Background
Diabetic macular edema (DME) is an important cause of visual impairment in patients with diabetes mellitus (DM), which affects greatly the quality of individual’s life [
1‐
3]. Since the prevalence of diabetes worldwide is increasing, DME has become a global health issue [
4,
5]. Laser photocoagulation has once been the standard treatment protocol for DME during the past three decades [
6]. Nowadays, treatment of DME shifts to anti-vascular endothelial growth factor (anti-VEGF) therapy [
7]. Recent randomized multicenter clinical trials have showed the benefits of anti-VEGF therapy on reducing DME and improving patient’s vision [
8‐
11].
Up to now, most of the studies recommend three loading doses of anti-VEGF injections followed by an as needed/pro re nata (PRN) regimen. However, three loading injections would be a great economic and psychological burden for patients with DME, especially for those who in developing countries. Meanwhile, a proportion of patients actually do not need three loading injections and yet maintain good vision over long period. Therefore, “1 + PRN” regimen, namely one anti-VEGF injection at the very first month, followed by an as needed retreatment protocol might be a treatment option for DME. However, this concept of “1 + PRN” regimen has not been well studied. Herein, we reported the functional as well as anatomical responses in eyes with DME treated with ranibizumab under the “1 + PRN” regimen.
Discussion
In this present study, our data showed that intravitreal injections of ranibizumab under “1 + PRN” regimen led to significant improvements in BCVA and reduction of the CFT over 12 months. Besides, our data revealed that older age, poor baseline BCVA, presence of VMT, as well as EZ disruption were more at risk of poor final VA than eyes without these findings, while development of PVD was associated with good final VA at month 12.
VEGF is an important mediator which responses for the abnormal vascular permeability in DME [
14,
15]. Ranibizumab, a recombinant humanized monoclonal antibody for VEGF-A [
16,
17], was approved by FDA for indication of DME in 2012. Many clinical trials, including READ-2 study [
18,
19], the RESOLVE study [
9,
20], the Diabetic Retinopathy Clinical Research Network (
DRCR.net) study [
7,
21,
22], the RESTORE study [
9], the REVEAL study [
23], RISE and RIDE study [
24], and the REFINE study [
11], have demonstrated the safety and effectiveness of IVR for treating DME. In some previous clinical trials, continuous monthly injections of ranibizumab has been recommended, which may optimize the efficacy of treatment [
25]. However, monthly injections are not practical in the real world, therefore, ophthalmologists are now seeking other alternative treatment regimens. Three loading doses of anti-VEGF injections followed by a PRN protocol is now widely adopted by clinicians for treating center-involved DME [
11,
25,
26]. However, three loading injections could still be a great economic and psychological burden for patients with DME, especially for those who live in developing countries. Meanwhile, a proportion of patients actually do not need the three loading injections and yet maintain good vision over long period [
27], therefore, for these patients three loading doses may be unnecessary and would be a waste of money. Recently, ophthalmologists are focus on other treatment modalities like the treat-and-extend regimen [
28] and “1 + PRN” regimen for the management of DME.
