Vision-related quality of life in patients receiving intravitreal ranibizumab injections in routine clinical practice: baseline data from the German OCEAN study

Being aware of a patient’s subjective QoL and disease burden, as objectively evaluated using the NEI VFQ-25, is crucial to understand a patient’s anxieties, to encourage compliance with initiated intravitreal anti-VEGF therapy and regular monitoring, as well as to support the physician’s and staff’s empathy. Furthermore, knowing the impact of different contributing factors to QoL scores allows the medical staff to estimate whether QoL can be influenced by the medical therapy itself or by supporting emotional attention [3]. For example, if age or gender had a major impact on QoL, these factors would be non-modifiable. On the other hand, if VA was found to be a key factor for QoL scores, there would be a good chance to improve these scores by adequate medical treatment and emotional attention.

The NEI-VFQ-25 measures the influence of visual disability on general health domains such as emotional well-being, social functioning and daily visual function. It allows judgement of the extent to which eye diseases impact anxiety, routine activities and the interaction with family and friends [20]. Previous research demonstrated a correlation between decreased visual function and depression development, which in turn hampers daily activity [23]. This was identified as one main reason for the high incidence of depressive disorders in patients with advanced AMD, comparable to patients with life-threatening diseases such as cancer or cerebrovascular diseases [24, 25]. In the light of these correlations, baseline VFQ-25 scores can help medical staff to provide patients with optimized medical treatment and emotional attention.

In the NIS OCEAN, 84 % of the large patient population performed the VFQ-25 at baseline and, thus, the results likely reflect the true situation in routine clinical care. In general, patients might be afraid of reporting their significantly reduced QoL and major disease burden to the examining and treating medical staff, especially at a higher age [26]. However, this is important information for judging patients’ mental strain, for providing psychological support and for increasing compliance, which will result in better visual outcomes and, consequently, in an improved QoL [23] during and after intraocular anti-VEGF treatment.

Previous reports evaluated the impact of treatment outcomes of better-seeing (BSE) and worse-seeing eyes (WSE) on VFQ-25 results. It was shown that an impaired QoL is even evident if only one eye is affected by the underlying disease, with unimpaired vision of the BSE [27]. Thus, the WSE appears to have a noticeable influence on QoL, contrary to the common assumption that the BSE mostly determines QoL. However, the “AMAs Guides to the Evaluation of Permanent Impairment” weighted average gives a factor of 0.75 to the BSE and of 0.25 to the WSE [26], stressing the importance of the BSE [28]. Impaired vision in the WSE per se might reduce QoL due to fears of losing vision in the BSE as well [27]. QoL can even be affected prior to vision loss due to a patient’s emotional reaction to diagnosis and treatment [29]. A recent study finally demonstrated that improvements in QoL scores were not significantly associated with the treatment of either WSE or BSE. Only VA improvements in the treated eye, irrespective of WSE or BSE status, were associated with an increase in QoL [15, 30]. Unfortunately, there is no distinction between WSE and BSE in the OCEAN study.

The comparison of the OCEAN VFQ-25 baseline scores with the results of former published phase III clinical trials of intravitreal ranibizumab for the treatment of nAMD, DME, and macular edema due to RVO is of clinical interest (Additional file 1: Table S1). Baseline VFQ-25 outcomes in MARINA/ANCHOR disclosed overall scores of 57.6/52.0 for the BSE as well as 78.3/79.4 for the WSE. This in turn emphasizes the impact of VA reduction on QoL in the BSE [15]. The mean OCEAN baseline score (irrespective of the treatment of BSE or WSE) of 72.8 in treatment-naïve nAMD patients is in between these MARINA/ANCHOR scores but closer to the results for the WSE. The same interrelation can be obtained for almost all subscale scores [15]. In patients suffering from DME, the overall VFQ-25 composite score at baseline was about 66 (BSE: 52 to 60) in a recent exploratory post hoc analysis of the RISE and RIDE data [16]. The corresponding baseline score of 78.5 in treatment-naïve DME patients in the OCEAN study is distinctly higher, even if compared to the composite score of 69 to 74 for the WSE in RISE/RIDE [16]. This correlation is seen for almost all subscale scores, especially for social function, mental health and dependency [16]. Patients with macular edema due to RVO (CRVO or BRVO) showed baseline VFQ-25 composite scores of between 76 and 77 in the BRAVO/CRUISE trials [17]. In OCEAN, the analogous scores are slightly higher with 79.9 to 82.5 points. Comparable results are seen for most subscale scores, while dependency, mental health and role limitations have notably higher scores in OCEAN.

In summary, these data show that VFQ-25 composite scores and especially emotional well-being as well as social functioning subscale scores (e.g. social functioning, mental health, role limitations and dependency) have increased from the initial phase III clinical trials of intravitreally applied anti-VEGF substances to today’s routine clinical care. This could on the one hand reflect the awareness and the increased expectations of patients suffering from neovascular eye disorders with respect to this innovative treatment option. This is supported by the comparison of VFQ-25 baseline scores from the OCEAN study with QoL evaluations prior to the era of anti-VEGF therapies. For instance, VFQ-25 scores were tremendously lower in patients with nAMD when only PDT or macular surgery were available [23], in patients with diabetes when focal or grid laser treatment were the only options to treat DME [31], as well as in RVO-affected eyes [32] when merely laser treatment and surgery for severe cases (e.g. vitrectomy in combination with radial optic neurotomy [RON] or arterio-venous sheathotomy [AVS9] [33]) were available. Thus, intravitreally injected anti-VEGF substances have, besides anatomic and functional considerations, a major impact on social and mental aspect and can distinctly increase patient QoL. On the other hand, these increased VFQ-25 composite and subscale scores herein might be attributed to a better baseline BCVA as compared with the pivotal phase III clinical trials (Additional file 2: Table S2).

