Ranibizumab for Neovascular AMD in Eyes With Good Vision
Ranibizumab for Neovascular AMD in Eyes With Good Vision
The prevalence of visual impairment due to AMD in UK has been estimated from 3.5% to 16% in those older than 75 or 77. It is assumed that approximately 400 000 people are registered blind or partially sighted in Great Britain due to AMD. The visual impairment and need for continuous treatment associated with nAMD causes a significant burden at individual and societal level. Therefore, earlier treatment that leads to the maintenance of better visual function may be critical in reducing the visual impairment related to AMD.
To date, the focus on outcomes of treatment of nAMD has been on change in VA from baseline. However, change in VA alone is not a good indicator of patients' visual function and perception of their quality of life. Instead, the maintenance of a good functional visual state that allows continued reading and driving is of greater importance. Thus, rather than the absolute gain in VA, the duration that one can maintain good VA or reasonable visual function should be emphasised and taken into consideration when evaluating the benefits of any therapy for nAMD.
NICE currently does not recommend funding for eyes with good VA (better than 6/12), which may result in some patients having to wait for their vision to drop below 6/12 to initiate therapy. The permitted VA for driving in UK is approximately 6/12, thus the ability to achieve and maintain VA equal or greater than 6/12 is critical in many of our patients. This study shows the importance of earlier treatment stratified by baseline VA. We demonstrate that the earlier treatment group with baseline VA is better than 6/12 is associated with better visual outcome and the longer maintenance of good VA without significant increase in the number of clinic visits or injections compared with the delayed treatment group.
The overall VA outcome is better in eyes treated when baseline VA is better than 6/12 compared with those with initial VA 6/12 to 6/24. This difference is significant for 2 years when sub-grouped into first eyes and for 3 years in second eyes. In addition, the second eyes tend to have better visual outcome than the first eyes as shown previously. The assumption is that there is a lower threshold to treat the second eye from the physician and the patient: the patient may monitor symptoms more regularly, and he or she may be under a closer follow-up regimen due to ongoing treatment of the first eye. Indeed, our data support better visual outcomes in second treated eyes. The difference in mean VA for baseline VA better than 6/12 vs 6/12 to 6/24 was still significant at the end of 3 years for the second eyes. Thus, second eyes that are treated at better VA maintain better VA for longer periods than first eyes. Interestingly, the patients whose second eyes were treated when VA was better than 6/12 were the only group that maintained similar VA to their baseline VA at the end of 3-year period (figure 4). Even though the visual outcome of the eyes with baseline VA better than 6/12 was better than the rest of the group, there was no difference in the number of visits or injections.
There are several studies supporting that visual outcome is better when treatment is initiated early. The time elapsed between the initial diagnosis of nAMD and treatment has been shown to correlate with the progression of visual loss. Weingessel et al reported worse VA at baseline, 6 and 12 months in patients with nAMD who had visual symptoms for longer period. Similarly, Canan et al demonstrated significantly better visual outcome in patients who had visual symptoms less than 1 month vs more than 1 month.
The pivotal trials have shown that, over extended time periods, the VA and function of patients with nAMD continue to deteriorate despite regular treatment. Even though all patients continue to decrease with time in terms of their VA, the amount of time that they retain relatively good VA is critical for each patient. Figure 4 shows that the patients who started their treatment earlier when VA was better than 6/12 retained better VA at year 1, 2 for first eyes and year 1, 2, 3 for second eyes when compared with worse baseline VA groups. However, the decreasing trend is similar to the rest of the group as expected from the results of trials.
In two recent reports, Muether et al showed the outcome in a cohort of patients in Germany whose public health insurance allows ranibizumab only after reviewing each individual case. This approval process leads to a delay in treatment and their results showed significantly more distance ETDRS VA loss during the wait period than the letters gained during the consecutive therapy (p=0.046). A similar trend was shown for near ETDRS VA but this was not significant (p=0.219). In the UK, patients who do not meet the upper limit VA criteria may be obligated to wait and are therefore at risk for losing more VA during latency than what they will regain during consecutive treatment. The longer they wait with symptoms, the worse the visual outcome as shown in multiple reports.
