Macular Edema

P.S. Silva • Z.A. Haddad • J.K. Sun • J.D. Cavallerano • L.P. Aiello

Introduction

For the past 20 years, diabetic retinopathy (DR) has remained the most common cause of blindness in the working age adult population in the United States and other developed countries.^1–3 DR is the most frequently occurring microvascular complication of diabetes, affecting nearly all persons with 15 or more years of diabetes.^4,5 Diabetic macular edema (DME) is a manifestation of DR that may occur in any stage of the retinopathy and often leads to loss of central vision.^6–8 The natural course of DME is characterized by chronic continued retinal vascular leakage and retinal thickening, often with intraretinal lipid deposition.⁶ The Wisconsin Epidemiologic Study of Diabetic Retinopathy reported that over a 10-year period, DME was present in 24% of patients and visually threatening clinically significant macular edema (CSME) was present in 10% of patients.^7,8 DME is more common in type 2 diabetes patients on insulin than in type 1 diabetes patients, and prevalence increases in both types as the duration of diabetes increases.⁸ The involvement of the center of the macula has been shown to be an important predictor in determining visual outcome among patients with CSME.^9–11 If left untreated, 24% of eyes with CSME and 33% with center involving CSME will have moderate visual loss (MVL; i.e., a doubling of the visual angle) within 3 years.¹² The Early Treatment Diabetic Retinopathy Study (ETDRS) established focal/grid laser photocoagulation as the standard of care in the treatment of CSME.¹² Focal/grid laser was shown to be effective at reducing the risk of MVL by 50%, but 15% of laser treated patients in the ETDRS continued to develop MVL after 3 years.¹² This continued development of visual loss following focal/grid laser has encouraged investigators to search for novel treatment modalities in the management of eyes with DME.

Rationale

Focal/grid laser is currently the only treatment modality for CSME that has been validated for long-term safety and efficacy by multiple large clinical trials.^12–14 Despite its proven benefit, focal/grid laser does not directly address the underlying pathophysiologic mechanisms of DME, and this may explain suboptimal response and continued visual loss in spite of adequate laser treatment in some patients.¹⁵ Furthermore, the pathogenesis of DME is multifactorial and likely involves multiple mechanisms including inflammation,¹⁶ angiogenesis,^17,18 endothelial junctional dysfunction,^19,20 and contribution from different growth factors^21,22 all of which contribute to significant variability in the response to specific treatment modalities.

Vascular endothelial growth factor (VEGF) has been shown to play a central role in the pathophysiologic process underlying neovascular eye diseases.^17,18 As such, anti-VEGF-based agents have emerged as a novel, highly specific treatment modality for retinal vascular pathology. Diabetic retinal neovascularization has been shown to be exquisitely sensitive to treatment with VEGF inhibitors, with regression of the neovascularization beginning as early as one day after treatment with complete regression commonly observed²³ (Fig. 15.1). Studies of limited size and duration suggest that the anti-VEGF treatment response may be more variable for DME, suggesting that DME is a multifactorial process involving pathways in addition to VEGF (Fig. 15.2). Determining the optimal treatment for DME has remained elusive and has prompted significant research and development of anti-VEGF and similarly based DME treatment modalities.

FIGURE 15.1. Anti-VEGF agents have been shown to be effective in inducing temporary regression of retinal neovascularization. Retinal neovascularization on the optic nerve shows marked regression following a single intravitreal injection of bevacizumab. (Images courtesy of Robert Avery MD, Santa Barbara, CA.)

FIGURE 15.2. The responses of diabetic macular edema to intravitreal anti-VEGF agents have significant variability and require repeated injections to prevent the recurrence. Following injections of ranibizumab, there is a substantial reduction in retinal thickness but the edema recurs when injections are withheld. (Images from the Beetham Eye Institute Image Library.)

