Abstract
Purpose:
To compare the functional and anatomical outcomes of ranibizumab, aflibercept, and dexamethasone implant monotherapy in treatment-naive eyes with diabetic macular edema (DME) in real-life conditions.
Methods:
In this retrospective cohort study, data were obtained from the hospital database of treatment-naive patients diagnosed with DME with at least 12 months of follow-up. Best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, third month, sixth month, ninth month, and 12th month were recorded. In addition, a subgroup analysis was performed based on having good (below 0.4 log of minimum angle of resolution [logMAR]) or poor (0.4 logMAR and above) vision.
Results:
A total of 219 eyes of 142 patients were included in the study. The change in the mean BCVA from baseline to 12th month was from 0.62 logMAR to 0.42 logMAR (P < 0.001) in the ranibizumab group, from 0.56 logMAR to 0.39 logMAR (P < 0.001) in the aflibercept group, and from 0.46 logMAR to 0.5 logMAR (P = 0.653) in the dexamethasone group. There was no significant difference between the treatment groups at any time point (P > 0.05). The mean amount of CRT change was statistically significant at 12 months in all groups (ranibizumab: -175.4 µm, aflibercept: -153.3 µm, dexamethasone: -71.4 µm) (P < 0.05). In eyes with initially good vision, the final BCVA at 12 months was significantly better in the ranibizumab group compared to the dexamethasone group (P = 0.008). The aflibercept group had better visual acuity than the dexamethasone group, but there was no statistically significant difference (P = 0.059). There was no significant difference in final BCVA in eyes with initially poor vision. No serious ocular/systemic complications were noted.
Conclusion:
At the 12th month, a significant decrease in CRT was achieved in all treatment groups, whereas only ranibizumab and aflibercept groups had a significant BCVA increase. In eyes with initially good vision, the final BCVA at 12 months was better in the ranibizumab group compared to the dexamethasone group, whereas it was similar in all groups having initially poor vision.
Keywords: Aflibercept, dexamethasone, diabetic macular edema, ranibizumab, real-life study
Diabetic retinopathy (DR), which is one of the leading causes of visual impairment in the working-age population, is a microangiopathy involving retinal precapillary arterioles, capillaries, and venules. The main cause of visual loss and impairment in diabetic patients is macular edema. Diabetic macular edema (DME) is characterized by the presence of exudation and accumulation of extracellular fluid in the retinal layers, which are caused by an increase in the permeability of retinal blood vessels.[1,2]
The current treatment of choice in central DME is intravitreal anti-vascular endothelial growth factor (anti-VEGF), steroid implant injections, and subthreshold micropulse laser. Awareness of the role of VEGF and inflammatory mediators in the pathogenesis of DME has prompted the development and widespread use of intravitreal steroid and anti-VEGF inhibitors that can target these pathways.[3] Intravitreal ranibizumab, bevacizumab, and aflibercept are the most commonly used anti-VEGF treatments for DME. There are three different synthetic preparations including triamcinolone acetonide, fluocinolone acetate, and dexamethasone implant for intravitreal corticosteroid administration.[4,5,6,7]
Clinical trials remain the most effective form of evaluation of the effects of treatment, yet their selection criteria limit the recruitment of patients in upper or lower age ranges or suffering from multiple comorbidities. It should also be kept in mind that patients in clinical trials may behave differently than real-life patients and the risk of bias cannot be completely avoided in practice. Real-life studies are qualified to remedy these limitations. They examine patients according to their real-life behaviors and aim to minimize the differences and biases due to patient or physician behavior. There are few real-life studies in the literature investigating the effectiveness of intravitreal injections in DME. The purpose of the present study was to evaluate the effectiveness and safety profile of intravitreal aflibercept, dexamethasone, and ranibizumab in treatment-naive patients with DME in daily clinical practice.
Methods
This retrospective study was conducted upon the approval of the institutional ethical committee and adhered to the tenets of the Declaration of Helsinki. The participants were treatment-naive adult diabetic patients who had intravitreal anti-VEGF or dexamethasone implant injections for DME with a regular follow-up of a minimum of 12 months. Exclusion criteria were concomitant retinal diseases, focal/grid laser in the last 3 months, and intraocular surgery within the study period or ≤6 months before study inclusion.
