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Interventions for diabetic macular oedema: a systematic review of the literature M O'Doherty, I Dooley and M Hickey-Dwyer Br J Ophthalmol 2008 92: 1581-1590 originally published online October 24, 2008

doi: 10.1136/bjo.2008.144550

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Review

Interventions for diabetic macular oedema: a systematic review of the literature M O’Doherty, I Dooley, M Hickey-Dwyer Limerick Regional Hospital, Limerick, Ireland Correspondence to: Dr M O’Doherty, Limerick Regional Hospital, Limerick, Ireland; maeveodoherty@gmail. com Accepted 6 October 2008 Published Online First 24 October 2008

ABSTRACT Objectives: This review discusses the evolution of the treatment of diabetic macular oedema and gives helpful guidelines in the treatment of diabetic macular oedema based on available evidence to date. Methods: A literature search of all English articles from the Medline and Cochrane database was performed. The search was limited to only English randomised controlled clinical trials in humans. Overall, 93 articles were cited from 1979 to 2007. Of these, 31 articles corresponded to subject matter. Studies were evaluated on a standardised data extraction form and tabulated for easy review. Results: There is good evidence that laser treatment preserves vision in eyes with diabetic macular oedema (DMO). However, laser is a potentially destructive form of treatment which may be of greater benefit in combination with newer forms of treatment such as intravitreal steroid or intravitreal antiangiogenic agents. Current evidence does not support a clear benefit for surgical intervention in DMO. Conclusions: Although laser treatment remains the cornerstone of treatment in diabetic macular oedema, the literature is beginning to support combination therapy. Using one or two intravitreal injections to reduce central macular thickness followed by focal or grid laser to give a sustained response may offer an alternative to treatment in DMO.

Diabetes mellitus affects 200 million people in the world.1 Diabetic retinopathy (DR) is the leading cause of blindness in the working-aged population in the USA.2 The prevalence of DR increases with duration of diabetes,3 and nearly all persons with type 1 diabetes and more than 60% of those with type 2 have some retinopathy after 20 years.3 Twenty-nine per cent of these have clinically significant diabetic macular oedema (CSDMO).3 Diabetic macular oedema (DMO), which can occur at any stage of DR, is characterised by increased vascular permeability and the deposition of hard exudates at the central retina. Diabetic macular oedema is now the principal cause of vision loss in persons with diabetes.3 Over the past 30 years, our knowledge and understanding of the pathogenesis of diabetic retinopathy have evolved. In conjunction with this evolution of knowledge has been the development of multiple treatments beginning with the use of laser and culminating with the use of intravitreal injections either alone or in combination with traditional treatments. With so much information available, the clinician is now faced with the task of deciphering which treatment is most suitable for a specific patient based on available evidence. In Br J Ophthalmol 2008;92:1581–1590. doi:10.1136/bjo.2008.144550

this review, we discuss the evolution of the treatment of diabetic macular oedema and give helpful guidelines in the treatment of diabetic macular oedema based on available evidence to date.

MATERIALS AND METHODS We performed a literature search of all English articles from the Medline and Cochrane database using the search words ‘‘Diabetic macular oedema/ edema,’’ ‘‘clinically significant macular oedema,’’ ‘‘CSMO,’’ ‘‘DMO,’’ ‘‘DME,’’ and ‘‘macular oedema.’’ We confined our search to randomised controlled clinical trials in humans in the english language. Any additional randomised controlled trials cited in reviewed articles were also analysed. Overall, 93 articles were cited from 1979 to 2007. Of these, 31 articles corresponded to subject matter. Studies were evaluated on a standardised data extraction form for (1) name of trial, (2) country of origin, (3) year of origin, (4) method of randomisation, (5) Diagnostic criteria for entry, (6) similarity of groups at baseline regarding the most important prognostic indicators, (7) clearly specified eligibility and exclusion criteria, (8) number of patients and eyes, (9) masking of outcome assessor, care provider and patient, (10) reporting of point estimates and measures of variability for outcomes, (11) intention-to-treat analysis, (12) length of follow-up, (13) adverse events and (14) acceptable loss to follow-up rate unlikely to cause bias. The articles were then tabulated to allow easy clarification of results.