Presently, there are many agents that target different points of the pathophysiologic cascade theorized to underlie the development of DME (Table 15.1). There are drugs that directly inhibit the VEGF molecule such as the anti-VEGF aptamer pegaptanib (Macugen; OSI Pharmaceuticals, Melville, NY), the monoclonal antibody fragment ranibizumab (Lucentis; Genentech Inc., San Francisco, CA), and the full-length monoclonal antibody bevacizumab (Avastin; Genentech Inc., San Francisco, CA). Modified soluble VEGF receptor analog VEGF-Trap (Regeneron Pharmaceuticals, Tarrytown, NY) is also being studied. It is a fusion protein of portions of VEGF-R1 and VEGF-R2 and the Fc region of human IgG that binds all VEGF isoforms with higher affinity than anti-VEGF antibodies. Other treatment modalities include small interfering RNAs (siRNAs) bevasiranib (Opko Health Inc., Miami, FL), Rapamycin (Sirolimus, MacuSight Inc, Union City, CA), and Sirna-027 (Sirna Therapeutics, San Francisco, CA). They inactivate mRNA ultimately by inhibiting mRNA translation, which suppresses VEGF production and VEGF receptor production. Oral agents with ocular bioavailability such as Vatalanib (PTK-787; Novartis International, Basel, Switzerland), which is an inhibitor of VEGF receptor tyrosine kinases, Ruboxistaurin (Eli Lilly, Indianapolis, IN), an oral protein kinase C β (PKC β) inhibitor, and oral and topically active multitarget kinase inhibitors (such as Src kinase inhibitors) have received significant interest. The future may lie in the development of treatment regimens that act on different points along multiple pathways responsible for the development of DME. The targeting of multiple points along more than one pathway may increase the clinical effectiveness and robustness of the therapeutic effect. Additionally, having a wide selection of highly specific agents may promote the development of an optimal treatment strategy tailored to the needs of a specific patient.

As of June 2009, there are 145 registered clinical trials assessing the efficacy or safety of response of various regimens in the treatment of DME. Twenty-two trials specifically target VEGF or VEGF-related pathways. A summary of the important highlights and results of published trials is presented in Table 15.2.

Pegaptanib

Pegaptanib (Macugen, OSI Pharmaceuticals, Melville, NY) is a ribonucleic acid aptamer that selectively binds to the VEGF165 isoform. Trials utilizing pegaptanib provided the proof of principle evidence regarding the effectiveness of anti-VEGF agents in the treatment of neovascular and exudative retinal disease. In December 2004, it was the first anti-VEGF agent to be approved by the United States Food and Drug Administration (U.S. FDA) for the treatment of neovascular wet age-related macular degeneration (AMD). Clinical trials assessing its efficacy and safety in the treatment of DME are currently ongoing.

In a prospective, randomized, double-masked, controlled multicenter phase 2 trial, pegaptanib (0.3, 1.0, or 3 mg) versus sham injection was administered at 6-week intervals via intravitreal injection in 172 subjects with center-involving DME (Fig. 15.3).²⁴ Intravitreous pegaptanib (0.3, 1, 3 mg) or sham injections were performed at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (p = 0.04). A larger proportion of those receiving 0.3 mg as compared with sham gained 10 or more letters in VA (approximately two lines) (34% vs. 10%; p = 0.003) or 15 or more letters (18% vs. 7%; p = 0.12). Mean central retinal thickness decreased by 68 μm with 0.3 mg versus an increase of 4 μm with sham (p = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both ≥100 μm (42% vs. 16%; p = 0.02) and ≥75 μm (49% vs. 19%; p = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; p = 0.04). All pegaptanib doses were well tolerated. Despite the observed differences in the efficacy of the three dosages, the study was not powered sufficiently to detect a difference between the different dosages. Furthermore, the eyes enrolled had focal laser treatment deferred at baseline and a laser treatment control arm was not utilized in the trial. It is unknown if these results are better than if focal photocoagulation had been given at study entry and it is unknown if these beneficial outcomes would provide lasting benefit that would persist for at least 3 years as is seen with focal/grid laser.²⁵ All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%) and was not associated with severe visual loss.

FIGURE 15.3. 1:From a representative subject, a baseline color fundus photograph (A), OCT image (B), and serial fluorescein angiographic images (C, D) before treatment with intravitreous pegaptanib, 0.3 mg, show intraretinal hemorrhage, microaneurysm formation, and exudates; a retinal thickness of 422 μm with cystic spaces evident at the center of the macula; and progressive development of diabetic macular edema (D). Previous focal laser photocoagulation scars are apparently superior and temporal to the fovea (C, D). Visual acuity at time of study entry was 68 Early Treatment Diabetic Retinopathy Study chart letters (Snellen acuity, 20/50). Laser photocoagulation was given 6 months before enrollment. 2:From the same subject as in Figure 5.3A, a week-36 color fundus photograph (A), OCT image (B), and serial fluorescein angiographic images (C, D) after 4 intravitreous injections (at day 0, week 6, week 12, and week 24) of pegaptanib, 0.3 mg, show partial resolution of retinal microaneurysms, hemorrhages, and exudates; a marked decrease in retinal thickness to 267 μm; complete resolution of the intraretinal cystic spaces; and decreased perifoveal leakage corresponding to the anatomic changes observed on OCT, version 2. Visual acuity at week 36 was 79 Early Treatment Diabetic Retinopathy Study chart letters (Snellen acuity, 20/25). No focal laser photocoagulation treatments were given after enrollment. (Reproduced with permission from Cunningham et al. Ophthalmology. 2005;112:1747–175.)

