Adherence to Anti-VEGF Treatment in Patients with Neovascular Age-Related Macular Degeneration: A Real-World Study

Age-related macular degeneration (AMD) is a chronic degenerative disorder of the retina, which leads to the progressive loss of central vision [1]. Neovascular AMD (nAMD), otherwise known as wet or exudative AMD, is characterized by aberrant angiogenesis originating from the choroidal or retinal circulation [2]. Neovascular AMD accounts for 7% of blindness worldwide [3] and is responsible for more than 80% of AMD-related vision loss, despite only accounting for approximately 15% of all AMD cases [4]. As such, early diagnosis and treatment of nAMD are essential to prevent permanent vision loss in the affected eye [5].

Intravitreal anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab, aflibercept, and unlicensed bevacizumab, are considered the gold standard for the treatment of nAMD, slowing the pathophysiological progression and reducing the severity of vision loss [6‐8]. Frequent and continuous treatment with anti-VEGFs has been shown to be critical in maintaining visual acuity (VA) and preventing vision loss in patients with nAMD; however, the burden of regular clinic visits on patients and their caregivers is substantial [9, 10]. Regular visits are crucial in maintaining vision gained during the loading phase of treatment, but these visits increase the treatment burden for patients, who tend to be elderly and have mobility issues or other comorbidities. It is also known that in chronic diseases, the absence of persons such as family members or nursing staff accompanying patients to medical appointments adversely affects patients’ adherence [11, 12]. Variation in adherence to anti-VEGF treatment has previously been reported, but its association with functional outcomes is not well established [13‐16]. As such, there is a need for a better understanding of the impact of patients’ adherence to treatment on visual outcomes in real-world clinical practice.

The aim of this retrospective cohort study was to investigate adherence to anti-VEGF treatment in patients with nAMD in a real-world setting.

Overall, 109 patients were included in the study (Fig. 1), 24 of whom had bilateral disease. Hence, 133 patient eyes were included; 129 (97.0%) were adherent and four (3.0%) were non-adherent. All non-adherent patients had unilateral disease. Baseline characteristics of patients are given in Table 1. The mean age in the overall cohort was 80.1 years and 63.9% were women.

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Mean (SD) baseline VA was similar in adherent and non-adherent patient eyes (57.0 [23.6] logMAR letters versus 53.8 [35.3] letters, respectively; Table 2). The mean (range) change in VA by month 12 of treatment was higher in adherent patient eyes (6.3 [− 55–56] letters) than non-adherent patient eyes (− 11 [− 30–0] letters). Figure 2 shows VA over time in patient eyes. In all non-adherent eyes, VA decreased from index date to month 12.

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In total, there were 1403 adherent visits (98.4%) and 23 non-adherent visits (1.6%), with 19 eyes having at least one non-adherent visit (Table 3). Most non-adherent visits (n  = 17/23; 73.9%) occurred between the sixth and twelfth month of treatment. Adherent visits were associated with an overall mean increase in VA of 0.67 logMAR letters at each visit; the greatest increase (2.43 letters) was seen during the loading phase (months 0–3). On the contrary, non-adherence was associated with a mean decrease of − 2.30 letters at each visit, with no VA gains from the previous visit during the loading phase and an overall decline in VA throughout months 3–12.

During the first year of treatment, the median number of injections in adherent patient eyes was 8; the corresponding figure for non-adherent patient eyes was 6 (Table 2). Of the total 1426 visits, 1111 (77.9%) were associated with an injection. The median number of visits that did not result in an injection was 1 per patient eye in adherent patient eyes and 1.5 per patient eye in non-adherent patient eyes (Table 2).

Injection intervals in adherent patient eyes tended to be shorter than those in non-adherent patient eyes. Most (78.2%) injection intervals for adherent visits were 4–8 weeks; however, for non-adherent visits most (72.2%) were 8 weeks or longer (Fig. 3).

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This non-interventional study found a high degree of adherence to treatment overall in a Swiss cohort of patients with nAMD and showed that adherence to anti-VEGF treatments was associated with favorable visual outcomes in real-world clinical practice.