Our data emphasise the importance of early detection and frequent surveillance. Interestingly, the visual outcomes of the first eye being treated at VA better than 6/12 vs the second eyes at better than 6/12 vision are not the same. Despite similar initial VA at the time of initiation of therapy, the first eyes did worse than the second eyes at 3 years. Presumably, all patients treated for their first eyes had visual symptoms at presentation. Some delay between initial symptoms and subsequent first treatment is likely based on NHS referral patterns. In contrast, second eyes may be initiated on treatment due to OCT abnormalities that are noted during regular follow-up for patients' first eyes. They may or may not have been symptomatic at the time of treatment. Therefore, it is reasonable to infer that the second eyes are treated at an earlier disease state than the first eyes even if VA measurement cannot detect the difference.
Given the correlation of better visual outcome with earlier detection, closer surveillance methods should be explored in patients with nAMD. Ideally, these methods would allow frequent, easy monitoring at the patient's own home and at the same time be specific enough to identify nAMD progression.
The main strength of this paper is the completeness of the data set by routine use of an EMR, which records all standardised data from each clinic visit. The data set represents real-world practice pattern and patients' outcome rather than from population studies or clinical trials. Nevertheless, limitations of this study are that it is retrospective in analysis (although the data is collected prospectively) and only includes UK hospitals that share the same EMR system. The results may not be as applicable in other countries that do not have similar treatment protocols or exclusion criteria. However, this provides real-world data that reflects daily clinical practice pattern rather than the protocols from the pivotal trials. There are few previously reported real-world data studies that provide insights into interpreting and incorporating the RCT data into daily clinical practice. In addition, this is the first study that demonstrates the visual outcome values in patients whose initial VA were excellent, given that these patients were excluded from most of the pivotal trials.
To our best knowledge, this is the first and largest study thus far reported in the literature to focus on the visual outcome of patients with baseline VA better than 6/12. This study supports the immediate treatment of nAMD when patients still maintain good vision. The cost-effectiveness of this early treatment to the healthcare system will be an important consideration and will be explored in a subsequent study. The study highlights important differences in the characteristics of the eyes with initial VA better than 6/12: significantly better mean VA compared with those with baseline VA 6/12 to 6/24 and the maintenance of this difference at 2 years for first eyes and 3 years for second eyes. This study may help inform future policy decision regarding the routine access to ranibizumab at visual acuities better than 6/12.
Discussion
The prevalence of visual impairment due to AMD in UK has been estimated from 3.5% to 16% in those older than 75 or 77. It is assumed that approximately 400 000 people are registered blind or partially sighted in Great Britain due to AMD. The visual impairment and need for continuous treatment associated with nAMD causes a significant burden at individual and societal level. Therefore, earlier treatment that leads to the maintenance of better visual function may be critical in reducing the visual impairment related to AMD.
To date, the focus on outcomes of treatment of nAMD has been on change in VA from baseline. However, change in VA alone is not a good indicator of patients' visual function and perception of their quality of life. Instead, the maintenance of a good functional visual state that allows continued reading and driving is of greater importance. Thus, rather than the absolute gain in VA, the duration that one can maintain good VA or reasonable visual function should be emphasised and taken into consideration when evaluating the benefits of any therapy for nAMD.
NICE currently does not recommend funding for eyes with good VA (better than 6/12), which may result in some patients having to wait for their vision to drop below 6/12 to initiate therapy. The permitted VA for driving in UK is approximately 6/12, thus the ability to achieve and maintain VA equal or greater than 6/12 is critical in many of our patients. This study shows the importance of earlier treatment stratified by baseline VA. We demonstrate that the earlier treatment group with baseline VA is better than 6/12 is associated with better visual outcome and the longer maintenance of good VA without significant increase in the number of clinic visits or injections compared with the delayed treatment group.
VA Outcomes of Eyes Treated at Better Baseline Visual Acuities
The overall VA outcome is better in eyes treated when baseline VA is better than 6/12 compared with those with initial VA 6/12 to 6/24. This difference is significant for 2 years when sub-grouped into first eyes and for 3 years in second eyes. In addition, the second eyes tend to have better visual outcome than the first eyes as shown previously. The assumption is that there is a lower threshold to treat the second eye from the physician and the patient: the patient may monitor symptoms more regularly, and he or she may be under a closer follow-up regimen due to ongoing treatment of the first eye. Indeed, our data support better visual outcomes in second treated eyes. The difference in mean VA for baseline VA better than 6/12 vs 6/12 to 6/24 was still significant at the end of 3 years for the second eyes. Thus, second eyes that are treated at better VA maintain better VA for longer periods than first eyes. Interestingly, the patients whose second eyes were treated when VA was better than 6/12 were the only group that maintained similar VA to their baseline VA at the end of 3-year period (figure 4). Even though the visual outcome of the eyes with baseline VA better than 6/12 was better than the rest of the group, there was no difference in the number of visits or injections.
