**5. Conclusion**

In this chapter, the three main treatment strategies to treat nAMD were presented and discussed. The first strategy examined was the fixed dose treatment method, where anti-VEGF agents are given on a routine basis, typically monthly or bimonthly after an initial loading phase. The advantage of this method is that it has been proven successful in multiple landmark clinical trials and patients may expect potentially the best visual outcomes. Fixed dosing disadvantages include the lack of individualized treatment with potentially no endpoint and the possibility of being overtreated. There is a potential for more episodes of endophthalmitis with more injections given and the chance for systemic effects, although this is still debated. The next treatment strategy presented was the PRN methodology, where patients are typically given a loading dose of three monthly anti-VEGF injections and then monitoring is begun once the macula is dry. Patients are then

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patients' response.

treatment of nAMD.

*Management Strategies and Visual Results for the Treatment of Neovascular Age-Related…*

treated only after the detection of new-onset decreased vision or increased fluid. The advantage of this treatment methodology is that patients receive fewer injections with potentially fewer systemic and ocular side effects. However, there is the potential for delayed detection of decreased visual or anatomic damage, increasing the risk for undertreatment with this methodology. Visual results of this method have definitely proven inferior compared to other dosing regimens, particularly over the long term. The final treatment strategy presented was the treat-and-extend regimen with its variant treat-extend-stop. After three loading doses of anti-VEGF therapy for nAMD, patients are then extended by 2-week intervals once a dry macular is achieved. In some patients, the therapy is stopped after patients are given two injections 12 weeks apart and held at the third 12-week interval, after which careful monitoring of patients' visual function and macular changes is begun. This personalized anti-VEGF regimen offers the greatest potential for success. The TAE/ TES regimen may be the best choice for managing patients with nAMD, particularly over the long term, regardless of the choice of the anti-VEGF agent. The TAE/ TES method provides comparable visual results to monthly fixed interval dosing, however at a decreased treatment burden and has the potential for decreased adverse events. This proactive and patient-specific method also has many benefits over the PRN strategy, including but not limited to greater visual improvement, better maintenance of visual improvement over the long term, increased potential for disease remission, fewer rates of CNV recurrence, and the ability for recovery of

This chapter also discussed the definition of recurrence versus increased disease activity. Increased disease activity was defined as increased intraretinal or subretinal fluid with potentially decreased vision and increased metamorphopsia that occurred during active treatment. If patients fail to respond to any one agent after 4–6 monthly anti-VEGF injections and still have worsening subretinal or intraretinal fluid, these patients may meet the definition of primary treatment failure and the anti-VEGF agent can be switched. If patients are in the extension part of the TAE/TES protocol and there is increased fluid and exudation, the time interval between treatments should be reduced by 1–2 weeks if there is minimally increased exudation. If there is a significant increase in exudation or hemorrhage, then the time interval should be decreased more aggressively, potentially restarting the TAE/TES protocol. Patients with nAMD likely require at least 1 year of therapy, extended to 12-week treatment intervals, before treatment cessation is considered since there is a subset of patients of whom are delayed responders and may demonstrate increased vision over a longer time frame. A true disease recurrence would be defined as one where a CNV shows increased exudation and hemorrhage after 4 months of no treatment and careful monitoring. This true recurrence rate was found to be 29% in the TES protocol and patients with a true recurrence had overall visual outcomes comparable to their vision at treatment cessation after re-initiation of anti-VEGF treatment. It is likely that partial, poor or non-responders are more inclined to receive consistent treatment at time intervals in the 4–8 week range, and these patients' visual acuity over the long run may be best maintained with this dosing interval. This conservative calibration strategy thus strives to proactively optimize the treatment regimen to the

Additional studies, particularly prospective randomized clinical trials evaluating the response of various treatment methodologies over the long term as well as those exploring the mechanisms underlying clinical outcomes, will help further optimize anti-VEGF therapy and spur the development of novel methods for the

*DOI: http://dx.doi.org/10.5772/intechopen.81466*

vision after recurrence.

*Management Strategies and Visual Results for the Treatment of Neovascular Age-Related… DOI: http://dx.doi.org/10.5772/intechopen.81466*

treated only after the detection of new-onset decreased vision or increased fluid. The advantage of this treatment methodology is that patients receive fewer injections with potentially fewer systemic and ocular side effects. However, there is the potential for delayed detection of decreased visual or anatomic damage, increasing the risk for undertreatment with this methodology. Visual results of this method have definitely proven inferior compared to other dosing regimens, particularly over the long term. The final treatment strategy presented was the treat-and-extend regimen with its variant treat-extend-stop. After three loading doses of anti-VEGF therapy for nAMD, patients are then extended by 2-week intervals once a dry macular is achieved. In some patients, the therapy is stopped after patients are given two injections 12 weeks apart and held at the third 12-week interval, after which careful monitoring of patients' visual function and macular changes is begun. This personalized anti-VEGF regimen offers the greatest potential for success. The TAE/ TES regimen may be the best choice for managing patients with nAMD, particularly over the long term, regardless of the choice of the anti-VEGF agent. The TAE/ TES method provides comparable visual results to monthly fixed interval dosing, however at a decreased treatment burden and has the potential for decreased adverse events. This proactive and patient-specific method also has many benefits over the PRN strategy, including but not limited to greater visual improvement, better maintenance of visual improvement over the long term, increased potential for disease remission, fewer rates of CNV recurrence, and the ability for recovery of vision after recurrence.