RESULTS Laser treatment Laser treatment for diabetic retinopathy is one of the oldest forms of treatment. There is good evidence that focal laser treatment preserves vision in eyes with DMO. The ETDRS trial, undertaken in 1985, was the first properly conducted randomised trial to establish the benefits of laser for both diabetic macular oedema and proliferative diabetic retinopathy. The ETDRS randomised 1490 eyes with DMO to receive focal laser treatment or observation. At 3 years, treatment significantly reduced moderate visual loss as compared with observation,4 with the greatest benefits in eyes with clinically significant DMO.5 In response to the clear benefit outlined in this trial, others began to question whether laser type had any influence on outcome. However, there is currently no definite evidence that the laser type (argon, diode, dye, krypton) or method used influences outcomes6–14 (table 1). Olk et al reported that not only was there no difference between using argon green 1581


Review Table 1 Laser treatment in diabetic macular oedema No of eyes in study

Author 7

Reeser et al

115

Early Treatment 2244 Diabetic Retinopathy 4 Study Research Group

Striph et al13

64

Intervention

Follow-up

Average 2.4 years Group 1: Argon laser photocoagulation to leaking vessels, primarily in the centre of the circinate ring (n = 68) Group 2: Matched controls (n = 47)

Group 1: Immediate photocoagulation (n = 754)

3 years

Group 2: Delayed photocoagulation (n = 1490) Group 1: Grid argon (green) laser 3 months Group 2: Krypton red laser

Olk6

160

Group 1: Modified grid argon (blue- 2 years green) laser photocoagulation (n = 82)

Group 2: Matched controls (n = 78)

Laursen et al15

23

Group 1: Focal oedema, Minimum of 5 months subthreshold micropulse diode laser (n = 6)

Group 2: Focal oedema, argon laser (n = 5)

91

Group 1: Grid argon laser (n = 48)

2 years

Group 2: Krypton grid (n = 43) Olk10

225

Group 1: Grid argon laser (n = 116) 2 years Group 2: Grid krypton laser (n = 109)

Comments

Data supported the contention that Group 1 circinate complex was photocoagulation to the centre of eliminated in 23 of the 24 (96%) versus two of the 10 (20%) of group 2 the circinate ring improves VA for at least 3 years Eyes with initial VAs of 6/18 (20/60) or better did significantly better with treatment; group 1 had a mean improvement in VA Group 1 half as likely to lose 15 or See text more letters on the ETDRS eye chart compared with group 2: 5% vs 8% at 1 year, 7% vs 16% at 2 years, and 12% vs 24% at 3 years

Both groups very slight improvement in VA After one treatment, the sensitivity of the central 5u dropped an average of 3.44 dB; the drop in the outer 5u averaged 3.86 dB No difference in outcomes between two types of laser Not possible to distinguish scotoma due to laser from that due to DMO Group 1 100% had reduced macular oedema as defined as reduced thickness on slit-lamp contact lens exam and fluorescein angiogram, versus 0% of group 2 Increased VA, gain of 2 or more ETDRS lines; decreased VA, loss of two or more ETDRS lines At 2 years: increased VA in 45% group 1 vs 8% group 2 p,0.05 Decreased VA in 9.5% group 2 vs 43% group 2 p,0.05 VA was stable (¡10 letters) all groups

Short follow-up Weak evidence showing laser beneficial in DMO but scotoma possible

None of the following had a significant effect on visual outcome in either group—poor VA, cystoid oedema, systemic hypertension, history of systemic vascular disease

Subthreshold micropulse diode laser and conventional laser showed an equally good effect on visual acuity; diode laser showed a stabilising or even improving effect on macular oedema

After 3 and 6 months, there were no significant differences in VA between the two treatments in patients treated focally or diffusely (p.0.05)

