Evaluation of intravitreal bevacizumab as monotherapy and in combination with macular grid laser photocoagulation in diffuse diabetic macular edema.

BACKGROUND AND
OBJECTIVE: The objective of the study was to compare the efficacy of intravitreal bevacizumab (IVB) as monotherapy versus combination with modified macular grid (MMG) laser photocoagulation in the primary treatment of diffuse diabetic macular edema (DDME).
MATERIALS AND METHODS: A prospective randomized trial was carried out in sixty eyes with DDME after Institutional Ethical clearance. Group A received three doses of IVB at a 1-month interval. Group B received MMG in addition to IVB. Complete examination including best-corrected visual acuity (BCVA) (Snellen's), central macular thickness (CMT) using spectral domain-optical coherence tomography was carried out at 0, 1, 4, 8, 12, and 24 weeks.
RESULTS: mean CMT at baseline, 12 and 24 weeks in Group A was 401 (±76), 280 (±49), and 307 (±46) and in Group B, 405 (±73), 237 (±33), and 242 (±45), respectively. Group B had significantly greater reductions (P < 0.001) from 12 weeks onward. BCVA and contrast sensitivity showed improvements with no significant difference.
CONCLUSION: Combined therapy has more advantage in primary DDME by reducing CMT on longer follow-up.

RCT Entities:   Population Interventions Outcomes

Introduction

Diabetes is a highly prevalent disease worldwide,[1] and in India[2] especially in the working age group. The loss of vision, due to diabetes, is commonly attributed to diabetic macular edema (DME),[3] which accounts for 12% of new cases of blindness each year[4] with heavy impact in terms of functional impairment and handicap, impaired quality of life, social burden, and economic loss.[5]

Macular grid photocoagulation has been the main treatment employed for diffuse DME.[6] However, it results in only 50% reduction in risk of vision loss[678910] and a significant gain in vision is uncommon.[6] The use of intravitreal steroids for DME has been limited by the high incidence of cataract, rise in intraocular pressure (IOP), and risk of endophthalmitis.[1112] Recently, studies on antivascular endothelial growth factor (anti-VEGFs) have shown promising results in diffuse DME when compared with laser monotherapy or with intravitreal steroids.[1314] However, the main limitation of anti-VEGF is their short duration of action which necessitates repeated injection. Combination of anti-VEGF and laser photocoagulation may be beneficial (laser may have more effect on a prethinned retina with prior anti-VEGF, thus requiring lesser energy and reducing collateral damage) and may even decrease the requirement of repeated injections. This study has been carried out to compare the efficacy between intravitreal bevacizumab (IVB) monotherapy versus combined treatment of IVB and macular grid laser photocoagulation

Materials and Methods

This study was conducted in sixty eyes of 36 diabetics recruited from the Outpatient Department of Guru Teg Bahadur Hospital, Delhi, with the following inclusion criteria:

Diabetes mellitus type 1or 2, with diffuse diabetic macular edema (DDME). (Diffuse macular edema is defined as having two or more disk areas of retinal thickening involving the center of the macula)

Central macular thickness (CMT) >300 μm, on spectral domain-optical coherence tomography (SD-OCT)

Good metabolic control (HbA1c <7.5 and blood pressure <140/90).

The exclusion criteria were significant media opacity, proliferative diabetic retinopathy, previous ocular surgery, any prior treatment for macular edema, traction maculopathy, ischemic maculopathy, the presence of any other macular pathology, history of coronary artery disease/stroke, or history of glaucoma.

Institutional Ethical clearance from University College of Medical Sciences Medical Board was ensured. A written informed consent was taken from all included participants. All patients underwent complete eye examination including best-corrected visual acuity (BCVA, Snellens), IOP measurement (Goldmann's Applanation tonometry), fundus imaging digital camera fluorescein angiography (Visu Cam–lite, Carl Zeiss Inc., Germany), and SD-OCT. CMT was measured using SD-OCT (Cirrus, 4000, Carl Zeiss Inc., Germany). Contrast sensitivity (CS) using Pelli Robson CS chart and 10-2 visual field using Humphrey automated Perimetry (Carl Zeiss, Meditech) were also documented.

