients’ anxiety and depression levels associated with receiving intravitreal injections [32, 33]. The first was a prospective observational study which was conducted in Israel. This study found a significant correlation between patients’ anxiety levels experienced before the injection and pain experienced when receiving the injection [32], with 25% of patients reported high levels of anxiety (score ≥ 6 on a scale of 0–10) measured by a visual analogue scale. The second study [33] was a prospective study in the United Kingdom and assessed the patient experiences while receiving anti-VEGF treatment for nAMD, measuring clinically significant levels of depression, anxiety, and post-traumatic stress using the Hospital Anxiety and Depression Scale (HADS) [39] and the Impact of Events Scale–Revised [40]. The study showed that 56% of patients reported anxiety related to the intravitreal injection. The main sources of anxiety included fear of going blind because of having an injection in the eye and worry about treatment effectiveness, rather than fear of pain associated with the injection. The questionnaires indicated that 17 and 12% of patients had clinical levels of anxiety and depression, respectively. The study found that the level of depressive symptoms, but not of anxiety, was significantly higher in patients who received up to three injections than in patients who received 4–12 injections and in patients who received > 12 injections (analysis of variance, P = 0.027 and P = 0.001, respectively). They also found that the frequency of clinical levels of depression (HADS-depression score ≥ 8) decreased with increasing numbers of injections. The authors concluded that patients who receive anti-VEGF therapy often experience with some level of anxiety, despite familiarity with the process from previous injections. On the other hand, depression seemed to be more frequent in patients at early stages of anti-VEGF treatment [33] and as anti-VEGF treatment proceeds, patients can become more optimistic about treatment success and disease stabilization [33].

Another prospective study (conference abstract) examined the determinants of perceived stress and depression after anti-VEGF treatment in 114 people with AMD [30]. Overall, the study found that greater social support at initiation of anti-VEGF treatment was associated with reduced depression at follow-up; a decrease in self-reported visual functioning was related to higher stress level at follow-up, whereas objectively measured VA change was not.