Group 3: Diffuse oedema, subthreshold micropulse diode laser (n = 6) Changes in retinal thickness were small both foveally and perifoveally Group 4: Diffuse oedema, argon laser (n = 6) Caswell et al8

Outcome

Group 1 had significant reduction in foveal thickness (9% 226 mm, p = 0.02) at 3 months After 2 years: improvement by 2 or p Values not given more Snellen lines in 12.5% group 1 and 2% group 2 Loss of vision by 2 or more lines in Used Snellen not ETDRS chart 15% group 1 and 21% group 2 No significant difference between 2 One centre study groups at 3 or 24 months Study claims that cystoid macular oedema is not a poor prognostic sign Continued

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Review Table 1 Continued Author Khairallah et al

9

No of eyes in study

Intervention

Follow-up

Outcome

Comments

151

Group 1: Argon green (n = 79)

1 year

No statistical difference in visual outcome between laser modes

Data suggest that differential absorption of the various wavelengths by haemoglobin within microaneurysms may not be an important factor for success of treatment

Group 2: Krypton red (n = 72)

Lovestam-Adrian14

221

Study looked at visual outcome and 5.5 years complications postmacular laser

Bandello et al12

29

Group 1: Classic laser, power 100–250 mW (n = 14)

Fong et al11

323

Group 2: Light Nd–Yag 532 nm green laser power ,100 mW (n = 15) Group 1: Modified ETDRS direct/ grid photocoagulation technique (n = 162)

1 year

1 year

Group 2: Mild macular grid laser photocoagulation (n = 161)

Focal oedema resolved in 81% of AG eyes and 78% of KR eyes; no statistically significant difference 51% of eyes did not show any complication after photocoagulation; 21% developed either subretinal fibrosis or atrophic creep within 1/3 ODD from centre of macula, with an extension of fibrosis or atrophy into the centre of fovea in 22%; no CNVM; 68% of eyes without complications had a VA .0.5 compared with 35% of eyes with any complication In type 1 diabetes, VA was . 0.5 in all eyes before treatment; at followup 86% still had VA.0.5, 14% had VA of 0.2–0.4 and 2% had VA,0.1 In type 2 diabetes, 72% had VA.0.5 before treatment; at follow-up this fell to 58%, 21% had VA of 0.2–0.4 and 21% were ,0.1 The average CMT in both groups did not change significantly from baseline at any follow-up visit in either group The initial VA of 20/32 in both groups remained unchanged at 12 months Central subfield thickening, weighted inner zone thickening, maximum retinal thickening and retinal volume all decreased during the 12 month period in both treatment groups p,0.002; diabetic macular oedema had decreased by 0.6 or more disc diameters in 31% group 1 and 22% group 2 p,0.03 and had increased by 17% and 20%, respectively, p = 0.26 No significant difference between two groups of mean change in VA at 1 year p = 0.1; in subjects treated bilaterally, there was no significant difference in retinal thickness or VA between eyes from baseline and at 12 months p = 0.13

DMO with hard exudates was more often associated with subretinal fibrosis or atrophic creep than photocoagulation of oedema without exudates; hard exudates as well as complications after photocoagulation more common in type 2 diabetes, resulting in a poorer outcome

No difference between light and classic laser treatment

After 12 months, there was no indication that the eyes treated with MMG technique had a better outcome than those treated with modified ETDRS treatment

CMT, central macular thickness; DMO, diabetic macular oedema; ETDRS, Early Treatment Diabetic Retinopathy Study; VA, visual acuity.

