|Year : 2020 | Volume
| Issue : 4 | Page : 1144-1149
Treat-and-extend vs pro re nata regimens of aflibercept in diabetic macular edema
Abd E Elsebaey, Asmaa M. A. Ibrahim, Eman A Elshaarawy
Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||02-Mar-2020|
|Date of Decision||21-Mar-2020|
|Date of Acceptance||05-Apr-2020|
|Date of Web Publication||24-Dec-2020|
Eman A Elshaarawy
Source of Support: None, Conflict of Interest: None
The aim of the present study was to compare between two regimens of intravitreal injection of aflibercept in diabetic macular edema (DME): treat-and-extend (T and E) vs pro re nata (PRN).
T and E and PRN (as needed) regimens of intravitreal antivascular endothelial growth factor treatment have been found to reduce the injection burden on patients and improve the cost-effectiveness of the treatment of macular edema.
Patients and methods
This prospective randomized comparative study was conducted on patients with DME, who were randomly divided into two groups. Eyes in group I were treated with T and E regimen of intravitreal injection of aflibercept and eyes in group II were treated with PRN regimen of intravitreal injection of aflibercept.
The mean baseline best-corrected visual acuity (BCVA) was 0.833 ± 0.159 logarithm of the minimum angle of resolution (logMAR) units in patients with T and E protocol and 0.880 ± 0.077 logMAR units in patients with PRN protocol; after the loading dose, the BCVA was improved to 0.673 ± 0.103 logMAR units in patients with T and E protocol and 0.700 ± 0.093 logMAR units in patients with PRN protocol; and after resolving edema, the BCVA was 0.353 ± 0.106 logMAR units in patients with T and E protocol and 0.407 ± 0.096 logMAR units in patients with PRN protocol, with no statistically significant differences between the groups. However, there was a highly statistically significant difference between the groups regarding number of injections (P = 0.005).
Overall, an individualized T and E regimen has the potential to reduce clinic burden and improve patient compliance, while still maintaining effectiveness and providing well-tolerated treatment for DME.
Keywords: aflibercept, best-corrected visual acuity, diabetic macular edema, intravitreal injection, pro re nata and treat-and-extend
|How to cite this article:|
Elsebaey AE, Ibrahim AM, Elshaarawy EA. Treat-and-extend vs pro re nata regimens of aflibercept in diabetic macular edema. Menoufia Med J 2020;33:1144-9
|How to cite this URL:|
Elsebaey AE, Ibrahim AM, Elshaarawy EA. Treat-and-extend vs pro re nata regimens of aflibercept in diabetic macular edema. Menoufia Med J [serial online] 2020 [cited 2021 Apr 19];33:1144-9. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1144/304507
| Introduction|| |
Diabetic macular edema (DME), one of the major complications of diabetic retinopathy (DRP), is also one of the leading causes of visual impairment. DME occurs in nearly 12% of patients with DRP. Duration and type of diabetes directly affect the prevalence rate of DME. Patients can develop DME in the first five years following diagnosis of type I diabetes. The prevalence rate gradually reaches up to 40% within 30 years. Approximately 5% of patients with type II diabetes already have DME at the time of diagnosis,. DME is defined as retinal thickening within one disk diameter of the center of the macula or definite hard exudates in this region. Clinically significant macular edema is the situation in which at least one of the following criteria is fulfilled: retinal thickening within 500 μm of the center of the macula, hard exudates within 500 μm of the center of the macula with adjacent retinal thickening, and one disk area of retinal thickening, where any part of which is within one disk diameter of the center of the macula. The pathogenesis of DME has not been thoroughly defined because there are complex processes with various contributing factors. Chronic hyperglycemia, hypercholesterolemia, free oxygen radicals, and protein kinase C are involved in the pathologic process. The common characteristic is the increase in levels of vascular endothelial growth factor (VEGF), which is responsible for the disruption of the inner blood–retinal barrier (BRB). Disruption of the BRB leads to the accumulation of subretinal and intraretinal fluid, which in turn alters the macular structure and function. Leukocyte chemotaxis to vascular endothelium is another element of BRB breakdown and vascular leakage.
Anti-VEGF drugs are effective at improving vision in people with DME, with three to four in every 10 people likely to experience an improvement of 3 or more lines visual acuity (VA) at 1 year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DME at 1 year in visual and anatomic terms. Relative effects among anti-VEGF drugs at 2 years are less well known, as most studies were short term.