Currently, a phase 2/3 randomized, controlled, double-masked, multicenter, comparative trial, in parallel groups is ongoing to further investigate the observed benefit seen in the initial phase 2 trial. Intravitreal injections of 0.3 mg pegaptanib will be given as often as every 6 weeks for 2 years in patients with center-involving DME with an open-label 3-year extension (ClinicalTrials.gov identifier: NCT00605280). The primary outcome measure is the proportion of patients after 1 year who experience an improvement in vision from baseline in the treatment group compared to the sham injection group. The trial has been completed with 260 subjects enrolled and preliminary unpublished results suggesting significant benefit with intravitreal pegaptanib treatment. The mean visual acuity gain in ETDRS letters with pegaptanib treatment compared to sham at one and two years were 5.2 vs 1.2 (p = 0.05) and 6.1 vs 1.3 (p = 0.01) respectively. The percentage of patients gaining ≥ 10 ETDRS letters at 2 years was significantly large in patients receiving pegaptanib treatment compared to sham (37% vs 20%, p=0.0005). Adverse events were reported to be consistent with those observed in clinical trials of pegaptanib in patients with neovascular AMD (Box 15.1).

Bevacizumab

Bevacizumab (Avastin, Genentech Inc., San Francisco, CA) is a full-length humanized monoclonal antibody that inhibits all isoforms of VEGF-A. It has two binding sites compared to ranibizumab. It has a molecular weight of 149 kDa whereas ranibizumab has a molecular weight of 48 kDa. Ranibizumab has a threefold to sixfold higher affinity to VEGF compared to bevacizumab.²⁶ Being larger, bevacizumab has a longer half-life. Bevacizumab was approved by the FDA in February 2004 for the treatment of metastatic colorectal cancer, metastatic breast cancer, and non–small cell lung cancer.²⁷ It has been used as an off label treatment for AMD, proliferative diabetic retinopathy (PDR), radiation retinopathy, uveitic macular edema, vein occlusions, and DME.²⁸ It has attracted interest partly because of its significantly lower cost and presumably (but unproved) similar efficacy to ranibizumab, given the similarities in molecular structure.

In a large interventional retrospective multicenter study from six different countries, 101 eyes of 82 patients with diffuse DME were randomized to either 1.25 or 2.5 mg of primary intravitreal bevacizumab injection. All patients were followed for 12 months (mean 57.6 ± 8.4 weeks). The mean number of intravitreal bevacizumab injections per eye was three (range: 1–2 injections) at a mean interval of 14.1 ± 10.5 weeks. Best corrected visual acuity (BCVA) in the 1.25 mg group at 1 month improved from 20/190 (logMAR = 0.97) to 20/85 (logMAR 0.62)(p = 0.0001). This improvement was maintained throughout the follow-up period. The mean final BCVA at 12 months was 20/76 (logMAR = 0.58) (p < 0.001). In the 1.25 mg group, the mean central macular thickness (CMT) decreased from 419.1 ± 201.1 μm at baseline to 268.2 ± 95.5 μm at 12 months (p < 0.0001). Similar visual and anatomic improvement was seen in the 2.5 mg group with no difference in the results. Adverse events included transient high blood pressure in one patient (1.2%), transient increased intraocular pressure in one eye (1%), and tractional retinal detachment in one eye (1%). Therefore, over a 12-month period, intravitreal bevacizumab at a dose of either 1.25 or 2.5 mg resulted in equal anatomic and visual improvement in 49.5% of patients with minimal, if any, serious side effects. The maximum benefit was seen during the first month and was maintained over 12 months and 82.2% of eyes had reduced risk of VA loss. Comparing eyes that had one or two injections to those that had three or more injections, a significant drop in BCVA at 6 months was seen in the former group, suggesting that repetitive injections are needed with at least three injections per year.²⁹

