Use of antivascular endothelial growth factor for diabetic macular edema.

BACKGROUND: Diabetic macular edema (DME) is one of the manifestations of diabetic retinopathy leading to loss of central vision and visual acuity. It manifests itself with swelling around the central part of the retina, the area responsible for sharp vision. Current treatment includes laser therapy and intravitreal steroids with preventative measures including diabetes control. No one treatment has guaranteed control of diabetic macular edema which leads to deteriorating visual acuity, function and quality of life in patients. Vascular endothelial growth factor (VEGF) has been shown to be a critical stimulus in the pathogenesis of macular edema secondary to diabetes.1 Antiangiogenic therapy encompassed treatment with anti-VEGF which inhibits VEGF-driven neovascularization hence macular edema leading to decreased visual acuity.
OBJECTIVE: For this review, we evaluated the effectiveness of intravitreal anti-VEGF in treating DME. DATA SOURCES: We identified five trials (n = 525) using electronic databases (Cochrane Central Register of Controlled Trials [Central], Medline((R)), and Excerpta Medica Database [EMBASE((R))]) in October 2008, supplemented by hand searching of reference lists, review articles, and conference abstracts.
METHODS: We included all randomized clinical trials (RCTs) evaluating any form of intravitreal anti-VEGF for treating DME. The main outcome factor was change in best-corrected visual acuity and central macular thickness. One author assessed eligibility, methodological quality, and extracted data. Meta analysis was performed when appropriate.
RESULTS: We included three trials of adequate methodological quality in our meta-analysis. Patients treated with anti-VEGF showed improvement in visual acuity of -0.17 (95% confidence interval [CI]: -0.23, -0.10) and central macular thickness -84.69 (95% CI: -117.09, -52.30). Patients treated with combined anti-VEGF and intravitreal triamcinolone showed improvement of visual acuity of -0.19 (95% CI: -0.27, -0.11) and central macular thickness mean change being -111.20 (95% CI: -148.13, -74.28).
CONCLUSIONS: Anti-VEGF has been associated with an improvement in visual acuity and central macular thickness in the analysis, however trial analysis was of a short duration and further research is needed to determine long-term benefits.

Introduction

Diabetic macular edema (DME) is one of the manifestations of diabetic retinopathy leading to loss of central vision and visual acuity.2 DME results from microvascular changes in the retina in both type 1 and type 2 diabetes mellitus.3 DME is defined as thickening located within two disc diameters of the center of the macula. When this is sent within or close to the central macula, it is termed clinically significant macular edema (CSME).4 DME is further classified descriptively into focal and diffuse DME. Focal DME describes the edema from individual microaneurysms where as diffuse DME implies extensive or generalized leakage from the posterior capillary bed and breakdown of the inner blood–retinal barrier. Combinations of the two are frequent.

It is important to detect DME in the assessment of diabetic retinopathy as this is the most frequent cause of decreased vision from retinopathy. Both macular edema (ME) and CSME, defined by proximity of these signs to the foveal center, are best assessed using slit-lamp biomicroscopy or by grading stereoscopic macular photographs. Optical coherence tomography (OCT) may be also used to provide valuable confirmation and quantification of the clinical grading for DME and facilitate monitoring of its response to therapy.4

This review is concerned with diabetic macular edema, both focal and diffuse. The treatment considered in this review is anti-vascular endothelial growth factor (anti- VEGF).

Epidemiology

Between 25% and 44% of people with diabetes have some form of diabetic retinopathy (DR) at any point in time. The United States National Eye Institute pooled data from eight well-conducted population-based studies of persons aged 40 years or older with consistent retinopathy grading from retinal photographs. Data included that from five United States (US) studies, one West Indian study, and two Australian studies (Blue Mountains Eye Study [BMES] and Melbourne Visual Impairment Project [MVIP]). The overall crude DR prevalence was 40%. The prevalence of sight-threatening retinopathy (CSME or proliferative diabetic retinopathy [PDR]) was 8.2%. The general US population prevalence of DR and sight-threatening retinopathy were 3.4% (4.1 million persons) and 0.8% (900,000 persons), respectively. Projected to the current Australian population, these rates suggest a prevalence of 300,000 and 65,000, respectively, for any DR and sight-threatening retinopathy (PDR or CSME) in persons aged over 40 years.4

Clinical presentation and diagnosis

Blurred vision is the most common clinical presentation of DME, as well as distortion of the visual image (metamorphopsia), floaters, and changes in contrast sensitivity. Photophobia, changes in color vision, and scotoma occurs in DME while a loss of vision is associated with increased severity and progression of the disease. Chronic macular edema can be associated with cystoid macular edema.