The treat-and-extend (T and E) dosing regimen is a strategy that aims to resolve macular exudation and maintain the macula in a 'dry state,' with, where possible, fewer patient visits for investigation and treatment as compared with monthly dosing. The regimen involves an initial loading sequence of at least three monthly injections until a maximal clinical response is observed. As long as VA is stable, treatment intervals are gradually increased by 2 weeks. If there are any changes, treatment intervals are shortened by 2 weeks. The T and E dosing therefore offers a practical solution to reduce treatment burden associated with multiple follow-up appointments. Furthermore, the T and E may represent a more cost-effective therapeutic option as compared with regular dosing.
Pro re nata (PRN) dosing involves initially giving regular injections, typically for a minimum of three months, followed by routine follow-up, and only further injections given reactively when there is evidence of changes.
The aim of the present study was to compare between two regimens of intravitreal injection of aflibercept in DME: T and E vs PRN.
| Patients and Methods|| |
This study is a clinical trial carried out at Tiba Eye Center, Shebin Elkom, Menoufia, from August 2018 till February 2020. This procedure was done by a Professor of Ophthalmology, Dr Abdel Elrahman Elsebaey, at the Faculty of medicine.
Patients with DME were randomly divided into two groups: group I was treated with T and E regimen of intravitreal injection of aflibercept, and group II was treated with PRN regimen of intravitreal injection of aflibercept. Patients with type I or II diabetes, DME in eyes clinically diagnosed with optical coherence tomography (OCT) [loss of the foveal pit, and central macular thickens (CMT) >300 μm], and decrease VA to 20/40–20/300 were included. We excluded patients with CMT less than 300 μm, presence of tractional retinal detachment or epiretinal membrane, presence of vitreous hemorrhage, glaucoma, evidence of intraocular inflammation, and previous ocular surgery or laser. Sample size was 30 patients with DME, with 15 patients in each group.
This study was performed using a systematic random sampling technique.
All patients underwent a complete ophthalmological examination, as well as full medical and ophthalmic history. The history was taken from the patients, and symptoms were asked about, such as decreased VA and metamorphopsia. BVCA assessments were done using logarithm of minimum angle of resolution (logMAR) units, anterior segment examinations using slit lamps, intraocular pressure evaluation using a Goldmann applanation tonometer, and posterior segment examinations using slit-lamp biomicroscopy with +90 and +78 diopters Volk lenses. Fundus fluorescein angiography (FFA) (TRC.50DX; 1 Chome-5-2 Azusawa, Itabashi City, Tokyo 174-0051, Japan) and OCT (Ziess Engineering, Oberkochen, Germany) were done for macular examination.
The degree of DME was determined from the images recorded by a Ziess OCT instrument (Ziess Engineering). The CMT is defined as the thickness between the internal limiting membrane and the retinal pigment epithelium at the fovea, and the value is automatically calculated from the center subfield of the macular thickness map using the bundled software.
Assessments at each study visit included best-corrected visual acuity (BCVA), IOP, OCT scans, and slit-lamp examination. At baseline and study completion, participants also underwent fluorescein angiography if indicated. At each follow-up visit, the participants were asked about any adverse events and any changes in their health or medications. All serious adverse events were reported to the manufacturers and the Local Ethics Committee.
All participants were given 3 monthly injections as loading doses of 2 mg/0.05 ml aflibercept from single-use vials. The intravitreal injections were performed according to the regular procedure of each investigator using a 30 G needle inserted after local anesthesia and using aseptic technique. After injection, hand movement perception was confirmed, the eye was irrigated with saline, and artificial tear drops were administered if required. After the loading injections, treatment intervals were determined according to a T and E regimen, based on the presence of disease activity, that is, decrease of VA at any time during the study (considered by the treating physician to be attributable to disease activity), or persistent macular edema, or increase in CMT of 50 μm. If none of these criteria were met, the participant's injection interval was increased by 2 weeks until a maximum of 12-weekly dosing was attained. If either criteria were met, the injection interval was decreased by 2 weeks (if 4 weeks) or returned to 4 weeks (at the discretion of the investigator) until disease activity was minimized. Participants who experienced significant and rapid progression of disease or became unresponsive to aflibercept had the option to withdraw and have rescue therapy, such as, for example, laser photocoagulation therapy or intravitreal steroids.
The primary outcome measure was the mean change in BCVA. Secondary efficacy end point was the mean changes in CMT. Follow-up of the patients was by monthly OCT.
Approval for this study was obtained from the local university ethical committee. Patients included in the study received information about the nature of the study, possible benefits, and complication of the treatment.