laser and krypton red laser but that poor initial visual acuity, presence of cystoid macular oedema, systemic hypertension or history of systemic vascular disease had no effect on overall outcome.10 Having established the clear benefit of laser, focus shifted to the adverse effect of this potentially destructive method of treatment. Adverse effects include inadvertent foveal burn, central visualfield defect, colour vision abnormalities, retinal fibrosis and spread of laser scars.13 14 16 Lovestain-Adrian et al reported the long-term outcome (5.5 years) of macular laser in 2000. This study showed that 51% of patients did not suffer any complication postlaser. However, 21% developed either subretinal fibrosis or atrophic creep within 1/3 of a disc diameter from the fovea with extension into the fovea in 22%. They also found that photocoagulation for DMO with hard exudates was more often associated with subretinal fibrosis or atrophic creep than photocoagulation of oedema without exudates. Hard exudates as well as complications Br J Ophthalmol 2008;92:1581–1590. doi:10.1136/bjo.2008.144550

after photocoagulation were more common in type 2 diabetes, resulting in a poorer outcome.14

Surgical management Widespread or diffuse DMO that is unresponsive to focal laser treatment may benefit from vitrectomy.17–29 As shown in table 2, the randomised controlled trials (RCCT) that have been published to date have small numbers (poor statistical power) and inconsistent results.17–24 An attached posterior hyaloid face without evidence of vitreomacular traction is an important inclusion criterion, as it is hypothesised that removing the posterior vitreous attachment allows some resolution of oedema. Most of the RCCTs show a significant improvement in macular thickness and volume postvitrectomy, but this does not consistently correlate with improvement in vision.18 19 21 23 Complications of vitrectomy include recurrent vitreous haemorrhage, retinal tears and detachment, cataract formation and 1583


Review Table 2 Surgery in diabetic macular oedema Author

No of eyes in study

Intervention

Follow-up

Outcome

18

58

Group 1: ILM peel Group 2: ILM peel

Vitrectomy with (n = 17) Vitrectomy without (n = 41)

12

Thomas et al17

40

Group 1: Vitrectomy (n = 19)

12

1 year postop VA significantly improved in both groups The change in VA was not significantly different between groups Neither the change in VA nor CMT is significant in either group

Bahadir et al

Yanyali et al19

20

Patel et al20

15

Yanyali et al21

24

Group 2: Further laser within 1 month (n = 21) Both groups had previous failed grid laser Group 1: Vitrectomy with ILM peel (n = 10) The mean decrease in CMT was 165mm in the group 1 and 37 mm in the group 2 (p = 0.016) Group 2: Untreated fellow eye (n = 10) Group 1: Vitrectomy without ILM peel (n = 7) Group 2: Argon laser as per ETDRS (n = 8)

Group 1: Vitrectomy with ILM peel (N = 12)

12

VA not significantly improved in group 1 (p = 0.125) or group 2 (p = 0.235) at 12 months

12

No significant difference in VA except at 12 months 1 patient from group 1 had moderate visual loss; group 2 had significant improvement in ETDRS vision p = 0.03; CMT decreased to a greater level in group 2, but did not reach significance Significant improvement in VA in group 1 postoperatively (p = 0.006), versus no significant improvement in group 2 (p = 0.058) VA remained stable in six eyes (50%) in the group 1 and in nine eyes (75%) in the group 2; group 1 significant decrease in CMT (p = 0.002) versus no significant change in group 2 (p = 0.433); the difference in CMT change between 2 groups is significant (p = 0.001) ETDRS VA showed a statistical significance in favour of goup 1 at all time points (p = 0.035 to 0.005; Fisher exact test) With Jaeger charts a significance for group 1 was found only at the 6-month examination (p = 0.01) CMT changes in both groups during follow-up was statistically significant; p values were ,0.0001 for month 1, 3 and 6, preferring group 1 The ETDRS VA difference between the two groups at the end of 6 months was not clinically significant (p = 0.525)

6

Group 2: Single session of modified grid laser in fellow eye (n = 12)

Stolba et al22

56

Group 1: Vitrectomy (n = 25)

6

Group 2: Controls (n = 31)

Kumar et al23

24

Group 1: Vitrectomy with LM peel (n = 12)

Group 2: Modified grid laser photocoagulation (n = 12)