Stereoscopic observation of the macular is considered the most acceptable way to diagnose DME, however use of OCT, stereofundus photography and fluorescein angiography have become acceptable tools for diagnosis in clinical practice.5

Treatment options

Strict glycemic control is the hallmark of prevention and halts progression of disease. Laser photocoagulation is used to coagulate tissue either by direct focal photocoagulation for focal macular edema or using grid photocoagulation for diffuse DME. The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that photocoagulation reduced the risk of moderate vision loss, especially for those eyes with macular edema that involved or threatened the center of the macular.6 This has become a standard treatment in clinical practice. Steroids including intravitreal triamcinolone (IVT) or surgical implantation have increased in popularity for treatment of DME due to their angiostatic effects and anti-permeabilty properties which minimize systemic toxicity. Vitrectomy is considered for treatment in eyes with chronic or diffuse DME that is not responsive to laser.7

Pathophysiology and intervention

Vascular endothelial growth factor (VEGF); also known as VEGF-A) has an important role in angiogenesis (ie, the migration and mitosis of endothelial cells) up-regulating methane monooxygenase and αvβ3 activity, and the creation of blood vessel lumen and fenestrations. As seen in preclinical models, VEGF has been shown to facilitate survival of existing vessels, contribute to vascular abnormalities (eg, tortuousness and hyper permeability) that may impede effective delivery of antitumor compounds, and stimulate new vessel growth.8

VEGF has been shown to be an endothelial cell specific mitogen, an angiogenic inducer, and is also known to increase retinal vessel permeability.2 Hypoxia-regulated VEGF release likely plays a key role in the normal development of the retina and, given its hypoxia inducibility, VEGF became an attractive candidate as a mediator of pathological intraocular neovascularization. Expression of VEGF messenger ribonucleic acid (mRNA) spatially and temporally correlates with neovascularization in several animal models of retinal ischemia.33 Elevations of VEGF levels in the aqueous and vitreous humor of human eyes with proliferative retinopathy secondary to diabetes, and other conditions have been previously described.9

Anti-VEGF modalities have been shown to potently suppress angiogenesis and growth in a variety of human tumor cells lines and also to inhibit neovascularization of ischemic retinal disease.

Bevacizumab is a full-length humanized monoclonal antibody against VEGF10 meaning it binds to all subtypes of VEGF. Pegaptanib is a synthesized anti-VEGF aptamer of a single ribonucleic acid strand that specifically targets VEGF-165 and binds only to it. Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets.11 Ranibizumab (rhuFab-VEGF) is an antibody fragment which neutralizes all VEGF isoforms and bioactive fragments.

Recent studies have demonstrated the usefulness of anti-VEGF in the reduction of macular edema secondary to central retinal vein occlusion, vascular permeability, and fibrovascular proliferation in retinal neovascularization secondary to PDR, and choroidal neovascularization secondary to aged-related macular degeneration (AMD).12

Rationale for a systematic review

Monoclonal antibodies against vascular endothelial growth factor (VEGF) were first developed in treatment of metastatic colorectal cancer.13 Anti-vascular endothelial growth factor is now commonly used for age-related macular degeneration to halt progression of abnormal growth of blood vessels in the back of the eye. A Cochrane review of five RCTs concluded the use of two anti-VEGFs to reduce the risk of visual acuity loss in neovascular age-related macular degeneration.14 More recently, these results have prompted trials in applying anti-VEGF in diabetic macular edema and macular edema secondary to central retinal vein occlusion.

In a 6-month follow-up study for anatomic and best-corrected visual (BCVA) acuity after primary intravitreal bevacizumab (Avastin®) in patients with DME, Arevalo et al2 showed improvements in visual acuity, OCT, and fluorescan angiography (FA) for all doses injected. Nguyen et al1 showed promising results with ranibizumab (a specific antagonist of VEGF) in a nonrandomized clinical trial. Results showed intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in 10 patients with DME.

In a retrospective review Chung et al15 concluded a decrease in mean visual acuity score after three months in an ischemic subgroup (patients with an enlarged foveal avascular zone [FAZ] or broken perifoveal capillary ring at the border of the FAZ, with a distinct area of capillary nonperfusion). Their findings indicate the use of anti-VEGF has a negative effect on short-term visual outcome in a particular subgroup of DME.

DME continues to progress in spite of a lack of a gold standard treatment, although options of vitrectomy, laser photocoagulation, and the emerging popularity of intravitreal steroids have been shown to halt progression of disease.

