We observed a prolongation of the injection interval after switching to aflibercept and shortening of injection interval after switching to ranibizumab. These findings suggest that the prolongation and shortening of the injection interval were related to a difference in the duration of effectiveness of the two agents.
In the R to A group, average injection interval before the switch was 85 days, and it increased significantly to 126 days after the switch. The increase in the injection intervals was 41 days which is 1.48 times longer than the average injection interval during the pre-switch period. In a prospective study, Casselholm et al compared the injection intervals for ranibizumab and aflibercept in eyes with a CRVO performed with the treat-and-extend protocol. They reported that the average injection interval for ranibizumab was 6.6 week and that for aflibercept was 10.0 weeks. These findings indicated that the effects of aflibercept lasted 1.5X longer than ranibizumab. Thus, their findings are comparable to our percentage prolongation of the injection interval in the R to A group.
There have been many studies on the effectiveness of switching from ranibizumab to aflibercept in patients with macular edema secondary to a BRVO. The patients studied can be classified into two types; one type is the patient who was not responding to ranibizumab and were then switched to aflibercept,[5,9,10] and the other type was the patient who had a difference in the duration of the effectiveness between two agents as indicated by the lengthening of the interval after switching to aflibercept. The difficulty in comparing these results is that there is a spontaneous healing in more than 30% of cases if macular edema secondary to BRVO develops within one year after the onset of BRVO. The RELATE study examined patients who had received ranibizumab treatment with a loading phase of 6 PRN injections for 3 years, and they found that the number of injections required for successful treatment decreased with time; 9.7 times in the first year, 6.9 times in the second year, and 4.0 times in the third year. Thus, we cannot eliminate the possibility that the prolongation of injection interval after switching to aflibercept was related to a natural attenuation of the disease progression. Therefore, after switching to ranibizumab, a prolongation of injection interval could also be expected. However, to our knowledge, there have been no studies performed to evaluate the change in the injection interval after switching therapy from aflibercept to ranibizumab in patients with BRVO. In our cases, in the A to R group, average injection interval before the switch was 104 days and after the switch to ranibizumab was 86 days. Therefore, the difference between the two injection intervals is 18 days, that is, 1.21 times shorter than the average injection interval after switching to ranibizumab. The results showed no prolongation of injection interval due to a time-dependent attenuation of the natural progression of the disease process.
The reason for the longer effectiveness of aflibercept is because it has different biochemical characteristics from ranibizumab. For example, aflibercept can bind not only to VEGF-A but also to other VEGF family members, such as VEGF-B and placental growth factor (PlGF). In addition, aflibercept has a strong affinity for VEGF-A. The intraocular PlGF levels are elevated in patients with macular edema secondary to BRVO suggesting that it may be involved in the recurrence of macular edema. In animal experiments, Stewart et al. reported that aflibercept had longer binding activity than ranibizumab. In addition, Niwa et al. compared the intraocular kinetics of ranibizumab and aflibercept after intravitreal injections in monkeys. They reported that the half-life of both agents in the aqueous after intravitreal injections was not significantly different, but aflibercept suppressed the VEGF level for a longer time. From these results, we can conclude that aflibercept has a longer period of effectiveness. This was true even after the agents decreased below the detection level which suggested that aflibercept has a better potential of preventing the recurrence of macular edema. Saishin et al. examined the effects of intravitreal injections of ranibizumab and aflibercept bimonthly on CRVO patients, and they reported that the CRT measured at the time of recurrence was thicker in the ranibizumab than the aflibercept group. Their findings are consistent with the results of our study in showing the difference in the CRTs at the time of recurrence in the R to A group.
In conclusion, the injection interval can be different between ranibizumab and aflibercept in patients with macular edema secondary to BRVO. Because the difference of injection interval affects patient’s medical cost, economic, or psychological burden, it is necessary to focus on the selection of agents for BRVO treatment as well as relieving the effects of macular edema by the anti-VEGF agents.
Our study was limited due to its retrospective nature and small sample size. Another limitation is the different assessment period among pre-switching and after switching agents. On one hand, a one-year assessment period was set before switching agents, but the assessment period after switching agents was not the same as the one before switching agents. This is because patients have a tendency to ask physicians to switch back to the previous one when a shortening of the injection interval occurs due to switching agents. This indicates that the prolongation or shortening of the injection interval becomes a sufficient reason for patients to select the agent.