The selection of the intravitreal drug was made by the physician according to the physician’s own criteria. In general, anti-VEGF agents were the treatment of choice; however, they were not preferred in patients with a history of stroke or heart attack ≤3 months before treatment. Steroid implants were mostly preferred in patients with a history of stroke or heart attack ≤3 months before the treatment and in eyes with inflammatory findings on optical coherence tomography (OCT) images, such as hyperreflective dots, chronicity findings, and diffuse and severe macular edema. Patients’ requests for not having injections on a monthly basis, having glaucoma, and a history of vitrectomy were also taken into consideration while taking the decision for treatment.
Information about age, gender, history of eye surgery, duration of diabetes, diabetic treatment, comorbidity, and glycated hemoglobin (HbA1c) value was obtained from the hospital database.
All patients initially underwent a complete ophthalmologic examination including best-corrected visual acuity (BCVA), intraocular pressure (IOP), central retinal thickness (CRT), and fundus fluorescein angiography (FFA). BCVA was evaluated by the Snellen chart and converted into log of minimum angle of resolution (logMAR) for statistical evaluations. Spectral-domain optical coherence tomography (SD-OCT; Spectralis/HRA, Heidelberg Engineering, Heidelberg, Germany) was used for detecting macular edema and measurement of CRT. In our study, FFA-based DME classification was divided into three types according to the leakage pattern as defined by Kang et al.[8] These are focal leakage type with well-circumscribed focal leakage areas from microaneurysms, diffuse type with large leak areas that are not well limited around the fovea, and diffuse cystoid type with fluorescein leakage in the cystoid spaces in the late period.
A single-dose injection was administered to the dexamethasone group at the beginning of the treatment. Ranibizumab and aflibercept groups were given three consecutive doses at 1-month intervals. Patients were monitored every 4 weeks with IOP, BCVA, CRT measurements and fundus examination. A decreased BCVA and/or foveal-involving intraretinal and/or subretinal fluid and/or CRT >250 µm were indications for retreatment. Two subgroup analyses were performed as those with BCVA values 0.4 logMAR and above (poor visual acuity) and those with BCVA values below 0.4 logMAR (good visual acuity) based on the Protocol T study.
Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) statistical software (SPSS 11.0.0 for MS Windows; SPSS, Inc, Chicago, IL, USA). Kolmogorov–Smirnov test was used for the determination of the distribution of the data. Parametric tests were used for the comparison of homogenously distributed data, whereas nonparametric tests were used for the comparison of nonhomogenously distributed data. Categorical variables were compared with the Chi-square test. A P value of 0.05 was considered significant.
Results
The records of 524 patients (including 863 eyes) having treatment for DME were screened. A total of 219 eyes of 142 patients met the inclusion criteria. Table 1 summarizes the baseline characteristics of the patients included in each group.
Table 1.
Patient demographic and baseline characteristics
| Study population (na=142) | Ranibizumab (n=64) | Aflibercept (n=58) | Dexamethasone (n=20) | P | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Demographics | ||||||||||
| Females, % (n) | 49.3 (70) | 54.7 (35) | 43.1 (25) | 50 (10) | 0.441 | |||||
| Age (years), mean (±SD) | 60.9 (±8.35) | 60.4 (±7.58) | 61.2 (±9.71) | 61.7 (±6.53) | 0.789 | |||||
| Metabolic factors | ||||||||||
| Duration of diabetes (years), mean (±SD) | 14.49 (±6.84) | 14.19 (±6.99) | 14.79 (±7.03) | 14.84 (±5.63) | 0.936 | |||||
| Hemoglobin A1c, % mean (±SD) | 8.73 (±1.79) | 8.63 (±1.80) | 8.83 (±1.84) | 9.03 (±1.73) | 0.821 | |||||
| Coronary artery disease, % (n) | 16.8 (22) | 18.8 (12) | 17.6 (9) | 6.3 (1) | 0.478 | |||||
| Hypertension, % (n) | 42.7 (56) | 42.2 (27) | 49 (25) | 25 (4) | 0.236 |
SD=Standard deviation. an=Number of patients
Mild nonproliferative diabetic retinopathy (NPDR) was the most common DR grade, with cystoid edema being the leading type of edema on SD-OCT images. As DME treatment, 100 eyes had ranibizumab, 86 eyes had aflibercept, and 33 eyes had dexamethasone injections. Baseline ocular findings are shown in Table 2.