The subjects were randomized and allocated to one of the following groups:

Group A: IVB Group (who were administered three doses of IVB 1.25 mg in 0.05 ml, at 1 month interval).

Under all aseptic precautions, intravitreal injections of Bevacizumab 1.25 mg in 0.05 ml were administered under topical anesthesia, 3–4 mm from the limbus. Postprocedure evaluation was done immediately and then on the next day. Broad-spectrum antibiotic eye drops were continued up to the 3rd day. Any additional medication was given as per individual assessment and department protocol.

Group B: Combined Group (IVB and Macular Grid Laser photocoagulation) received modified macular grid (MMG) photocoagulation just before the second IVB injection after measurement of CMT, in addition to the three doses of IVB 1.25 mg in 0.05 ml, at 1 month interval.

After obtaining informed written consent, MMG photocoagulation was carried out with frequency doubled neodymium: yttrium aluminum garnet laser according to the ETDRS protocol (100–200 μm in diameter, with width spacing of 1–2 burns, exposure time of 0.1–0.2 s, and a laser power of 100–150 mW was delivered). Minimally white laser burns were created over the entire areas with thicknesses of ≥300 μm, as documented on OCT scans. The papillomacular bundle, the central area (up to 500 μm from the center of the fixation point), and the nonedematous retina were avoided.

For both groups, before each setting, preliminary local examination of eye was conducted including BCVA and IOP. Fundus examination was recorded at each follow-up at week 1, 4, 8, 12, and 24. Macular thickness using OCT was assessed at 1st, 2nd, 3rd, and 6th month in both groups. CS and perimetry were also performed in the 3rd and 6th month of follow-up and repeat fundus fluorescein angiography at 6 months of follow-up. Any adverse effects of therapy were documented in each follow-up.

Results

The two groups had no significant difference in age [Table 1], gender [Table 2], glycosylated hemoglobin level [Table 3], and duration of diabetes [Table 4].

Table 1

Age comparison between groups

Table 2

Gender distribution

Table 3

Glycosylated hemoglobin level comparison between the two groups

Table 4

Duration of diabetes comparison among the two groups

Both the groups showed a decreasing trend of mean CMT till 3-month follow-up after which a gradual slow-increasing trend in noticed at 6 months [Table 5, Figures 1 and 2]. The difference in mean CMT between the two groups at each follow-up was compared, and the mean CMT at baseline was found to be significant at 12 weeks and 24 weeks only (P < 0.001) between the two groups [Table 5]. In both groups, the mean CMT difference a 1, 4, 8, 12, and 24 weeks were all statistically significant when compared to the baseline mean CMT (P < 0.001) [Tables 6 and 7]. In both groups, the mean CMT at 4, 8, 12, and 24 weeks were also all statistically significant when compared to 1-week mean CMT [Tables 6 and 7]. In Group B (combined treatment), unlike Group A, the mean CMT was still significant when 4 weeks compared with 12 and 24 weeks of follow-up [Table 7].

Table 5

Mean central macular thickness in different follow-up

Figure 1

Trend in mean central macular thickness over time

Figure 2

Comparison of central macular thickness of individual eyes of Group A and B at baseline and 24 weeks

Table 6

Comparison of mean central macular thickness in different follow-ups within Group A

Table 7

Comparison of mean central macular thickness in different follow-up within Group B

In terms of visual outcome, both groups showed improving trends over time [Figures 3 and 4]. In Group A (IVB group), change in mean BCVA was significant when compared to baseline at 4 weeks, 8 weeks, 12 weeks, and 24 weeks (P < 0.001) [Table 8]. Within Group B, mean BCVA change from baseline was significant at 8, 12, and 24 weeks. The difference in the mean BCVA between the two groups at each follow-up was not statistically significant. At 24 weeks, when compared to baseline, seven eyes (24.1%) had gain of three Snellen's line in Group A compared to eight eyes (25.9%) in group B. Five eyes (17.2%) in Group A had loss of two Snellen's line as compared to four eyes (14.8%) in Group B [Table 9].