Analysis of data was done using Statistical Program for Social Science version 20 (SPSS Inc., Chicago, Illinois, USA). Quantitative variables were described in the form of mean and SD. Qualitative variables were described as number and percentage. To compare parametric quantitative variables between the two groups, Student's t-test was performed. Qualitative variables were compared using χ2 test or Fisher's exact test when frequencies were below five. Pearson correlation coefficients were used to assess the association between two normally distributed variables. When a variable was not normally distributed, a P value less than 0.05 is considered significant.
| Results|| |
Regarding age, in patients with T and E protocol, it ranged between 59 and 78 years, with mean ± SD of 68.53 ± 5.854 years, whereas in patients with PRN protocol, it ranged between 55 and 78 years, with mean ± SD of 65.40 ± 7.239 years. There was no statistically significant difference between groups, where P = 0.203 [Table 1].
Regarding sex, in patients with T and E protocol, 11 (73.3%) were male and four (26.7%) were female, whereas in patients with PRN protocol, six (40%) were male and nine (60%) were female. There was no statistically significant difference between groups, where P = 0.139 [Table 2].
Regarding diabetes mellitus (DM) type, in patients with T and E protocol, nine (60%) were type I and four (40%) were type II, whereas in patients with PRN protocol, seven (46.7%) were type I and eight (53.3%) were type II. There was no statistically significant difference between groups, where P = 0.715.
Regarding DM treatment, in patients with T and E protocol, 10 (66.7%) were treated with insulin and five (33.3%) were treated orally, whereas in patients with PRN protocol eight (53.3%) treated with insulin and seven (46.7%) were treated orally. There was no statistically significant differences between groups, where P = 0.710.
Regarding HbA1C, in patients with T and E protocol, it ranged between 6.6 and 10.60, with mean ± S.D. of 8.24 ± 1.416, whereas in patients with PRN protocol, it ranged between 6.60 and 9.30, with mean ± SD of 7.960 ± 0.808. There were no statistically significant differences between groups, where P = 0.511.
Regarding DM duration, in patients with T and E protocol, it ranged between 16 and 35 years, with mean ± SD 27.93 ± 5.574 years, whereas in patients with PRN protocol, it ranged between 15 and 36 years, with mean ± SD of 24.47 ± 7.539 years. There were no statistically significant differences between groups, where P = 0.163.
The mean baseline BCVA was 0.833 ± 0.159 logMAR units in patients with T and E protocol and 0.880 ± 0.077 logMAR units in patients with PRN protocol; after loading dose, the BCVA was improved to 0.673 ± 0.103 logMAR units in patients with T and E protocol and 0.700 ± 0.093 logMAR units in patients with PRN protocol; and after resolving edema, the BCVA was 0.353 ± 0.106 logMAR units in patients with T and E protocol and 0.407 ± 0.096 logMAR units in patients with PRN protocol, with no statistically significant differences between groups [Table 3].
The mean baseline CMT were 454.87 ± 33.293 in patients with T and E protocol and 474.53 ± 46.854 in patients with PRN protocol; after loading does, the CMT was improved to 437.33 ± 37.418 in patients with T and E protocol and 423.40 ± 33.964 in patients with PRN protocol; and after resolving edema, the CMT was 301.47 ± 15.606 in patients with T and E protocol and 306.33 ± 5.024 in patients with PRN protocol, with no statistically significant differences between groups [Table 4].
|Table 4: Comparison between two groups regarding central macular thickness|
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The mean number of injection in patients with T and E protocol was 8.53 ± 2.774, whereas in patients with PRN protocol was 11.60 ± 2.746, with highly statistically significant differences between groups, where P = 0.005 [Table 5].
|Table 5: Comparison between two groups regarding patients' number of injections|
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Correlation between CMT and other parameter shows that there was a negative but nonsignificant correlation between CMT and each of age, DM type, DM duration, and number of injections, and there was a positive but nonsignificant correlation between CMT and each of sex and BCVA [Table 6].
|Table 6: Correlation between central macular thickens and other parameter|
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| Discussion|| |
Diabetes accounts for a significant burden of global chronic disease, with the ophthalmic complications of DRP and DME representing the commonest causes of early-onset blindness worldwide.
In clinical trials and clinical practice, T and E and PRN regimens of anti-VEGF treatment, in response to signs of disease activity, have been found to be beneficial in reducing the injection burden on patients and improving the cost effectiveness of treatment with little reduction in clinical outcomes.