Although the ETDRS demonstrated that immediate focal photocoagulation reduced moderate visual loss by 50% (from 24% to 12%, 3 years after initiation of treatment), 12% of treated eyes still lost >15 ETDRS letters at 3 year follow-up. Approximately 40% of treated eyes with retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months. Only 3% of laser-treated eyes experienced a gain of >3 lines of vision.6

Anti-VEGF provides an option to treatment for these patients and it may also be a very useful adjunctive treatment before laser or vitrectomy surgery or a potentially important role as an adjunct to laser in the management of DME. Recently, RCTs have been published and continued to examine various antiangiogenic therapies. There has been no systematic review published evaluating RCTs conducted with treatment of VEGF for DME. Given the disease burden and significance of vision in terms of quality of life, a systematic review is needed to examine the evidence regarding the effectiveness and safety of antiangiogenic therapy with anti-VEGF modalities for treatment of DME.

Objective

The objective of this review was to assess the effectiveness of antiangiogenic therapy with anti-VEGF modalities in the treatment of diabetic macular edema. Tables 1 and 2 show inclusion and exclusion criteria for the studies considered for this review.

Table 1

Inclusion criteria for considering studies for this review

Types of studies	Randomized controlled trials
Participants	We included trials that have enrolled participants of any age and sex with any type of DME (focal or diffuse), as diagnosed in the included studies.
Interventions	We included trials that compared any anti-VEGF of any dose and duration. This was compared with another treatment, sham treatment, or no treatment.
Outcome measures	Primary outcome: BCVA: the difference in BCVA as continuous data (converted in LogMAR).
	One or more lines of improvement from baseline (ETDRS, Snellen or LogMAR equivalent).
	Central macular thickness: retinal thickness from baseline as measured by ocular coherence tomography.5
Secondary outcomes	Anatomical measures: One or more grade reduction of macular edema. Presence of edema via direct fundoscopy. Fluorescein angiography leakage.
Adverse effects	Ocular hypertension
	Anterior chamber reaction Lens opacity progression (cataract formation)
	Endophthalmitis and inflammation Fibrous proliferation
	Iris or retinal neovascularization Reduction in visual acuity and blindness
	Death
Quality of life measures	No data
Economic data	No data

Abbreviations: BCVA, best-corrected visual acuity; DME, diabetic macular edema; anti-VEGF, anti-vascular endothelial growth factor; ETDRS, Early Treatment Diabetic Retinopathy Study.

Table 2

Exclusion criteria for considering studies for this review

Exclusion criteria	RCTs for interventions of VEGF for diabetic retinopathy with no mention of diabetic macular edema or clinically significant diabetic macular edema were excluded in the analysis.
	Studies of macular edema due to another cause other than DME were excluded.
	Full text was reviewed and discussed.
	Studies that were not RCT.

Abbreviations: RCT, randomized clinical trials; VEGF, vascular endothelial growth factor; DME, diabetic macular edema.

Data sources

We searched the Cochrane Central Register of Controlled Trials (Central) (which contains the Cochrane Eyes and Vision Group Trials Register) in the Cochrane Library, Medline® and EMBASE®. There were no language or data restrictions in the search for trials. The databases were last searched on October 9, 2008. Reference lists of included trials were searched. The Australian National Health and Medical Research Council (NHMRC) guidelines for diabetic retinopathy references were searched. Archives of Ophthalmology, Ophthalmology, Retina, and the New England Journal of Medicine were searched for clinical trials and reviews. Hand-searching of references and their associated clinical trials was conducted.

We also searched for unpublished clinical trials and those in progress using clinical trials repositories including the National Institute of Health repository,16 the Current Controlled Trials repository,17 and the National Research Register Repository.18 Authors were contacted of unpublished closed trials for initial results. For full search details, see Appendix.

Selection of studies

Screening of titles and abstracts resulting from electronic and manual searches were reviewed. Abstracts were classified as relevant, potentially relevant, or not relevant for this review. Full copies of abstracts were obtained for relevant and potentially relevant reviews. Abstracts and full reviews were read to determine inclusion. Only randomized clinical trials were eligible. Study findings are in concordance with the Quorom statement. Figure 1 illustrates this selection of studies with a flow diagram.

Figure 1

Selection of studies flow diagram.

Methods

Data extraction and management

Table 3 illustrates extracted data for the primary and secondary outcomes for this review.

