Consequences of long-term discontinuation of vascular endothelial growth factor inhibitor therapy in the patients with neovascular age-related macular degeneration.

Abstract

Age-related macular degeneration (AMD) is the commonest cause of blindness in the developed world mainly affecting the people over the age of 50 years. As the treatment of neovascular AMD places a substantial burden on the economy and the healthcare system, research into how this load might be reduced is of high practical clinical significance. The two pivotal trials, MARINA (Rosenfeld et al. 2006) and ANCHOR, (Brown et al. 2009) demonstrated the efficacy and safety of monthly ranibizumab (Lucentis - Genetech/Roche, South San Francisco, USA) injections for the preservation and improvement in visual acuity using a fixed monthly dosing regimen. The ongoing nature of this treatment has led to studies of dosing regimens designed to reduce the treatment load while maintaining good treatment outcomes. The present report indicates that there is a high risk of recurrence after suspending intravitreal VEGF inhibitors for neovascular AMD, even if the lesion has been inactive for 3 months. Careful, indefinite follow-up of all patients who appear to have been successfully treated is necessary to detect recurrence early. This was a retrospective review of observational study data of a single Australian private practice. Patients in whom treatment with intravitreal ranibizumab or bevacizumab was discontinued for more than 3 months during a 3-year period from March 2006 to April 2009 were included in the analysis. Of 115 eyes of 103 patients, 105 (91%) eyes of 93 patients (35 male; 90 Caucasians, three Asians with mean age of 81.6 [range, 50 to 95] years) developed reactivation of choroidal neovascular lesion with a significant decline in the mean visual acuity from 58.2 letters at the time of last injection to 50.2 letters at the time of recurrence (p < 0.001, paired t test). Eighty-two per cent recurrences were picked up on routine fixed interval examination, while 18% returned earlier with metamorphopsia or decrease in vision. The mean number of injections received by this group before the treatment was discontinued was 5.6 (range, 3.0 to 22.0). Kaplan–Meier survival analysis (Fig. 1) showed that the median time to recurrence in all eyes with lesion recurrence after treatment discontinuation for more than 3 months was 33.1 weeks (95% CI: 28.1 to 40.9). Subgroup analysis based on the angiographic type and size of the lesion did not show any significant difference in the time to reactivation (p = 0.47 and 0.26, respectively, log-rank test). Only 9% of eyes did not show any signs of reactivation without significant change in vision with a mean follow-up of 18 months. Due to ongoing nature of the treatment, determining the optimal dosing schedule for intravitreal therapy for neovascular AMD remains a challenge. Various approaches such as pro re nata and treat-and-extend regimens have been tried, but an optimal regimen has yet to be established. Even though patients treated with these regimens received fewer injections, the rate of recurrence over a longer period of time was higher (Fung et al. 2007; Dadgostar et al. 2009). A recent study reported a mean recurrence interval time of 5.5 ± 3.4 months, with no difference in the eyes with regular or irregular recurrence intervals. (Horster et al. 2011). Our study, aimed at identifying the subset of patients that might be able to discontinue treatment or be treated less frequently, indicates that the risk of recurrence is high (91%) on long-term treatment discontinuation. It might not be advisable to discharge patients or consider them ‘cured’ despite no signs of activity for even a year. Further research is warranted to determine at what intervals capped injections need to be performed to prevent long-term recurrences in eyes with a good initial response to treatment.