Regarding the BCVA, in patients treated with T and E protocol, there were highly statistically significant differences between mean BCVA values after resolving edema and baseline (P < 0.001). This is consistent with the results of Sugimoto et al., who reported that the mean baseline BCVA was 0.41 ± 0.19 logMAR units, which improved to 0.24 ± 0.22 logMAR units after loading dose, and the final mean BCVA significantly improved to 0.16 ± 0.28 logMAR units. Our results were also similar to that of Pak et al., which reported that the final BCVA significantly improved (P < 0.001).
In patients treated with PRN protocol in this study, there was a highly statistically significant difference between mean BCVA values after resolving edema and baseline (P < 0.001). Our finding are similar to that of the study by Ozcaliskan et al., which reported significant improvement of BCVA with PRN protocol of aflibercept in different morphological pattern of DME cystoid macular edema (CME) and diffuse retinal thickness (DRT) (P = 0.01). The mean baseline BCVA was 0.46 ± 0.35 logMAR in DRT group and 0.47 ± 0.21 logMAR in CME group, which improved at 3 months to 0.40 ± 0.33 logMAR and 0.39 ± 0.22 logMAR in DRT and CME, respectively (P < 0.001). At the end of the study, there was significant improvement, which became 0.35 ± 0.31 logMAR and 0.40 ± 0.31 logMAR in DRT and CME, respectively (P = 0.001).
On the contrary, our results were different from those of Plaza-Ramos et al., which reported significant improvement of the mean BCVA after three injections from 0.48 ± 0.29 at baseline to 0.40 ± 0.27 logMAR. However, the final BCVA was maintained at 0.40 ± 0.29 logMaR. This difference may be owing to the number of patients treated in PRN protocol, where in our study, it was 15 patients, whereas in Plaza-Ramos et al., 91 patients were treated and had better baseline BCVA. Our result is also different from Abdallah et al., where 10 eyes were enrolled in their study, in which aflibercept was injected monthly for 3 months. There was no significant improvement in BCVA after 3 months (0.64 ± 0.34 logMaR) compared with baseline BCVA (0.54 ± 0.32 logMaR). This difference may be owing to the patients included in Abdallah et al., who were not responding to injection of aflibercept.
Regarding the CMT, the present study revealed that there was a highly statistically significant difference between mean CMT after resolving edema and baseline (P < 0.001). In agreement with our findings, the study by Sugimoto et al. reported that the mean baseline CMT was 348.7 ± 53.5 μm, which improved to 332.9 ± 72.6 μm after loading dose. The mean final CMT was significantly improved to 317.8 ± 71.2 μm. Our results were also close to the study of Curry et al., which reported that the baseline CMT was 416.6 μm, which improved to 290.6 μm after loading dose. The mean final CMT was 127.2 μm. There was a statistically significant difference between the mean final CMT and baseline CMT, with P less than 0.001. Moreover, our result is similar to that of Pak et al., which reported that the mean baseline CMT was 489.4 μm, which improved to 317.7 μm at the end of the study, with statistically significant differences, as P less than 0.001.
In patients treated with PRN protocol in this study, there was a highly statistically significant difference in mean CMT after resolving edema compared with baseline (P < 0.001). Our result is similar to that of Abdallah et al., which reported that the final CMT significantly improved (P = 0.027). Moreover, our result agreed with that of Ozcaliskan et al., which reported that the mean baseline CMT was 403.46 ± 77.77 and 448.50 ± 110.05 μm in DRT group and CME group, respectively, which significantly improved to 322.51 ± 73.96 and 346.22 ± 108.24 μm in DRT group and CME group, respectively, at the end of the study (P = 0.01). In agreement with our findings, the study of Plaza-Ramos et al. reported that the mean baseline CMT was 419.46 ± 104.61 μm, which improved to 354.73 ± 96.16 μm after 3 injections. At the end of the study, the mean CMT was maintained at 365.56 ± 105.22 μm. This maintenance may be owing to the patients need more injections.
In our study, we compared between the two group regarding BCVA and CMT. There was no statistically significant difference between the two group regarding BCVA after loading dose, as P = 0.463, and after resolving edema, as P = 0.160. Moreover, in CMT, there was no statistically significant difference between the two group after loading dose, as P = 0.295, and after resolving edema, as P = 0.260.
Regarding the number of injection among patients, there was a highly statistically significant difference between the two groups, as P = 0.005.
| Conclusion|| |
The T and E regimens for DME may be a good option for patients with DME because it will result in good vision and fewer injection numbers. The results of this study indicate that a T and E regimen of aflibercept is effective and a practical alternative to a PRN treatment schedule for most patients presenting with DME.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]