Table 3

Extracted data

Participant characteristics	Total number
	Gender
	Age
	Country
	Type of diabetic macular edema
	Diagnostic criteria
	Baseline visual acuity or changed in BCVA
	Visual fields
	Fluorescein angiography
	OCT-determined thickness of diabetic macular edema
	Patient inclusion and exclusion criteria
Intervention	Agent
	Dose
	Timing of first dose in relation to diagnosis
	Delivery route
	Frequency and treatment length
Study and methodology	Study design
	Trial identifiers
	Study size
	Randomization
	Masking, allocation concealment
	Duration of each study
Primary outcomes	BCVA
	Change in visual acuity
	OCT
Secondary outcomes	Retinal thickness from baseline as measured by OCT5
	Anatomical measures:
	Presence of edema via direct fundoscopy
	Fluorescein angiography leakage
	Adverse effects:
	Ocular and systemic toxicity
	Ocular hypertension
	Anterior chamber reaction
	Lens opacity progression
	Endophthalmitis
	Blindness
Additional data	Economic data, quality of life data
	Treatment compliance and losses to follow-up
Missing data	Authors contacted
	Data has been entered in Review Manager 5
	Fixed effect models used
Data collection	Microsoft Excel® spreadsheet

Abbreviations: BCVA, best-corrected visual acuity; OCT, optical coherence tomography.

Data synthesis

BCVA and central macular thickness (CMT), the primary outcome variables, are expressed as continuous variables. Standard deviations were calculated by Cunningham et al using actual P values obtained from t-tests quoted by Cochrane.19

For every study, we calculated the mean difference for the primary outcome BCVA, LogMAR, and the CMT using 95% confidence intervals. The outcome measures were pooled by use of the fixed-effect model as there were only three trials used in the meta-analysis.

Heterogeneity was calculated using Cochran’s Q statistic and quantified using the I2 statistic. These indicated the proportion of variability across studies due to heterogeneity, rather than sample error. Despite a high I2, results were pooled as examination of these studies on a forest plot indicated that the individual trial results were consistent in the direction of the effect (ie, the mean difference and confidence intervals largely fell on one side of the null line).

Clinical heterogeneity was present between the studies in relation to dosage and type of anti-VEGF use. Treatment duration and follow-up varied from 12 to 36 weeks. Despite clinical heterogeneity, trials were pooled and overall efficacy from any type of dose or duration of anti-VEGF was assessed in the objectives. Subgroup analysis was not performed due to the limited trials. Characteristics of age, gender ratios, and baseline visual acuity were similar across all trials, however variability in trial quality and intervention type, dose, and timing of administration varied. Table 4 highlights the characteristics of the included studies.

Table 4

Summary of characteristics of included studies

Trials	Year	Country	Duration	Total subjects (n)	Mean age	Participants	Participants’ VA (Snellen)	Interventions	Outcomes	Trial quality1
Ahmadieh et al20	2007	Iran	24 weeks	115	59.7 ± 8.3	CSME unresponsive to laser	<20/40	1.25 mg IVB 1.25 mg IVB, 2 mg IVT control	BCVA CMT	C
Cunningham et al21	2005	USA	36 weeks	172	61.9 62.8 61.3 64.0	DME	20/50–20/320	0.3 mg IVP 1 mg IVP 3 mg IVP control	BCVA CMT	B
Scott et al22	2007	USA	24 weeks	109	65	DME on clinical exam, retinal thickening	20/32–20/320 median 20/50	Laser baseline 1.25 mg IVB × 2 2.5 mg IVB × 2 1.25 mg IVB 1.25 mg laser week 3	BCVA CMT	C
Soheilian et al23	2007	Iran	12 weeks	103	62.4 ± 6.1	CSME	20/40–20/320	1.25 mg of IVB 1.25 mg IVB/4 mg IVT Laser	BCVA CMT	C
Paccola et al24	2007	Brazil	24 weeks	26	65.58 67.08	Refractory DME despite one session of laser	<20/40	IVB 1.5 mg IVT 4 mg	BCVA CMT	B

Abbreviations: CSME, clinically significant macular edema; DME, diabetic macular edema; BCVA, best-corrected visual acuity; CMT, central macular thickness; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; VA, visual acuity.

Asymmetry assessment of the funnel plot was not conducted for publication bias as only three trials were used in the final analysis. In future analyses, asymmetry of the funnel plot will be used to identify publication bias if at least seven studies are used. In the case of missing data, efforts to contact authors were made. Data was entered in Review Manager 5 (Cochrane, Sanfrancisco, CA) and fixed effect models were used.

Assessment of risk of bias in included studies has been considered using methods described in chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions.19 The following parameters were assessed: randomization process, allocation concealment, and masking of participants and investigators. Table 4 offers a summary of included studies characteristics for trial quality assessment score.

Description of studies

Electronic searches conducted in July 2008 and October 2008 resulted in 279 abstracts with 28 abstracts reviewed. Of those, 15 full-texts were read and five were found to meet our eligibility criteria. The reference list of each of the 15 full-text articles was searched for other relevant articles. Nine studies were excluded. Table 4 provides a summary of included studies characteristics and the Appendix lists included and excluded studies. Eight publications were not RCTs and one did not mention DME with an intervention of vitrectomy surgery in the assessment and primary outcome measure.