There are several studies supporting that visual outcome is better when treatment is initiated early. The time elapsed between the initial diagnosis of nAMD and treatment has been shown to correlate with the progression of visual loss. Weingessel et al reported worse VA at baseline, 6 and 12 months in patients with nAMD who had visual symptoms for longer period. Similarly, Canan et al demonstrated significantly better visual outcome in patients who had visual symptoms less than 1 month vs more than 1 month.
Time to Losing 6/12 Vision
The pivotal trials have shown that, over extended time periods, the VA and function of patients with nAMD continue to deteriorate despite regular treatment. Even though all patients continue to decrease with time in terms of their VA, the amount of time that they retain relatively good VA is critical for each patient. Figure 4 shows that the patients who started their treatment earlier when VA was better than 6/12 retained better VA at year 1, 2 for first eyes and year 1, 2, 3 for second eyes when compared with worse baseline VA groups. However, the decreasing trend is similar to the rest of the group as expected from the results of trials.
In two recent reports, Muether et al showed the outcome in a cohort of patients in Germany whose public health insurance allows ranibizumab only after reviewing each individual case. This approval process leads to a delay in treatment and their results showed significantly more distance ETDRS VA loss during the wait period than the letters gained during the consecutive therapy (p=0.046). A similar trend was shown for near ETDRS VA but this was not significant (p=0.219). In the UK, patients who do not meet the upper limit VA criteria may be obligated to wait and are therefore at risk for losing more VA during latency than what they will regain during consecutive treatment. The longer they wait with symptoms, the worse the visual outcome as shown in multiple reports.
Importance of Early Detection
Our data emphasise the importance of early detection and frequent surveillance. Interestingly, the visual outcomes of the first eye being treated at VA better than 6/12 vs the second eyes at better than 6/12 vision are not the same. Despite similar initial VA at the time of initiation of therapy, the first eyes did worse than the second eyes at 3 years. Presumably, all patients treated for their first eyes had visual symptoms at presentation. Some delay between initial symptoms and subsequent first treatment is likely based on NHS referral patterns. In contrast, second eyes may be initiated on treatment due to OCT abnormalities that are noted during regular follow-up for patients' first eyes. They may or may not have been symptomatic at the time of treatment. Therefore, it is reasonable to infer that the second eyes are treated at an earlier disease state than the first eyes even if VA measurement cannot detect the difference.
Given the correlation of better visual outcome with earlier detection, closer surveillance methods should be explored in patients with nAMD. Ideally, these methods would allow frequent, easy monitoring at the patient's own home and at the same time be specific enough to identify nAMD progression.
The main strength of this paper is the completeness of the data set by routine use of an EMR, which records all standardised data from each clinic visit. The data set represents real-world practice pattern and patients' outcome rather than from population studies or clinical trials. Nevertheless, limitations of this study are that it is retrospective in analysis (although the data is collected prospectively) and only includes UK hospitals that share the same EMR system. The results may not be as applicable in other countries that do not have similar treatment protocols or exclusion criteria. However, this provides real-world data that reflects daily clinical practice pattern rather than the protocols from the pivotal trials. There are few previously reported real-world data studies that provide insights into interpreting and incorporating the RCT data into daily clinical practice. In addition, this is the first study that demonstrates the visual outcome values in patients whose initial VA were excellent, given that these patients were excluded from most of the pivotal trials.
To our best knowledge, this is the first and largest study thus far reported in the literature to focus on the visual outcome of patients with baseline VA better than 6/12. This study supports the immediate treatment of nAMD when patients still maintain good vision. The cost-effectiveness of this early treatment to the healthcare system will be an important consideration and will be explored in a subsequent study. The study highlights important differences in the characteristics of the eyes with initial VA better than 6/12: significantly better mean VA compared with those with baseline VA 6/12 to 6/24 and the maintenance of this difference at 2 years for first eyes and 3 years for second eyes. This study may help inform future policy decision regarding the routine access to ranibizumab at visual acuities better than 6/12.