A prospective, noncomparative case series on 126 patients evaluated the effect of 1.25 mg bevacizumab on chronic (>12 months) diffuse macular edema not responsive to previous treatments; 62% had received focal laser treatment, 38% panretinal laser treatment, 11% vitrectomy, and 41% intravitreal injection of triamcinolone. Patients were followed every 4 weeks for up to 12 months. Only 59 patients completed the 12 months follow-up. Thirty-eight percent of patients did not receive focal laser treatment prior to enrollment because of extensive macular ischemia, close proximity of the source of leakage to the fovea as assessed by fluorescein angiography (FA), and anatomic alterations of the retina such as cystoid spaces reflecting the chronicity of the macular edema; however, the investigators did not withhold photocoagulation from any patient, if indicated. Patients had additional injections at 4-week intervals if they responded to the previous injection by retinal thickness reduction or visual acuity improvement. Injections were postponed if either no further reduction of retinal thickness was noted on optical coherence tomography (OCT) scans or no further improvement of VA was measured. The decision to perform a reinjection was based on the recurrence of macular edema (change in OCT > 100 μm centrally) and associated deterioration of VA (>5 ETDRS letters) during follow-up. Patients were classified as nonresponders if there was no change in retinal thickness detected after three injections and no further reinjections were performed. No other treatments including laser photocoagulation were applied during the study period. Within this period, 48% received at least three intravitreal injections of bevacizumab. Mean diameter of foveal avascular zone (FAZ) was 858 ± 341 μm. Forty-four percent had FAZ > 800 μm indicating marked macular ischemia. Mean VA at baseline was 40.3 ETDRS letters. Mean VA change was -1.6 ETDRS letters at 6 months (p = 0.3) and +5.1 ETDRS letters at 12 months (p = 0.02). Throughout follow-up, VA changes were not significant except at 12 months. Mean central retinal thickness on OCT was 463 μm at baseline, 374 μm at 6 months (p < 0.001), and 357 μm at 12 months (p < 0.001). Macular ischemia did not progress as a result of injections, and the FAZ diameter was not found to be related to central retinal thickness or visual acuity. There was no correlation between the visual and anatomic outcomes. Age, prior treatments, and central retinal thickness were not predictive of visual outcome. The authors concluded that patients with advanced stages of macular edema (diffuse and chronic) not responsive to prior treatments had long-term decrease in central retinal thickness after repeated injections of bevacizumab; however, a better functional outcome could be achieved if macular ischemia was not present and if tighter inclusion criteria were applied.³⁰

Bonini-Filho et al. noted more favorable changes in BCVA and in CMT and total macular volume (TMV) in patients with DME and “severe capillary loss” after treatment with bevacizumab. This was a multicenter, open-label, nonrandomized study on 10 consecutive patients with DME, CMT > 250 μm, and “severe” capillary loss within 1,500 μm of the center of the macula (as assessed by FA according to ETDRS criteria). Patients received 1.5 mg (0.06 mL) of intravitreal bevacizumab at baseline with reinjections at 8-week intervals if subretinal or intraretinal fluid were persistent or recurrent on OCT. Main outcome measures were changes in BCVA and OCT variables (CMT and TMV) at 1 year. The mean logMAR ETDRS BCVA was 0.786 (20/125^–1) at baseline, 0.646 (20/80^–2) at week 8, 0.580 (20/80^–1) at week 16, 0.574 (20/80^–1) at week 24, and 0.558 (20/80^–2) at week 54. A significant change in BCVA was noted at all follow-up visits (p < 0.008) compared to baseline. The mean CMT (μm)/TMV (mm³) values were, respectively, 472.6/10.9 at baseline, 371.4/9.9 at week 8, 359.5/9.8 at week 16, 323.9/9.4 at week 24, and 274.6/8.7 at week 54. Compared with baseline, a significant change in both CMT and TMV was noted only at 24 and 54 weeks (p < 0.007). At 54 weeks, bevacizumab reduced dye leakage on FA compared to baseline with no worsening of macular ischemia in all patients. The improvement in BCVA and in OCT variables at week 24 was maintained up to week 54, even after a period of approximately 6 months (30 weeks) with no additional reinjections. This study, however, was limited by its small sample size and by having no control arm.³¹