To our knowledge, there are 10 ongoing clinical trials using anti-VEGF for treatment of DME. Authors and trial groups were contacted, but we were unable to obtain preliminary data. Cunningham et al21 was funded by a pharmaceutical company (Pfizer).

Participants

We included five studies from three countries (United States, Iran, and Brazil) with a total of 525 eyes represented in the review. The range of eye enrollments in the trials varied with the largest study enrolling 172 eyes,21 however this was a study with three intervention groups and one control group. The numbers of subjects within each group, therefore, become smaller (n = 42–44). The study by Paccola et al24 was the smallest trial, enrolling 28 eyes.

Participants were male and female adults. All studies excluded patients who had undergone previous laser treatment at least 3–6 months prior. Soheilian et al23 included patients without prior laser treatment, whereas Ahmadieh et al20 and Paccola et al24 included participants unresponsive to previous macula laser photocoagulation at least 3 months prior. The studies by both Scott et al22 and Cunningham et al21 included patients who had had no laser treatment within 3 and 6 months, respectively.

No study included patients with other ocular conditions affecting assessment and progression of Visual acuity, such as central retinal vein occlusion, uveitis, or recent cataract surgery. All trials included patients with clinically significant macular edema and generally defined the edema as focal or diffuse and as persistent or refractory. All trials mentioned diabetic macular edema. None of the trials mention whether the patients also had cystic macular edema.

All of the trials explicitly report the primary outcome factor of BCVA according to the ETDRS. CMT is reported in all the studies either at baseline to follow-up measurements or as a mean change in thickness, measured in μm. Duration of diabetes and baseline intraocular pressure (IOP) measurements were not explicitly mentioned in all the trials. Adverse events were described within trials. Scott et al22 presented safety summary data on adverse event rates between groups, while Ahmadieh et al20 and Soheilian et al23 described percentages of adverse reaction rates amongst the different groups. Cunningham et al21 listed adverse events among their subjects with pooled results for certain subgroups (eg, hypertension). Two-way analysis of variance was performed by Paccola et al24 for raised IOP and description of adverse effects. Adverse events described were tabled see table of adverse events but data for analysis was not performed.

Interventions

Ahmadieh et al20 was a three arm trial comparing intravitreal becavizumab (IVB) to IVB intravitreal triamcinolone acetonide (IVT) to sham. Cunningham et al21 compared three doses of IVB to sham. The Scott et al22 study was a 5 treatment-arm trial divided as follows: a) focal laser at baseline with no intervention; b) 1.25 mg of IVB; c) 2.5 mg of IVB; d) baseline IVB and sham; e) and 1.25 mg of IVB plus laser therapy. The Soheilian et al23 study was a three-arm trial comparing IVB and IVB/IVT to macular photocoagulation. Paccola et al24 compared IVB to IVT interventions.

Bevacizumab was employed in four studies and one study used pegaptanib. No studies were included using ranibizumab. Table 4 gives a summary of included studies characteristics.

Outcome measures

All trials considered visual acuity using ETDRS charts and CMT using OCT as their major outcome. Definitions of visual acuity varied across the trials. BCVA was quantified in all trials. All trials used OCT to measure CMT in μm, however some studies reported CMT change whilst others reported mean baseline and follow-up results. CMT was quantified in all trials.

Adverse events of interest included: IOP increase reported in five trials; anterior chamber reaction reported in three trials; nil progression of leno pacification reported in all trials; iris neovascularization reported in three trials; and endophthalmitis, which was considered in all trialsm but only reported as events in two trials. There was no data on blindness or loss of color vision. General adverse events such as hypertension, thromboembolic events, and death were reported in four trials.

Methodological quality

Overall, three of the trials’20–22 assessors were adequately masked. Intravitreal injections were masked in one23 and there was masking for the measurement via OCT and fluorescein angiography in the other.24 The fundus assessments were performed by two retina specialists who were aware of the treatment assignment. Study data were collected, interpreted, and analyzed by two other masked investigators. Intentionto-treat analysis was performed in three trials.20,21,23

Randomization consisted of varying length of permuted blocks, simple randomization, and applying a dynamic minimization procedure using a stochastic treatment allocation algorithm based on a variance method. The process of randomization was described in one study,24 but allocation concealment was not described in any of the trials.

In the Ahmadieh et al20 study, one patient in the control group died during the study period. Cunningham et al21 left out nine patients from the study as a result of one death and eight patient requests. Scott et al22 had two subjects withdraw before completion of the study and their overall visit completion rate was 93%. Paccola et al24 reported that two subjects missed two consecutive treatments, while Soheilian et al23 reported no losses to follow-up.