All clinical trials mentioned above demonstrated not only medical improvements (e.g. in BCVA, central retinal thickness [CRT]), but also a significant increase in QoL scores during and after anti-VEGF treatment [15‐17], further supporting the beneficial effect of intravitreally applied anti-VEGF substances. This effect can be useful to reduce anxieties and to encourage patients’ compliance.

As analysed herein, the OCEAN baseline VFQ-25 scores show no major differences between indications overall. However, a tendency towards a more decreased visual function for nAMD in comparison to DME and RVO patients is noted. As the indication per se cannot be modified, there is almost no scope for QoL improvement in this respect. Especially nAMD patients with severe bilateral affection have serious difficulties in performing most vision-dependent daily activities (e.g. reading, seeing well close up and navigating around their homes and neighbourhoods) due to loss of central vision [5]. This causes distinctly low subscale scores for dependency, role limitations, mental health and social function, all of which demonstrate the potential isolating effect of bilateral severe AMD [5]. Considering this, medical staff should encourage patients to demand psychological support, if needed, or to attend meetings of specialized support groups, for instance. Patients suffering from DME showed comparable scores to nAMD patients, but a significantly worse VFQ-25 composite score in comparison to glaucoma or cataract patients and in comparison to a healthy reference group [20]. Furthermore, DME-affected type II diabetics were significantly more affected overall than type I diabetics [20]. The severity of peripheral retinal alterations (diabetic retinopathy, DR) showed an immediate impact on QoL scores. Especially the progression from unilateral to bilateral non-proliferative diabetic retinopathy (NPDR) caused most substantial decreases [34]. If DR progresses to the proliferative variant (PDR), a patient can lose 25 to 30 VFQ-25 points in comparison to NPDR patients, especially in the “mental health” category [26]. Finally, lower VFQ-25 scores were independently associated with poorer VA, older age and a history of loss of tactile sensation as a marker of advanced systemic diabetic alterations [35]. Another publication demonstrated that, in eyes with BRVO, QoL was significantly less affected than in nAMD and DME eyes. This difference was attributed to the one-sided event in RVO; whereas diabetic changes and nAMD most frequently occur on both sides during the course of disease [36].

With respect to the impact of patients’ age on QoL, no major differences are found between the age groups in OCEAN. There is a tendency towards decreased visual function with increasing age, particularly in patients 75 years or older. This observation is supported by previous investigations [1, 5], demonstrating a significant age-dependency of VFQ-25 scores by approximately 1.0 point for every life decade [1]. In patients suffering from severe bilateral AMD, QoL tended to correlate negatively with increasing patient age and duration of vision loss, especially for quality of vision and vision-related QoL subscales [5]. Depression might occur more frequently in older patients and it was formerly demonstrated that depression interferes with VFQ-25 scores, irrespective of VA impairment [37]. This is of importance because the proportion of older patients will increase in the future [38].

In OCEAN, no major differences between VFQ-25 scores by gender are detected. A tendency towards a more decreased visual function for females is observed. However, in the OCEAN study, females are older than males (≥75 years: 748 [50 %] males, 1179 [61.9 %] females at baseline) and this age difference might be reflected in the gender difference. Other investigations reported better VFQ-25 scores in females than in males [39].

With regard to the impact of baseline BCVA on VFQ-25 scores, no major differences between groups are detected in OCEAN. There is a tendency towards a more decreased visual function for patients with a lower baseline VA. This observation is in accordance with former findings describing a major impact of BCVA on QoL [19, 30, 35, 40, 41]. A summary of the mean baseline BCVA values in OCEAN and selected clinical trials is provided in Additional file 2: Table S2. As BCVA at the beginning of any therapy might only be influenced marginally by the medical staff involved, attention should be shifted towards the following intervention period. Former investigations demonstrated that in all neovascular diseases discussed herein, BCVA increased significantly during anti-VEGF treatment [42‐46], along with significant improvements in VFQ-25 scores [15‐17, 19, 40, 47, 48]. This in turn can nourish patients’ hope that the impaired BCVA (and QoL) will improve further. Treatment outcomes are often less good in routine clinical care than in phase III clinical trials because the treatment population is more diverse and treatment tends to be less intense [19, 30, 40, 49]. Nevertheless, a strict anti-VEGF treatment, possibly including a treat-and-extend strategy [41, 50], has the potential to significantly increase the medical and mental condition of patients, to reduce anxiety, prevent depression development and to support therapeutic compliance. An analysis of the VFQ-25 changes in OCEAN during and after the treatment period, in relation to therapeutic success, will be reported separately after completion of the ongoing study.

Overall, no major differences of VFQ-25 scores are detected in OCEAN with respect to the type of health insurance (private versus statutory health insurance). However, there is a tendency towards a more decreased visual function for statutorily insured patients. This is of interest because the type of health insurance might have an impact on QoL scores due to patients’ expectations to receive better medical care in private health insurance. However, this could not be demonstrated herein and is only addressable to some extent.

The ANOVA analysis shows that, besides age and gender, the eye-specific contributing factors (indication, baseline VA, interactions of age and indication as well as baseline VA and indication) have a significant impact on the composite as well as on general and distance vision subscale scores. Especially the general and distance vision scores, as assessed by an ophthalmologist, are of fundamental importance for patients’ ability to drive.