The Diabetic Retinopathy Clinical Research Network (DRCR.net) conducted a randomized phase 2 clinical trial evaluating the effect of intravitreal bevacizumab on DME over a 70-week period. Efficacy was assessed at 12 weeks and safety at 24 weeks. One-hundred-twenty-one eyes with center involving DME, CST of ≥275 μm on OCT, and BCVA ranging from 20/32 to 20/320 were randomly assigned to one of the five groups: 19 eyes were randomized to focal laser at baseline, 22 eyes to 1.25 mg of intravitreal avastin injection at baseline and 6 weeks, 24 eyes to 2.5 mg of intravitreal avastin injection at baseline and 6 weeks, 22 eyes to 1.25 mg of intravitreal avastin injection at baseline and sham injection at 6 weeks, and 22 eyes to 1.25 mg of intravitreal avastin injection at baseline and 6 weeks with laser photocoagulation at 3 weeks. At baseline, median central subfield thickness (CST) was 411 μm and median Snellen VA equivalent was 20/50. Compared with the laser group, the second and third groups had a greater reduction in CST at 3 weeks and about one line better median visual acuity over 12 weeks. There were no meaningful differences in CST observed with bevacizumab relative to photocoagulation after the 3-week time point. There was no benefit demonstrated by using the larger dose of avastin. A CST reduction >11% (the reliability limit) was present at 3 weeks in 36/84 (43%) bevacizumab-treated eyes and in 5/18 (28%) eyes treated with laser alone, and at 6 weeks in 31/84 (37%) and 9/18 (50%) eyes, respectively. There appeared to be no short-term benefit to combining focal photocoagulation with bevacizumab; however, a beneficial effect of combining focal laser with bevacizumab injection could occur over a time longer than the duration of the study. Systemic safety evaluation of bevacizumab was limited by the modest sample size and the short follow-up; however, few adverse events were reported. Endophthalmitis developed in one eye. During the first 24 weeks, two patients treated with bevacizumab had myocardial infarction without attributing the cause to the drug, one patient had congestive heart failure, three patients had elevated blood pressure, and three patients had worsened renal function.³² A large phase 3 randomized clinical trial is needed to determine if there is a clinically meaningful benefit of intravitreal avastin injection for DME.

In a retrospective study, 11 previously vitrectomized eyes with internal limiting membrane peel and persistent DME showed no improvement after three intravitreal avastin injections at 6 months. This result could be secondary to the rapid wash out of the drug in vitrectomized eyes. The study was limited by its small sample size and short follow-up.³³

There have been additional studies comparing bevacizumab to triamcinolone and evaluating triamcinolone as an adjunct to bevacizumab in treating DME. A prospective comparative interventional case series compared the effect of an intravitreal injection of bevacizumab with that of triamcinolone acetonide for DME on 28 eyes of 14 patients with bilateral DME. Each patient received an intravitreal injection of 4 mg triamcinolone acetonide in one eye and 1.25 mg bevacizumab in the other eye. Subjects were followed for 24 weeks after the injection. At week 1, foveal thickness and VA in the triamcinolone group improved from 522.3 ± 91.3 μm and 0.64 ± 0.28 logMAR at baseline to 342.6 ± 85.5 μm and 0.33 ± 0.21 logMAR. The central foveal thickness remained at this level till week 12, whereas in the bevacizumab group, the foveal thickness and VA improved from 527.6 ± 78.8 μm and 0.61 ± 0.18 logMAR at baseline to 397.6 ± 103.0 μm and 0.37 ± 0.17 logMAR. The central foveal thickness remained at this level till week 4; however, DME recurred in both groups at 24 weeks with the triamcinolone group faring better. The foveal thickness and visual acuity were 410.4 ± 82.4 μm (p = 0.002) and 0.47 ± 0.25 logMAR at 24 weeks in the triamcinolone group and 501.6 ± 92.5 μm (p = 0.012) and 0.61 ± 0.17 logMAR in the bevacizumab group. In summary, bevacizumab led to a 24% reduction in foveal thickness at week 1 that persisted till week 4, then decreased gradually to a 5% reduction by week 12. Triamcinolone led to a 35% reduction in foveal thickness at week 1 that persisted until week 12. The modest improvement seen in the bevacizumab group could be explained by the fact that only one injection was given during the follow-up period; triamcinolone is a multipotency drug that targets different pathophysiologic pathways in DME; injecting bevacizumab in one eye could have some effect on the fellow eye, biasing the results with triamcinolone; and lastly, the central retinal thickness in this subgroup of patients was higher at baseline compared to other studies.³⁴