Adherence to anti-VEGFs was found to be very high in the present study (97% of all patient eyes). This finding is consistent with previous studies, which have reported that patients with nAMD are more adherent to treatment than patients with other disorders of the macula, such as diabetic macular edema [15]. Gillies et al. previously suggested that, owing to the paucity of other treatment options for patients with nAMD and the consequences of non-adherence, patients with nAMD may be particularly motivated to be adherent to treatment [18].

Adherent patient eyes were shown to have a mean change in VA from baseline of 6.3 letters after 12 months of treatment: 17.3 letters more than non-adherent patient eyes. Eyes with adherent visits gained vision during the loading phase, with stability or further gains in the months following the loading phase. This is in contrast to patient eyes with non-adherent visits, in which overall there was no vision gain during the loading phase, followed by vision loss between months 3 and 12. Successful completion of a loading phase, as demonstrated here, has previously been shown to predict VA outcomes after 12 months of treatment [19, 20]. Together, these results demonstrate the positive impact of adherence to treatment on patients’ visual outcomes. Since most non-adherent visits occurred between the sixth and twelfth month of treatment, it can be assumed that patients who do not perceive a clinically relevant visual improvement during the loading phase tend to exhibit non-adherence later in the course of treatment. A lack of visual improvement in the loading phase could act as a negative influencing factor on therapy adherence—patient might perceive treatments as not helpful for their condition.

The real-world treatment burden of nAMD on patients and their carers is substantial owing to the frequency of clinical visits, as such, real-world outcomes are rarely as favorable as those reported in randomized clinical trials [21, 22]. Nevertheless, the change in VA observed in adherent patients in the present study is within the range of that reported in randomized controlled trials, and higher than that often reported in real-world studies. The inclusion of the fellow eye, which typically has a higher baseline VA than the first-treated eye, and therefore less opportunity to improve vision, further highlights the noteworthiness of our results.

Overall, 78% of visits to the clinic were associated with an injection. The median number of visits not associated with an injection was only one. The minimal deviation between the number of visits and the number of injections suggests that in the present study, physicians were successfully administering a treat and extend (T&E) protocol similar to that used in randomized controlled trials [7, 8]. Our results are in line with current literature, which suggests that in real-world clinical practice, approximately 80% of visits are associated with an injection [23].

As expected, most (78%) injection intervals for adherent visits were 4–8 weeks, whereas most (72%) were 8 weeks or longer for non-adherent visits. This suggests that an extended injection interval for patients receiving aflibercept or ranibizumab might decrease their likelihood of good visual outcomes. A recent study has similarly shown that delayed treatment has a detrimental effect on VA [24], highlighting that with injection intervals of greater than 3 months, VA can be maintained only in a small minority of patients receiving aflibercept or ranibizumab. Thus, there is an unmet need for alternative treatment options that remain effective with longer injection intervals. This will, in turn, reduce the treatment burden on patients and will allow less-adherent patients to maintain their VA gains following the loading phase. These findings emphasize that if patients are adherent to an adequate dosing regimen (i.e., T&E) and come to the clinic within the critical timeframe, then it is possible to achieve very good visual outcomes in real-world clinical practice. The consequences of non-adherence should be included in patients’ counseling when treatment starts.

The relatively short follow-up period (12 months) may be a limitation of this study; by not including patients with less than 12 months of follow-up, the likelihood of capturing the most adherent patients was increased. Because only 10% of patients were included after implementation of the inclusion and exclusion criteria, the overall number of patients was low for a real-world study. Furthermore, only four patients were non-adherent; hence, results in non-adherent patients should be interpreted with caution. Finally, although there could be the concern of limited generalizability of the results owing to the use of a single medical practice in Switzerland, previous studies carried out in a single center in Switzerland have demonstrated similar outcomes [25].

The adherence rates to anti-VEGF treatment reported in this study were very high. Furthermore, good adherence was associated with favorable visual outcomes, likely to be associated with the use of a T&E protocol. These results demonstrate the importance of adhering to appropriate dosing regimens, such as T&E, for the treatment of nAMD. Physicians should emphasize to patients the importance of good adherence to treatment. Further studies are warranted on the effect of treatment adherence on visual outcomes in a real-world clinical practice, over a longer period.