Table 2.
Baseline ocular findings
| Study population (na=219) | Ranibizumab (n=100) | Aflibercept (n=86) | Dexamethasone (n=33) | P | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Pseudophakic, % (n) | 15.1 (33) | 11 (11) | 19.8 (17) | 15.2 (5) | 0.249 | |||||
| Epiretinal membrane, % (n) | 1.8 (4) | 2 (2) | 1.2 (1) | 3 (1) | 0.792 | |||||
| Serous macular detachment, % (n) | 30.1 (66) | 41 (41) | 19.8 (17) | 24.2 (8) | 0.005 | |||||
| Laser photocoagulation,% (n) | 60.7 (133) | 57 (57) | 65.1 (56) | 60.6 (20) | 0.528 | |||||
| Classification of diabetic retinopathy | 0.983 | |||||||||
| Mild NPDR, % (n) | 39.3 (86) | 43 (43) | 34.9 (30) | 39.4 (13) | ||||||
| Moderate–severe NPDR, % (n) | 30.1 (66) | 29 (29) | 24.4 (21) | 48.5 (16) | ||||||
| PDR, % (n) | 30.6 (67) | 28 (28) | 40.7 (35) | 12.1 (4) | ||||||
| Classification of diabetic macular edema | 0.162 | |||||||||
| Focal, % (n) | 36.1 (79) | 29 (29) | 45.3 (39) | 33.3 (11) | ||||||
| Cistoid, % (n) | 38.8 (85) | 46 (46) | 30.2 (26) | 39.4 (13) | ||||||
| Diffuse , % (n) | 25.1 (55) | 25 (25) | 24.4 (21) | 27.3 (9) |
NPDR=Nonproliferative diabetic retinopathy, PDR=Proliferative diabetic retinopathy. an=Number of eyes
The mean BCVA was compared within the groups according to the baseline values and also between the groups throughout the follow-up. The change in the mean BCVA values over time is shown in Fig. 1. In the ranibizumab and aflibercept groups, the mean BCVA improved statistically significantly at all time points compared to baseline, but in the dexamethasone group, statistically significant improvement was found only in the third month. The mean BCVA was worse in the dexamethasone group at the 12th month compared to the baseline, but there was no statistically significant difference (P = 0.653).
Figure 1.
Comparison of change in the mean BCVA over time between the treatment groups. BCVA = best corrected visual acuity
CRT was measured at every visit during the follow-up period. There was no statistically significant difference in CRT between the groups at any time point (P > 0.05). Fig. 2 shows the evolution of CRT in each group over time.
Figure 2.
Comparison of change in the mean CRT over time between the treatment groups. CRT = central retinal thickness
At month 12, the mean change in CRT was -175.4 µm in the ranibizumab group, -153.3 µm in the aflibercept group, and -71.4 µm in the dexamethasone group, and there was a statistically significant difference between the groups (P = 0.005, one-way analysis of variance [ANOVA] test). While the mean CRT was lower in ranibizumab and aflibercept groups compared to that in the dexamethasone group, there was no statistically significant difference between ranibizumab and aflibercept groups (ranibizumab/dexamethasone P = 0.03, aflibercept/dexamethasone P = 0.032, ranibizumab/aflibercept P = 0.608, paired samples t-test).
All patients were divided into two groups as having poor visual acuity and good visual acuity, according to the initial BCVA. There were 64 (29.22%) eyes in the group with good vision, while there were 155 (70.78%) eyes in the group with poor vision. In the good vision group, 43.75% had aflibercept, 40.62% had ranibizumab, and 15.63% had dexamethasone treatment. In the poor vision group, 47.74% had ranibizumab, 37.42% had aflibercept, and 14.84% had dexamethasone treatment.