Results

Meta-analysis of data was only possible for three trials.20,21,23 We were unable to use data from one trial,22 as results were expressed in medians and interquartile ranges. The authors have been contacted for their raw data, including means and standard deviations. This trial will be added to the meta-analysis once appropriate results obtained.

The study by Paccola et al24 was not included in the meta-analysis as this study compared intravitreal bevacizumab to intravitreal triamcinolone instead of a control or standard therapy such as laser. The study by Paccola et al24 has been included in the qualitative analysis of anti-VEGF.

It should be noted that with respect to the forest plots reported in this review, for outcomes such as gain in visual acuity and CMT, effect estimates to the right of the vertical line favor test treatment.

Anti-VEGF treatments were shown to have a benefit in improving BCVA. For instance, Cunningham et al21 compared three differing doses of intravitreal pegaptanib compared to a control injection. Three forests plots each with a differing dose of pegaptanib showed a consistent benefit with the intervention on visual acuity. Using pegaptanib 0.3 mg in the meta-analysis, the mean change in visual acuity was −0.17 (95% confidence interval [CI]: −0.23, −0.10). A similar treatment effect was seen using 1 mg and 3 mg of pegaptanib with a mean difference of −0.17 (95% CI: −0.23, −0.10) and −0.14 (95% CI: −0.20, −0.07), respectively (Figures 2–4).

Figure 2

Effect of best corrected visual acuity using anti-VEGF (0.3 mg of pegaptanib in one study).

Abbreviations: anti-VEGF, anti-vascular endothelial growth factor; SD, standard deviation; CI, confidence interval; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib.

Figure 4

Effect of best-corrected visual acuity using anti-VEGF (3 mg of pegaptanib in one study).

Abbreviations: CI, confidence interval; IV, intravenous; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; SD, standard deviation; VEGF, vascular endothelial growth factor.

Anti-VEGF therapy has a benefit on CMT. Cunningham et al21 compared three differing doses of intravitreal pegaptanib to a control injection. Three forests plots, each demonstrating a differing dose of pegaptanib, showed a consistent benefit of the intervention on CMT. Using pegaptanib 0.3 mg in the meta-analysis, the mean change on CMT was found to be −84.69 (95% CI: 117.09, −52.30). A similar treatment effect was seen using 1mg and 3 mg of IVP with a mean difference −84.69 (95% CI: −117.09, −52.30) and −72.47 (95% CI: −106.67, −38.27) in evidence (Figures 5–7).

Figure 5

Effect of central macular thickness using anti-VEGF (0.3 mg of pegaptanib in one study).

Abbreviations: CI, confidence interval; IV, intravenous; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; SD, standard deviation; VEGF, vascular endothelial growth factor.

Figure 7

Effect of central macular thickness using anti-VEGF (3 mg of pegaptanib in one study).

Abbreviations: CI, confidence interval; IV, intravenous; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; SD, standard deviation; VEGF, vascular endothelial growth factor.

Combined anti-VEGF with intravitreal triamcinolone was shown to benefit both visual acuity and central macular thickness compared to the control. Mean difference for visual acuity was −0.19 (95% CI: −0.27, −0.11) and the CMT mean change was −111.20 (95% CI: −148.13, −74.28) (Figures 8 and 9).

Figure 8

Effect of best-corrected visual acuity using IVB/IVT.

Abbreviations: CI, confidence interval; IV, intravenous; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; SD, standard deviation; VEGF, vascular endothelial growth factor.

Figure 9

Effect of central macular thickness using IVB/IVT.

Abbreviations: CI, confidence interval; IV, intravenous; IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; SD, standard deviation; VEGF, vascular endothelial growth factor.

Scott et al22 revealed a benefit in central macular thickness when using the intervention of 1.25 mg and 2.5 mg of intravitreal bevacizumab compared to the use of laser. There was only a trend towards reduction up to 12 weeks, however. Visual acuity also improved with the two IVB interventions compared to laser at 3 weeks.

There was significant heterogeneity amongst the trials: 65%–81% for the assessment of visual acuity and 49%–73% for CMT. Despite the high I2, results were pooled and reported, as examination of the forest plot indicated that the individual trial results were consistent in the direction of the effect (ie, the mean difference, standard deviation and confidence intervals largely fell on the side of the null line favoring the intervention).

Subgroup analysis and assessment of publication bias could not be preformed due to small study numbers and data set. Meta-regression may be preformed in future to group the differing interventions in the Cunningham21 and Scott22 studies compared to a control group once data becomes available.

The pooled trend favors intervention using anti-VEGF to increase visual acuity and encourage CMT changes. Further-more, trial quality was found to be better among those showing an improvement of BCVA and CMT using anti-VEGF.