A prospective, placebo-controlled, randomized clinical trial compared intravitreal bevacizumab with triamcinolone to intravitreal bevacizumab without triamcinolone for refractory DME. One-hundred-fifteen eyes of 101 patients with refractory DME were randomly assigned to one of the three study arms: (a) three injections of intravitreal bevacizumab (1.25 mg/0.05 mL) at 6-week intervals, (b) combined intravitreal injections of bevacizumab and triamcinolone (1.25 mg/0.05 mL and 2 mg/0.05 mL, respectively) followed by two intravitreal injections of bevacizumab at 6-week intervals, and (c) sham injection (control group). CMT was reduced significantly in both the bevacizumab and combination groups. At week 24, CMT change compared to the baseline was -95.7 μm (95% CI, -172.2 to -19.26) in the bevacizumab group, -92.1 μm (95% CI, -154.4 to -29.7) in the combination group, and +34.9 μm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between each of the two treatment groups and control groups (p = 0.012 and 0.022, respectively). Improvement of BCVA was measured at weeks 6 and 12 in the bevacizumab/triamcinolone group and the bevacizumab groups, respectively. Compared to baseline, BCVA at 24 weeks in the bevacizumab and bevacizumab/triamcinolone groups was significantly better than the control group (p = 0.01 and 0.006, respectively); however, there was no significant difference in the change of CMT and BCVA between the bevacizumab and bevacizumab/triamcinolone groups (p = 0.99). Elevation of IOP occurred in three eyes (8.1%) in the bevacizumab and triamcinolone groups. The study results suggest that by adding triamcinolone in the first injection, earlier visual improvement can be achieved; however, there was no demonstrated significant additive effect during later follow-up.³⁵

Paccola et al.³⁶ randomly assigned 28 patients to receive a single intravitreal injection of either 4 mg/0.1 mL triamcinolone acetonide or 1.5 mg/0.06 mL bevacizumab. CMT was significantly reduced in the intravitreal triamcinolone group compared with the bevacizumab group at weeks 4, 8, 12, and 24 (p < 0.05). LogMAR best-corrected visual acuity was significantly higher at weeks 8 (0.69; ~20/100⁺¹) and 12 (0.74; ~20/100^–2) in the intravitreal triamcinolone group compared with the bevacizumab group at weeks 8 (0.83; ~20/125^–1) and 12 (0.86; ~20/160⁺²) (p < 0.05), also suggesting that a single intravitreal injection of triamcinolone may offer certain advantages over bevacizumab in the short-term management of refractory DME; however, a significant change from baseline in mean intraocular pressure was seen at week 4 (+2.25 mm Hg) in the intravitreal triamcinolone group (p < 0.0001).

Soheilian et al.³⁷ conducted a randomized three-arm clinical trial comparing intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular laser photocoagulation as a primary treatment of DME. One-hundred-fifty eyes of 129 patients with clinically significant DME and no previous treatment were randomly assigned to one of the three groups: (a) 1.25 mg of intravitreal bevacizumab injection (50 eyes), (b) 1.25 mg of intravitreal bevacizumab and 2 mg of intravitreal triamcinolone (50 eyes), and (c) the laser group (50 eyes). Whenever indicated, retreatment was performed at 12-week intervals. The bevacizumab group had better visual acuity outcomes at 36 weeks compared with the combination and laser groups with a logMAR change of -0.28±0.25 compared with baseline (p = 0.053). Significant CMT reduction was observed in all groups only up to 6 weeks; however, CMT changes were not significant among the groups in all visits. Retreatment up to 36 weeks was required for 14 eyes in the bevacizumab group, 10 eyes in the combination group, and 3 eyes in the laser group. Only one intravitreal bevacizumab injection was required in 72% of cases in the first group. Visual acuity improved by two or more Snellen lines at 36 weeks in 37%, 25%, and 14.8% of patients in the bevacizumab, combination, and laser groups, respectively. Intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation with no additive effect from triamcinolone; however, this finding did not correlate with a similar anatomic outcome. The better results seen with the bevacizumab group could be secondary to cataract progression or adverse effects from the triamcinolone preservatives. A more beneficial effect of laser could be seen with a longer follow-up. This study is currently being extended for up to 2 years.