In eyes with poor vision, the mean BCVA did not show a statistically significant difference between the groups at any time point (P > 0.05). In eyes with good vision, a statistically significant difference was found at only the 12th month between the groups (baseline P = 0.420, third month P = 0.566, sixth month P = 0.684, 12th month P = 0.012, one-way ANOVA test). At month 12, the mean BCVA was statistically significantly better in the ranibizumab group than in the dexamethasone group (P = 0.008), whereas the difference in mean BCVA did not reach statistical significance between the aflibercept–dexamethasone groups despite the mean BCVA showing a better value in the former one (P = 0.059).
In eyes with poor vision, no statistically significant difference was observed in the mean CRT between the groups at any time point (P > 0.05). In eyes with good vision, the mean CRT was statistically significant between the groups only at the 12th month (baseline P = 0.173, third month P = 0.381, sixth month P = 0.520, 12th month P = 0.009). In the 12th month, statistically significant differences were found between the dexamethasone group and both ranibizumab and aflibercept groups, with thicker CRT found in the dexamethasone group (ranibizumab/dexamethasone P = 0.010, aflibercept/dexamethasone P = 0.014). There was no statistically significant difference between ranibizumab and aflibercept groups (P = 0.983).
The number of injections in ranibizumab group ranged from three to nine with an average of 4.96 ± 1.49, in aflibercept group ranged from three to eight with an average of 4.81 ± 1.31, and in dexamethasone group ranged from one to three with an average of 1.96 ± 0.58 (ranibizumab/aflibercept P = 0.73, ranibizumab/dexamethasone P < 0.001, aflibercept/dexamethasone P < 0.001).
No serious complications, including infectious endophthalmitis, retinal detachment, posterior capsule disruption, or lens subluxation, were noted during the study period. The injection result of patients who did not take antiglaucomatous medication before the study but started taking it during the study period was considered to be an increase in IOP. Medical treatment was sufficient for all patients, and glaucoma surgery was not applied to any patient. To assess the development of cataracts, 33 eyes that were initially pseudophakic were not evaluated; the remaining 186 eyes were examined [Table 3].
Table 3.
Cataract development and intraocular increase rates
| Study population | Ranibizumab | Aflibercept | Dexamethasone | P | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cataract development, % (n) | 14.5 (27) | 11.2 (10) | 13 (9) | 29.6 (8) | 0,069 | |||||
| IOP increase, % (n) | 7.3 (16) | 8 (8) | 4.7 (4) | 12.1 (4) | 0.351 |
IOP=Intraocular pressure
Discussion
Currently, there is very limited real-world data comparing the long-term treatment results with different anti-VEGF agents and dexamethasone implants in treatment-naive patients with DME. In this real-world design study, we found that ranibizumab and aflibercept significantly increased visual acuity by three loading doses followed by the pro re nata (PRN) regimen, whereas dexamethasone, which was injected at baseline and repeated as needed during the follow-up, did not improve visual acuity significantly at the 12-month visit in treatment-naive DME patients. CRT significantly decreased in all groups at the 12-month visit. When classified as having poor and good initial visual acuity, there was no significant difference in BCVA between the treatment groups in the former, whereas ranibizumab was superior to dexamethasone with no significant difference between ranibizumab and aflibercept in the latter. There were no serious complications in the treatment groups.
Although many studies have compared the efficacy of anti-VEGF agents in the treatment of naive DME, only a few studies have compared intravitreal steroids and anti-VEGF treatments. In the study INVICTUS, which is a real-life study comparing ranibizumab, aflibercept, and dexamethasone, anatomical and functional efficacy was reported in all groups. BCVA improved significantly to 69.6 ± 12 letters (+7.2 letters) at 12 months for the ranibizumab group and to 67.5 ± 12.2 letters (+8.5 letters) at 12 months for the aflibercept group. For the dexamethasone group, BCVA improved to 68.4 ± 11.2 letters (+9.4 letters) at 12 months. Similar to our study, the PRN regimen treatment was applied for anti-VEGF agents after a 3-month loading phase, and reinjection was administered to patients treated with dexamethasone, without time limitation, in worsening BCVA and/or increase in CRT. This study had a smaller sample size than our study; 19 eyes were treated with ranibizumab, 20 eyes with aflibercept, and 21 eyes with dexamethasone, a total of 60 eyes.[9] Unlike our study, it was predicted that there was an improvement in BCVA due to the higher mean number of injections in the dexamethasone group and a statistically significant decrease in CRT.