Complications

There were no significant increases in complications reported among the interventions trialed. Complications associated with intravitreal injections, including ocular hypertension, were noted in a few studies. All trials noted to have ocular hypertension comment of successful treatment of increased IOP. Table 5 shows a summary of included study adverse events.

Table 5

Summary of included studies’ adverse events

Trials	Iris or retinal neovascularization	Anterior chamber reaction	Endophthalmitis	Lens opacity progression	Ocular hypertension	Fluorescein angiography reduced leakage and edema	Blindness	Fibrous proliferation	Death
Ahmadieh et al20	Zero	IVB 19.5%IVB/IVT 18.9%	No data	Zero	3 eyes IVB/IVT groups		No data	1 eye in IVB group (2.4%)	1 patient in control group
Cunningham et al21	Zero		1 injection out of 652 in IVP dose	Zero			No data
Scott et al22			1 post injection	No data	1 eyes IVB 1.25 mg		Zero		1 patient pancreatic cancer
Soheilian et al23	3 eyes IVB2 eyes IVB/IVT2 eyes laser	7 eyes (18.9%) in IVB 4 eyes (12.1%) in IVB/IVT	No data	Zero	3 eyes in IVB/IVT group	IVB 26 (70.2%)IVB/IVT 19 (57.6%)Laser 17 (51.5%)	No data
Paccola et al24	Zero	Zero	Zero	Zero	3 eyes in IVB/IVT group significant increase in IVT group compared to IVB		Zero

Abbreviations: IVB, intravitreal bevacizumab; IVP, intravitreal pegaptanib; IVT, intravitreal triamcinolone.

Discussion

In this systematic review of randomized controlled trials our meta-analysis has shown that anti-VEGF alone or in combination with triamcinolone is effective in the treatment of diabetic macular edema with an improved change in BCVA and CMT. Over with the treatment duration ranging from 12 to 36 weeks the initial analysis has shown a short-term benefit for the intervention and available information of adverse effects does not suggest potentially vision threatening complications with intravitreal injections.

Only the three trials included in the meta-analysis were of good methodological quality. There is no direct evidence comparing different types of anti-VEGF therapies so far published. The Scott et al22 trial was conducted by a pharmaceutical company, thus has potential for bias due to conflict of interest. As mentioned above, we were also unable to use this trial in the meta-analysis due to the presentation of data using medians and interquartile ranges. Our assumption was that the outcome distributions were skewed.

Cunningham et al21 used three differing doses of IVP compared to a control. We were unable to scrutinize these interventions together in the same analysis as the same group of control subjects would have been entered twice. Hence, three separate analysis tables were calculated, each representing a different dose, from this trial. Future meta-regression to pool these groups may be performed.

Paccola et al24 suggest intravitreal triamcinolone has a significant benefit in visual acuity over intravitreal bevacizumab. There was also a significant reduction in CMT in the intravitreal triamcinolone group at week 24 (P = 0.024), with similar results for visual acuity compared with IVB. Analysis of IVB was not performed to control so, although a benefit was anecdotally noted to improve visual acuity and CMT from baseline, this provides no significance statistically.

Subgroup analysis was not performed due to the limited number of studies. Similarly, assessment of publication bias was not performed due to the limited number of studies included in meta-analysis. Future inclusion of more clinical trials is needed for meaningful subgroup analysis including assessment of publications bias.

Quality of life and economic data were not available in any of the included studies making it is difficult to assign meaning to LogMAR changes in visual acuity. However, the trend is favorable towards intervention with regards to improvement of vision and perhaps slowing further progression of disease and its associated morbidity. Reduction in macular thickness, especially in regards to CMT, is considered a mechanism for visual improvement in the treatment of macular edema. Therefore, a corresponding reduction in CMT would be expected if there was a trend towards vision improvement. This is confirmed in the analysis where the intervention using anti-VEGF favored CMT improvement.

As current treatment is directed at stabilizing or reducing vision loss, an important finding is that there were no significant increases in complications among the interventions.

The results were limited by heterogeneity in the included trials. The difference in the intervention doses and duration of treatment contributed to this. A strength within the studies is that the exact definition and measurement of outcomes were fairly consistent and our pooled results should not be biased due to misclassification. The limited data for the Scott et al22 study made it difficult to quantify the trial results concerning the effect of the intervention in a meaningful way.

Overall, most studies show a promising trend towards benefits in visual acuity and central macular thicken with use of anti-VEGF. Excluded studies continue to confirm this trend for most patients, although subgroups of patients with DME with ischemia were found to have a negative outcome.15

Conclusion

Strict glycemic and blood pressure control are still the hallmarks of prevention and progression of diabetic macular edema. The ETDRS brought laser therapy into consideration for mainstream use for diabetic macular edema with some modest benefit to visual acuity evidenced.6

Anti-VEGF was associated with an improvement in visual acuity and CMT in our analysis. Trials studied were all of a short duration and there were no long-term follow-up studies found. There was no evidence found comparing the different types of anti-VEGF. The use of anti-VEGF is promising to improve visual acuity and CMT caused by diabetic macular edema. Further trials are being conducted, at present, with ongoing follow-up studies to assist in determining overall long-term benefit. The Appendix outlines some of the characteristics of these ongoing studies.