There are still very few studies evaluating the effectiveness of “1 + PRN” regimen for treating center-involved DME. In our study, we demonstrated that more than one third of the cases did not need three loading doses at month 3, which was consistent with the findings showed by James et al. [
26]. James reported that 24 out of 180 eyes (13%) need only one injection of ranibizumab, 52 out of 180 eyes underwent 2 injections, and the left 104 eyes had 3 injections on a monthly basis [
26]. Therefore, James considered that there would be considerable reduction in health care cost if one third of patients did not received the three loading doses for treating DME [
26]. Further, in a recent retrospective study, Ebneter et al. compared outcomes of PRN injections based on BCVA versus OCT-based treat-and-extend regimen for DME, and they found that two groups had similar visual acuity outcomes, but patients in the PRN injections group based on BCVA received significantly fewer intravitreal injections than patients in the OCT-based treat-and-extend regimen group [
28]. Specifically, the mean number of the IVR was 6.83 times during the one-year follow-up visit in our study, which was similar with the mean number of 5 times reported by James et al. under “1 + PRN” regimen [
26]. Interestingly, this mean number of 6.83 injections under “1 + PRN” regimen in our study was relatively fewer than the number of 7.9 injections reported by REFINE study [
11] and average 7 injections reported by RESTORE study under “3 + PRN” regimen [
9]. In our study, the logMAR VA improved from 0.64 before treatment to 0.46 at the final visit of month 12, namely increasement of 0.18 logMAR VA, which was similar with “3 + PRN” studies such as REFINE study [
11] and RESTORE study [
9] but lower than the increasement of 0.29 logMAR VA under monthly injection regimen reported by Nepomuceno et al. [
29]. In addition, in our study, the mean CFT decreased from 478.23 μm before treatment to 270.39 μm at final visit of month 12, which was a reduction of 207.84 μm of CFT for the patients over one-year “1 + PRN” treatment. Interestingly, the mean changes of CFT varied in different studies with different treatment regimens. The REFINE study showed a mean reduction of 146.5 μm for CFT after 12 months’ treatment under “3 + PRN” regimen [
11]. The RISE and RIDE study reported a mean reduction of 249.3 μm for CFT after monthly intravitreal injections of ranibizumab for 12 months [
30] while Nepomuceno et al. reported a mean reduction of 126 μm for CFT under monthly injection regimen [
29]. We believed that the mean changes of BCVA and CFT varied not only related to the treatment regimens but also related to other factors such as inclusion criteria and exclusion criteria. Therefore, future randomized controlled clinical trials are still needed to compared the efficacy between “1 + PRN” and other treatment regimens.
It is important for the ophthalmologists to know whether baseline characteristics would predict the final visual outcome for the patients treated by the ranibizumab. Sophie et al. found that good baseline BCVA was a predict factor for final BCVA of 20/40 or better, and submacular fluid and severe cystic edema were predict factors for poor visual outcome without treatment but respond well when treated with monthly IVR [
31]. Channa et al. revealed that poor baseline BCVA predicted poor visual outcomes [
32]. Yucel et al. reported that older age, female, poor BCVA at baseline, VMT, and disruption of EZ were predictors for final poor BCVA prognosis, while PVD and leaking microaneurysms were predictors for the good final BCVA [
27]. Our “1 + PRN” regimen data had similar results with previous studies [
27,
31‐
33]. Interestingly, in our study we found it that although there was statically difference between the SFCT at baseline and SFCT at 12 months’ follow-up time-point after intravitreal injections of ranibizumab under “1 + PRN” regimen, multivariate linear regression analysis demonstrated that SFCT at baseline was not a predictive factor for BCVA at the final visit of month 12. Actually, there is still controversy on the role of SFCT for predicting the VA outcome. Rayess et al. reported that greater baseline SFCT were associated with better anatomic and functional responses [
34]. Similarly, Nourinia et al. reported in their prospective interventional case series that SFCT reduction was correlated with CFT reduction as well as vision improvement [
35]. However, Campos et al. found that baseline SFCT decreased was not a predictor for anatomic or functional outcome for treatment of DME outcome [
36]. In our study, although there was statically difference between the SFCT at baseline and SFCT at month 12 after intravitreal injections of ranibizumab under “1 + PRN” regimen, multivariate linear regression analysis demonstrated that SFCT at baseline was not a predictive factor for BCVA at the final visit of month 12. However, the role of SFCT still requires further investigations.
Our study has some limitations including relatively small number of patients and short-term follow-up visit. Besides, although we have full data of the patients treated with ranibizumab, there was no control group in our study. Even with these limitations, our results have enough strength to conclude that the intravitreal injections of ranibizumab under “1 + PRN” regimen is a safety and effective way to improve BCVA and reduce the CFT of DME patients, which could be an option for the treatment of center-involved DME.
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