In the study MAGGIORE, a multicenter (12 countries, 60 centers), open-label, randomized, parallel-group, noninferiority study comparing ranibizumab and dexamethasone, 181 patients in the dexamethasone group (55.8%; treatment naive) and 182 patients in the ranibizumab group (55.5%; treatment naive) were evaluated. The mean change from baseline CRT at 12 months was similar in the dexamethasone (DEX) implant and ranibizumab groups (−173.9 and −163.5 μm, respectively). The mean BCVA change from baseline at 12 months was found to be unequal (+7.6 letters and +4.34 letters, respectively). The 95% confidence interval (CI) of the difference between groups was − 4.74 to − 1.88, with the lower bound of −4.74 letters within the predefined, clinically relevant, noninferiority margin of 5 letters. Unlike our study, when FFA and fluorescent leaking areas at 12 months were compared to baseline, they reported that there were fewer leaks in the dexamethasone group at 12 months (P < 0.001).[5] They reported that the differences in BCVA outcomes between treatment groups may be due to the 5-month interval between dexamethasone implant treatments.
In our study, anatomical improvement was found with a change in CRT of -175.4 µm in the ranibizumab group, -153.3 µm in the aflibercept group, and -71.4 µm in the dexamethasone group at 12 months. At the end of a 1-year follow-up, the change in CRT was reported as -133.9 µm with ranibizumab treatment in the study of Patrao et al., -121 µm with aflibercept therapy in the study of Kern et al., -135 µm with dexamethasone treatment in BEVORDEX study, and -173.54 µm with dexamethasone treatment in the study of Chhablani et al.[2,10,11,12] In our study, the change in BCVA and CRT in the ranibizumab and aflibercept groups was consistent with the literature; however, in the dexamethasone group, poorer results were noted. The mean CRT change from baseline was statistically significantly greater in ranibizumab and aflibercept groups compared to that in the dexamethasone group at the sixth month, ninth month, and 12th month, whereas there was no statistically significant difference between ranibizumab and aflibercept. In addition, consistent with the previous studies, the peak effect after dexamethasone implant was observed approximately 3 months posttreatment.[13]
In the current studies conducted in clinical practice, treatment with the dexamethasone implant in DME patients resulted in visual acuity improvement, which was compatible with a decrease in retinal thickness.[14] In our study, mean BCVA improved only at 3 months from baseline, consistent with the reduction in CRT in the dexamethasone group. There was a statistically significant difference from baseline at all time points in the ranibizumab and aflibercept groups. Baseline visual acuity in the ranibizumab (0.62 logMAR) and aflibercept (0.56 logMAR) groups was lower than that of the dexamethasone group (0.46 logMAR). This may have supported further gains in the anti-VEGF groups. In addition, limited visual gains in the dexamethasone group may have been related to the duration of macular edema, the limited amount of CRT change, and increased lens opacity and other inflammatory biomarkers. Another important issue to take into account is the difference in sample sizes, with the dexamethasone group being the smallest one including 33 eyes (15.06%).
Protocol T was the largest randomized clinical trial that compared aflibercept, bevacizumab, and ranibizumab in patients with DME. At the end of the first year, aflibercept seemed to be more efficient in terms of improving visual acuity and reducing CRT, especially in eyes with low BCVA, whereas there were no significant differences between the groups when the initial visual acuity loss was mild. At the end of the second year, the BCVA values did not significantly differ between the groups.[5] In our study, when classified according to initial visual acuity, those with poor visual acuity made up the majority and there was no significant difference in BCVA between the treatment groups at the end of the follow-up period. It is worth noting that the ranibizumab dose was 0.3 mg in the Protocol T study and 0.5 mg in our study, which might explain the difference in the findings between the studies. In eyes with good visual acuity, there was no statistically significant difference in BCVA between ranibizumab and aflibercept groups, whereas only the ranibizumab group was statistically significantly better than the dexamethasone group. In eyes with good visual acuity, the ratio of cataract development was higher in the dexamethasone group (25%) compared to the other groups (ranibizumab 12%, aflibercept 13%). On the other hand, in eyes with good visual acuity, the mean CRT value worsened at 12th month compared to baseline in the dexamethasone group, whereas an improvement was noted in the anti-VEGF groups. These findings suggest that both deterioration of macular edema and cataract development might play a role in limited visual gain in the dexamethasone group.