Implications for future research

The five studies in included in our report dealt primarily with persistent or refractory diabetic macular edema and raised issues including the duration of intervention, dosage, timing of repeats and follow-up, and the role of combination therapy with intravitreal triamcinolone in relationship to control or laser therapy. The question arises whether treatment should be reserved for just this chronic or refractory group of patients or introduced during earlier stages of diabetic macular edema. Economic and quality of life data need to be considered, as well as further quantitative analysis of overall effects of complications. Long-term, follow-up studies with considerations for adverse effects need to be quantified and documented to provide a better understanding of risk benefits for patients with diabetic macular edema.

Table 1

Search: Central

diabetic macular edema.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 18 diabetic macula odema.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 0 Diabetic Retinopathy.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 843 macular edema.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 53 Macular Edema, Cystoid.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 74 Macular Degeneration.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 609 (DME or DMO or CME or CSME).mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 197 6 or 4 or 1 or 3 or 7 or 2 or 5 1620 angiogenesis inhibitors.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 96 angiogenesis inhibitors.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 96 endothelial growth factors.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 68 vascular endothelial growth factors.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 65 (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$).tw. 120 (anti adj2 VEGF$).tw. (endothelial adj2 growth adj2 factor$).tw. 265 (macula$ adj2 swell$).tw. 1 11 or 13 or 10 or 9 or 12 or 15 or 14 414 8 and 17 71 from 18 keep 10, 33, 45, 47, 51, 53–54... 9

Table 2

Search: Medline®

randomized controlled trial.pt. (randomized or randomised).ab,ti. placebo.ab,ti. randomly.ab,ti. trial.ab,ti. groups.ab,ti. dt.fs. or/1–7 exp animals/ exp humans/ 9 not (9 and 10) 8 not 11 exp clinical trial/ (clin$ adj3 trial$).tw. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. placebo$.tw. random$.tw. exp experimental design/ exp control group/ 18 or 19 or 16 or 13 or 17 or 15 or 14 angiogenes$.tw. exp angiogenesis inhibitors/ exp angiogenic factor/ endothelial cell growth facto$.tw. exp vasculotropin/ (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$).tw. (anti adj2 VEGF$).tw. (endothelial adj2 growth adj2 factor$).tw. exp angiogenesis inducing agents/ 27 or 25 or 28 or 21 or 26 or 22 or 24 or 23 or 29 exp diabetic retinopathy/ exp macular edema cystoid/ exp macular degeneration/ (macula$ adj2 edema).tw. (macula$ adj2 edema).tw. DME.tw. DMO.tw. CME.tw. CSME.tw. (macula$ adj2 swell$).tw. microaneurysm$.tw. (dilat$ adj2 capillar$).tw. 35 or 33 or 32 or 39 or 40 or 36 or 41 or 42 or 38 or 34 or 37 or 31 30 and 43 and 20 from 44 keep 2, 9, 11–12, 15, 22–23, 27... 28 from 45 keep 1, 3, 5, 7, 9–10, 12... 15 from 46 keep 5, 7–9, 12–15 8 from 47 keep 1–3, 5–6 5

Table 3

Search: Embase®

randomized controlled trial.pt. (randomized or randomised).ab,ti. placebo.ab,ti. randomly.ab,ti. trial.ab,ti. groups.ab,ti. dt.fs. or/1–7 exp animals/ exp humans/ 9 not (9 and 10) 8 not 11 clinical trial.pt cluster trial exp control group double blind$.tw single blind$.tw (blind$ or mask$).tw exp cross over exp comparative study prospective$.tw or 13–21 or 12–22 angiogenes$.tw. exp angiogenesis inhibitors/ exp angiogenic factor/ endothelial cell growth facto$.tw. exp vasculotropin/ (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$).tw. (anti adj2 VEGF$).tw. (endothelial adj2 growth adj2 factor$).tw. exp angiogenesis inducing agents/ or 24–32 exp diabetic retinopathy/ exp macular edema cystoid/ exp macular degeneration/ (macula$ adj2 edema).tw. (macula$ adj2 edema).tw. DME.tw. DMO.tw. CME.tw. CSME.tw. (macula$ adj2 swell$).tw. microaneurysm$.tw. (dilat$ adj2 capillar$).tw. or 34–45 23 and 33 and 46