This chapter also discussed the definition of recurrence versus increased disease activity. Increased disease activity was defined as increased intraretinal or subretinal fluid with potentially decreased vision and increased metamorphopsia that occurred during active treatment. If patients fail to respond to any one agent after 4–6 monthly anti-VEGF injections and still have worsening subretinal or intraretinal fluid, these patients may meet the definition of primary treatment failure and the anti-VEGF agent can be switched. If patients are in the extension part of the TAE/TES protocol and there is increased fluid and exudation, the time interval between treatments should be reduced by 1–2 weeks if there is minimally increased exudation. If there is a significant increase in exudation or hemorrhage, then the time interval should be decreased more aggressively, potentially restarting the TAE/TES protocol. Patients with nAMD likely require at least 1 year of therapy, extended to 12-week treatment intervals, before treatment cessation is considered since there is a subset of patients of whom are delayed responders and may demonstrate increased vision over a longer time frame. A true disease recurrence would be defined as one where a CNV shows increased exudation and hemorrhage after 4 months of no treatment and careful monitoring. This true recurrence rate was found to be 29% in the TES protocol and patients with a true recurrence had overall visual outcomes comparable to their vision at treatment cessation after re-initiation of anti-VEGF treatment. It is likely that partial, poor or non-responders are more inclined to receive consistent treatment at time intervals in the 4–8 week range, and these patients' visual acuity over the long run may be best maintained with this dosing interval. This conservative calibration strategy thus strives to proactively optimize the treatment regimen to the patients' response.

Additional studies, particularly prospective randomized clinical trials evaluating the response of various treatment methodologies over the long term as well as those exploring the mechanisms underlying clinical outcomes, will help further optimize anti-VEGF therapy and spur the development of novel methods for the treatment of nAMD.

*Visual Impairment and Blindness - What We Know and What We Have to Know*

considered a true recurrence.

treated with a PRN methodology, and there is increased fluid at a time interval of less than 4 months without treatment, again this should be considered increased disease activity. If increased exudation occurs outside of 4 months, this should be

Reports on true CNV disease recurrence are currently limited. Two retrospective studies have reported this phenomenon. In the first, Haddad et al. utilized a PRN dosing method in 132 eyes over an average follow-up of 7.75 years [40]. Eighty-three (63%) eyes experienced long-term remission without requiring treatment for 1 year at least one time during the duration of the study [40]. However, among them, 42 (51%) eyes experienced a true recurrence of CNV [40]. The average vision of the entire cohort improved 5.0 letters after 1 year compared to baseline [40]. However, by the end of 7.75 years, this visual improvement was not maintained and decreased to −3.4 letters below baseline, a total loss of 8.4 letters [40]. Conversely, in a study by Adrean et al., 143 of 385 eyes (37.3%), treated with a TES protocol, experienced long-term disease remission with a minimum treatment cessation period of 4 months [43]. Prior to this time, these eyes were treated with a TES protocol for an average of 33 months [43]. The average initial presenting vision was 20/70 and improved to 20/50 at the completion of the treatment phase, or approximately 7.5 ETDRS letters [43]. The average time to true disease recurrence was 14 months later and occurred in 42/143 (29.4%) eyes [43]. At this point, average vision decreased to 20/60, with 54.8% of eyes experiencing a recurrence without a decrease in vision [43]. However, once eyes were restarted on the TES protocol, average vision recovered to 20/50 and was maintained throughout the remaining average 27 months of follow-up [43]. Although the criteria for remission of disease are different between these two studies, the average time observed of quiescent disease not requiring treatment was around 1 year [40, 43]. Notably different, however, is that the final vision of eyes treated with the more robust TES method was better and was able to be salvaged should a recurrence occur [40, 43]. This is likely due to the undertreatment of active disease that is commonly experienced from PRN methods, even if eyes demonstrate signs of good response [66]. Eyes demonstrating good response under a PRN method may require more vigilant monitoring over a greater period of time before one may conclude that active disease has been controlled. On the other hand, eyes that have received more robust treatment under the TES method may be carefully monitored at longer intervals if good response has been demonstrated throughout the course of treatment for

In this chapter, the three main treatment strategies to treat nAMD were presented and discussed. The first strategy examined was the fixed dose treatment method, where anti-VEGF agents are given on a routine basis, typically monthly or bimonthly after an initial loading phase. The advantage of this method is that it has been proven successful in multiple landmark clinical trials and patients may expect potentially the best visual outcomes. Fixed dosing disadvantages include the lack of individualized treatment with potentially no endpoint and the possibility of being overtreated. There is a potential for more episodes of endophthalmitis with more injections given and the chance for systemic effects, although this is still debated. The next treatment strategy presented was the PRN methodology, where patients are typically given a loading dose of three monthly anti-VEGF injections and then monitoring is begun once the macula is dry. Patients are then

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active disease.

**5. Conclusion**