In this study, the patients were injected with monthly three loading doses of anti-VEGF agents; then, during 12 months of follow-up period, the anti-VEGF and dexamethasone implant were reinjected if the macular edema was still present. The ranibizumab group received a mean of 4.96 ± 1.49 injections, the aflibercept group had a mean of 4.81 ± 1.31 injections, and the dexamethasone group had a mean of 1.96 ± 0.58 injections. The anti-VEGF groups showed significantly lower injection numbers compared to the dexamethasone group. This is explained by the release of active substances into the vitreous for up to 6 months by dexamethasone implants. Our injection numbers are lower than the real-world studies. After 12 months of follow-up, Fouda and Bahgat[6] reported 5.62 injections in the aflibercept group and 6.02 in the ranibizumab group, Plaza-Ramos et al.[15] reported 5.56 injections in the ranibizumab group and 6.07 injections in the aflibercept group, whereas Matonti et al.[16] reported 2.16 injections in the dexamethasone group. Since these findings reflect real-world conditions, the differences in findings might be due to delays in injection appointments secondary to patient noncompliance and the growing number of injection requirements over the constant and limited injection capacity of clinics.
While temporary and sudden IOP increase is a common complication after intravitreal injection, prolonged and continuous IOP elevation that requires medical or surgical intervention is rarely seen.[17] In a retrospective study conducted to determine the IOP changes of patients treated with anti-VEGF treatment for DME, Al-Abdullah et al.[18] reported 7% transient and 5.8% persistent IOP elevation in the mean 18-month follow-up period. Ozkaya et al.[19] reported that among patients receiving intravitreal dexamethasone for persistent DME, in the 1-year follow-up, 14% of patients had an increase in IOP of ≥ 10 mmHg and only 4% needed chronic antiglaucomatous medication. In our study, the frequency of increase in IOP after 1 year of follow-up was similar to that reported in literature. There was no statistically significant difference in IOP increase rates between groups. Medical treatment was successful in all patients, and no surgical treatment was required.
Cataract is another common complication of intravitreal injection. Cataract development was reported at 4.4% in the APOLLON study,[20] 22.2% in the PLACID study,[21] and 9.9% in a real-life study by Hodzic-Hadzibegovic et al.[22] assessing the efficacy of 12-month treatment with ranibizumab in DME. In our study, cataract development rates were found to be similar compared to the literature. Serious complications such as retinal detachment, vitreous hemorrhage, sudden vision loss, cerebrovascular disease, and myocardial infarction were not detected.
Limitations of the study include its retrospective design, small sample size, and practice biases.
Conclusions
In conclusion, our real-world data indicates that significant anatomical improvement was achieved in all treatment groups in DME patients at the end of the first year. In terms of functional improvement, ranibizumab and aflibercept groups revealed a significant BCVA increase, whereas the dexamethasone group did not show a significant change in BCVA at the end of the first year. In eyes with poor vision, BCVA was not significantly different between groups throughout the follow-up period; however, in eyes with good vision, the ranibizumab group had better BCVA than in the dexamethasone group at month 12. No serious complications or significant increases in cataract and IOP were noted during the study period. Unlike in phase studies, our real-life study also reveals the possible consequences of the limited injection capacity compared to the growing number of patients requiring injection, as well as patient noncompliance issues. Finally, the current study is one of the rare real-life studies in the literature, which involves treatment-naive DME patients and documents the efficacy and safety of ranibizumab, aflibercept, and dexamethasone treatments. Future real-life studies with larger sample sizes might enable physicians and patients to establish better treatment protocols and set more realistic expectations.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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