Figure 3

Trend in mean best-corrected visual acuity over time

Figure 4

Comparison of best corrected visual acuity of individual eyes of both groups at baseline and 24 weeks

Table 8

Mean best-corrected visual acuity (in logarithm of the minimum angle of resolution) at different follow-ups

Table 9

Gain or loss of best corrected visual acuity at 24 weeks

There was an improving trend in CS with time. The change in mean log CS was significant when baseline was compared to both 12 weeks and 24 weeks in both groups (P < 0.001) [Table 10]. Furthermore, both groups had no significant difference in mean log CS in each follow-up (P = 0.959).

Table 10

Comparison of mean contrast sensitivity at different follow-ups

There was also no significant change in mean IOP when compared within the individual groups at different follow-up (P = 260). Two eyes from Group A (IVB Group) deteriorated in staging of retinopathy. The rest other eyes did not show any changes in staging from baseline. There were no serious adverse effects encountered in any of the eyes in both groups in this study during the follow-up period which necessitated deferral of intravitreal injections. On further follow–up, beyond 6 months, two patients underwent cataract surgery from IVB group and one patient in IVB group underwent trabeculectomy within 1 year. There were no systemic adverse effects noticed in any of the subjects.

Discussion

Bevacizumab is often preferred over ranibizumab in DDME due to easier availability and lower cost per injection (per patient) and has been widely used, especially in the Indian population. Indirect comparison of the efficacy of anti-VEGF using the Bucher method[15] did not demonstrate statistically significant differences between bevacizumab and ranibizumab or bevacizumab and Aflibercept. Recently, it has been seen that IVB with laser photocoagulation yielded improved visual outcomes, better anatomy, and treatment cost over monotherapy in ARMD.[16] It is possible for this additive effect to exist in DME as well. Hence, this study has been formulated to evaluate any additional benefit of combined treatment over monotherapy.

A search on world literature showed only a handful of studies on IVB for primary DME with only one study (Solaiman et al.[17]) comparing its efficacy with laser photocoagulation. To our knowledge, this is the only study with a preplanned three injections scheduled in both groups (only one other study had preplanned three injections, but it was done for refractory DME[18]). An extensive systemic review by the Canadian Agency of Drug and Technologies[19] on IVB on DME revealed four other trials comparing IVB and laser (with or without intravitreal triamcinolone acetonide) which met standard criteria. Solaiman et al.[17] noted improvement in BCVA significant only at 3 months between IVB and combined group (P < 0.05). Six months after either one injection of IVB or laser photocoagulation, there was no significant improvement; however, vision did not deteriorate from baseline. In our study, significant improvement in mean BCVA was seen in both groups when compared to the baseline. However, this difference was not significant when compared between the two groups in each follow-up. Total 17.9% had deterioration of one or more lines at week 24 whereas 59.2% showed a gain of one or more lines. Nearly 17.9% did not have any change in vision at 6 months.

Analysis of the five major trials on IVB[19] showed that mean change in CMT did not significantly differ at week 6, and at week 24, laser outperformed IVB. Median CMT which was reported in two trials (Michaelides et al.[18] and DCRN[20]) did not differ between monotherapy of either IVB and laser. In our study, CMT showed decreasing trends till 3 months followed by a gradual slow-increasing trend at 6 months in both group, significant when compared to baseline in each follow-up. Combined group had significantly lower CMT at 12 weeks and 24 weeks when compared to IVB group.

Conclusion

Our study which compared IVB as monotherapy against combined therapy with laser photocoagulation, found both treatment to be similarly efficacious in terms of improvement in BCVA and CS. The advantage of combined group was reflected in a significantly lesser CMT on longer follow-up, without any increase in adverse effects. Whether this benefit translates to a decrease in the requirement for repeated injections in future needs to be further studied.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.