6

Comments

No adverse events

Mild progression of nuclear sclerosis in four eyes (36.3%) group 1 and two eyes (18.1%) of group 2 Two eyes (16.6%) in group 1 showed a transient increase in intraocular pressure

In 32% (eight of 25) of the eyes, vitrectomy was combined with extraction of the mild cataract and posterior chamber lens implantation In two cases, a vitreous haemorrhage developed resolved spontaneously in both eyes

In the ILM group one patient developed rhegmatogenous RD 4 months postop, which was successfully operated with belt buckling, endolaser and silicone oil injection

However, CMT and macular volume decreased significantly more in group 1 compared with group 2 (p = 0.001, p,0.001, Mann–Whitney U test) There was no correlation between the improvement in VA and the reduction of CMT (r = 20.158, p = 0.6) (group 1), r = 20.155, p = 0.7) (group 2) in both groups Continued

1584



Review Table 2 Continued Author

No of eyes in study

Intervention

Follow-up

Outcome

Bardak et al24

24

Group 1: ICG-assisted ILM peeling (n = 11)

6

Nil In ICG-assisted ILM peeling group, preoperative VA (1.3 (0.4), mean (SD), logMAR) improved postoperatively to 0.9 (0.5) (p = 0.011) In eyes that underwent triamcinolone-assisted posterior vitreous removal, the baseline BCVA of 1.4 (0.4) improved to 1.0 (0.5) (p = 0.007); there was no difference between baseline as well as postoperative sixth-month BCVA results of both groups (p = 0.59 and p = 0.57, respectively)

Group 2: Triamcinoloneassisted posterior vitreous removal (n = 13)

Comments

BCVA, best-corrected visual acuity; CMT, central macular thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; ILM, internal limiting membrane.

glaucoma. The presence of vitreous traction and macular oedema, now readily documented with optical coherence tomography, in association with visual impairment is also a common indication for vitrectomy.

Intravitreal corticosteroids Corticosteroids have potent anti-inflammatory and antiangiogenesis effects. Intravitreal triamcinolone (IVTA) has been used for treatment of DMO,30–43 with a number of RCTs demonstrating significant improvements in DMO and visual acuity.32–42 As shown in table 3, many of these trials, had small participant numbers and short follow-up. Additionally, there were substantial adverse effects, including infection, glaucoma and cataract formation.37 44–46 In the largest RCT having the longest follow-up yet reported, eyes with persistent DMO were randomised to receive 4 mg of IVTA or sham injection (saline injection into the subconjunctival space).35 After 2 years, 19 of 34 IVTA-treated eyes (56%) had a visual acuity improvement of five letters or more compared with nine of 35 placebo treated eyes (26%) (p = 0.007). Overall, IVTA-treated eyes had twice the chance of improved visual acuity and half the risk of further loss. However, many eyes required repeated injections (mean 2.2), and there was significant intraocular pressure elevation (5 mm Hg in 68% of treated eyes vs 10% of controls). Cataract surgery was required in 55% of IVTA-treated eyes. Thus, while this study demonstrated significant efficacy with IVTA in persistent DMO, larger RCTs are needed to provide further data on long-term benefits and safety. Additionally, the ideal dose of triamcinolone remains unclear. Recently, Lam et al compared the visual outcome of treatment with variable doses (4 mg, 6 mg and 8 mg) of intravitreal triamcinolone.38 They reported that higher doses of IVTA may prolong the duration of visual benefit in diabetic CSMO and seemed to result in more sustained reduction in macular oedema. However, higher doses also led to more sustained need for antiglaucoma medication. More recently, intravitreal or retinal implants have been developed, allowing an extended duration of drug delivery. Surgically implanted intravitreal fluocinolone acetonide (Retisert; Bausch & Lomb, Rochester, New York) was evaluated in 97 patients with DMO randomised to receive either implantation or standard care (laser treatment or observation).47 At 3 years, 58% of implanted eyes versus 30% of controls had resolution of DMO (p,0.001) and associated improvement in visual acuity. However, adverse effects included a substantially higher risk of cataract formation and glaucoma than that Br J Ophthalmol 2008;92:1581–1590. doi:10.1136/bjo.2008.144550

