Neovascular age-related macular degeneration: Insights into treatment

This thesis describes the treatment of exudative ARMD with bevacizumab. Initial therapy of bevacizumab for exudative ARMD has mimicked the registration trials of ranibizumab, which mainly concentrated on either continues or on-demand every 4 weeks therapy. The main object of the thesis was to evaluate the viability of less frequent bevacizumab dosage regiments. Furthermore, the reactivation interval of CNV was observed, and we delved deeper into a specific kind of CNV and its characteristics using a novel diagnostic technique.

Chapter 1, is general introduction to ARMD. It describes the function of the eye, the retina and, in particular the macula. The macula is the main location of the disease ARMD. ARMD can be broadly divided into dry ARMD and exudative ARMD. This thesis mainly concentrates on the disease process of exudative ARMD. Current golden standard for diagnosing exudative ARMD is based on the
clinical signs seen in fundoscopy, the OCT characteristics, and evaluation with FA/ICG. Intravitreal injections of anti-VEGF have taken a firm place in the therapy of exudative ARMD. While, there are several types of anti-VEGF variants available for the treatment of exudative ARMD, at present time the cheapest, and arguably most cost-effective option is bevacizumab.

Chapter 2, describes our randomized controlled trial on the effect of bevacizumab injections every 4 weeks, 6 weeks and 8 weeks for the treatment of exudative ARMD. Visual acuity gain and reduction in CFT at 1 year were comparable for all 3 treatment groups. This study showed the viability of treating patients with exudative ARMD, in less frequent fixed dose injection regimens than the standard fixed dose every 4 weeks.

Chapter 3, in this chapter we compare on-demand every 4 weeks to on-demand every 8 weeks therapy of bevacizumab for exudative ARMD. In chapter 2 the study concentrates on a continues schedule of bevacizumab wherein the time between injections was only varied. However, injections were obligatory in that study on either a 4 weekly, 6 weekly or 8 weekly frequency for 1 year. In this
on-demand study, at each study visit it was evaluated if an injection was needed. Each study visit was either every 4 weeks or every 8 weeks. The results show that visual acuity gain and reduction in CFT at 1 year were comparable for either every 4 weeks or every 8 weeks on-demand.

Chapter 4, in this study we evaluated the QoL in patients that participated in the study of chapter 2. The generic quality of life instrument SF-6D was used. Usually in QoL evaluations in ophthalmic patient the utility of VA gain in the worst seeing eye is reported as negligible. However, in our study we found there is an effect in treating the worst seeing eye in exudative ARMD on the QoL. The implications of this study are that future economic analysis of exudative ARMD should take into
account the treatment results of both eyes, not just the better seeing eye.

Chapter 5, looked at the impact of different therapy frequencies of bevacizumab for the treatment of exudative ARMD on the QoL. NEI VFQ-39 and SF-36 were used to assess QoL at baseline and at one year. We found non-inferiority on general and vision-related QoL in patients treated with every 6 and 8 weekly fixed dose compared to 4 weeks. Whilst these results are very encouraging, the power of the study meant that only large differences would have been detected.

Chapter 6, an important conundrum in the therapy of exudative ARMD is tackled. What are the prospects when anti-VEGF therapy is halted? In this study all patients with inactive CNV at the end of the study that was described in chapter 3 were observed, to evaluate the reactivation interval after discontinuation with anti-VEGF. The result show that 67% of patient with inactive CNV have a recurrence in the first year after discontinuation, and that most of these recurrences take place in the first 6 months. It is therefor, very important that even when discontinuing anti-VEGF in an inactive CNV that follow-up must be sufficient, and patients be made aware the recurrence are highly likely.

Chapter 7, delves deeper in type 3 CNV, also known as RAP. This type of exudative ARMD has been known to look and react differently to anti-VEGF than the other types of CNV. The study shows an overview of the features of RAP using Phase-resolved Doppler OCT. This novel technique was able to detect and localize abnormal intra- and transretinal blood flow. A comparison with the ICG findings in the same patients shows that Phase-resolved Doppler OCT is able to pinpoint the RAP lesion, as seen on ICG and provide additional information about the intra- and transretinal blood flow.

Chapter 8, we revisit our initial group of 191 patient that were treated with bevacizumab in a continuous frequency. Treatment frequency was far lower during clinical care, and the mean injection rates varied between 2.9 - 5.5 injection per year. At 10 years follow-up data was available for 69 patients. In 40% of these patient’s visual acuity was stable or better than baseline. We could not show any significant differences in visual acuity outcome at 10years between initial treatment group, baseline vison, baseline fluid type, and CNV type. Which was expected considering the small left over follow-up group.

Chapter 9, pertains the general discussion of this thesis. A main goal of this thesis was to expand our knowledge of less frequent bevacizumab treatment. Our studies showed that treatment of exudative ARMD with bevacizumab either fixed-dose or on-demand can be extended from 4 weeks to up to 8 weeks.