Faghihi et al.³⁸ showed that a single intravitreal bevacizumab injection or triamcinolone plus bevacizumab injection had significantly greater macular thickness reduction at 16 weeks in comparison to standard laser treatment; however, the response for bevacizumab alone was short-lived compared with the combination group (bevacizumab and triamcinolone) maintaining their superiority to the laser group at week 16 (p < 0.001). Visual acuity improvement in the combination group was marginal and at most was 0.1 logMAR and did not correlate with the reduction in the retinal thickness.

Currently, there are seven active clinical trials designed to test the effect of bevacizumab on DME. They include head-to-head trials comparing intravitreal bevacizumab injection to intravitreal ranibizumab or triamcinolone acetonide injection. Clinical trials testing the efficacy of combined intravitreal bevacizumab with triamcinolone acetonide injection and intravitreal bevacizumab as an adjunct to pars plana vitrectomy are also underway. Posterior subtenons injection of avastin for DME is being investigated as well.

A phase 4 interventional, randomized, double-masked trial is underway to compare the effect of intraocular bevacizumab with intraocular triamcinolone in patients with CSME (TRIASTIN) (ClinicalTrials.gov identifier: NCT00682539). This study is currently recruiting patients. Patients with center involved CSME will be randomized to either intravitreal injection of 2.5 mg avastin or 8 mg triamcinolone. In order to be eligible, patients should have a CMT of at least 300 μm in the central subfield as measured by OCT with no history of systemic corticosteroids intake within the past 3 months prior to enrollment or concurrent corticosteroid use. In the avastin arm, intravitreal injection is given monthly for the first 3 months after which a sham injection will be performed if the CMT is <300 μm. Patients in the triamcinolone arm will be injected with triamcinolone monthly for the first 2 months. At month 3, they will receive a sham injection. After 3 months, reinjection of triamcinolone is performed if the CMT stays more than 300 μm or else they will receive a sham injection. Primary outcome measure is to evaluate the efficacy of avastin as assessed by ETDRS visual acuity and CMT on OCT over a 12-month period.

A phase 2 randomized, double-blind, uncontrolled study compared over 6 months a single intravitreal injection of 4 mg triamcinolone acetonide to 1.25 mg of bevacizumab in 13 patients with DME and CST greater than 300 μm (Tribeva-DME). This study has recently been completed (ClinicalTrials.gov identifier: NCT00874744). The results are not yet available. Primary outcome measure included treatment efficacy, and secondary outcome measures included visual acuity and intraocular pressure differences at baseline and follow-up visits (4, 12, and 24 weeks) in the same treatment group and between both treatment arms.

In addition, a phase 4 interventional, double-blind, randomized clinical trial is currently recruiting patients to compare the efficacy of intravitreal injections of triamcinolone and bevacizumab individually or simultaneously for the treatment of DME with a central thickness >275 μm on OCT (ATEMD) (ClinicalTrials.gov identifier: NCT00737971). It is currently recruiting patients for a total sample size of 300 patients randomized to intravitreal bevacizumab injection (0.05 mL/1.25 mg), triamcinolone (0.1 mL/4 mg), or a combination of intravitreal triamcinolone + bevacizumab administered on day 0, week 4, and week 8. The primary outcome measure is ETDRS Snellen visual acuity measured monthly, and secondary outcome measures are intraocular pressure and retinal thickness by OCT. The study is still currently recruiting participants with an enrollment target of 300 subjects.

A single posterior subtenon’s capsule injection of bevacizumab (2.5 mg /0.1 mL) is being investigated in a phase 4 trial for DME with no prior treatment and a retinal thickness of ≥250 μm (ClinicalTrials.gov identifier: NCT00567372). Macular volume, macular thickness, and BCVA will be assessed at baseline, weeks 3, 6, and 12. The study has not been completed, and is still recruiting participants.

A head-to-head phase 3 trial comparing intravitreal bevacizumab to ranibizumab for persistent DME and persistent PDR after laser treatment is currently recruiting patients. The primary outcome measures will be the effect on macular edema and neovascularization, and the absolute change in visual acuity (ClinicalTrials.gov identifier: NCT00545870).

The 12 month results from a prospective single center randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) is presented in Box 15.2.

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