observed in eyes receiving IVTA, with 5% requiring implant removal to control glaucoma. An injectable, biodegradable intravitreal dexamethasone extended release implant (Posurdex; Allergan, Irvine, California) was evaluated in an RCT, with reported improvements in visual acuity and macular thickness.48 Having established a clear benefit with either laser or triamcinolone interest is now focusing on trials that evaluate combination therapy or direct comparisons between treatments. The first significant trial comparing treatments was reported by Avitable et al in 2005 in which they randomised patients to receive intravitreal triamcinolone alone or combined with grid laser at 3 months or grid laser alone in the treatment of cystoid macular oedema.40 After treatment, the eyes of the two groups receiving triamcinolone had better visual acuity and lower central macular thickness (CMT) than those receiving photocoagulation at all time points. At 45 days, the two triamcinolone groups had increased vision by three lines in 16 eyes, and CMT had increased by 40% in 20 eyes. However, the triamcinolone effect regressed at 6 months. More recently, Lam et al reported a comparative randomised controlled trial.42 Patients were randomised to grid laser photocoagulation (37 eyes), 4 mg of intravitreal TA (38 eyes) or 4 mg of intravitreal TA combined with sequential grid laser about 1 month later (36 eyes). After treatment, significant central foveal thickness reductions were noted in both the intravitreal TA and combined groups at all follow-up visits (p = 0.01) but not in the laser group. However, the difference between the three groups was not significant at 6 months. The standardised reduction in macular thickening at 17 weeks was significantly greater in the combined group versus the intravitreal TA group (p = 0.007), suggesting that combined treatment might prolong the effects of intravitreal TA.42 Best-corrected visual acuity (BCVA) improved significantly at 4 and 9 weeks for the intravitreal TA group but did not change significantly in the other two groups. No significant difference in BCVA was observed between the three groups at any time point.42

Intravitreal antiangiogenesis agents Several RCTs are currently evaluating three agents that suppress vascular endothelial growth factor (VEGF) for treatment of DMO (table 4). Pegaptanib (Macugen; Pfizer, New York) targets the 165 isoform of VEGF for treatment of neovascular age-related macular degeneration (AMD). An RCT of 172 patients with DMO randomised to receive repeated 1585


Review Table 3 Intravitreal triamcinolone in diabetic macular oedema Author Massin et al

32

Sutter et al39

No of eyes Intervention

Follow-up month

Outcome

24

6

Significant difference between CMTs of 2 groups at 4 weeks In six of the 12 injected eyes; IOP (p,0.001) and 12 weeks (p = 0.005); at 12 weeks in group exceeded 25 mm Hg and was controlled by topical medication 2, CMT had returned to normal (,206 mm) in nine of 12 eyes; 24 weeks after injection, difference between CMTs in both groups was no longer significant (p.0.1); at no time was the difference between the ETDRS scores for injected and control eyes significant

3

Improvement of five or more letters of BCVA was found in 55% group 2, compared with 16% treated with placebo (p = 0.002)

69

Group 1: 4 mg IVTA (n = 12)

Group 2: Fellow eye as control (n = 12) Group 1: 4 mg IVTA (n = 34)

Group 2: Placebo, subconjunctival saline (n = 35)

Gillies et al35

Lam et al38

69

63


Group 2: Placebo (n = 35) Group 1: 4 mg IVTA (n = 23)

24

6


Gillies et al37

33

Group 3: 8 mg IVTA (n = 20) 24 Patients were administered 4 mg IVT; the number of doses was determined clinically

Group 1: One dose (n = 6)

Lam et al42

111

Group 2: Two doses (n = 8) Group 3: Three doses (n = 13) Group 4: Four or five doses (n = 6) Group 1: Grid laser (n = 37)

6

Comments/adverse events

IOP .25 mm Hg in 18% group 1, versus 3% group 2; IOP controlled satisfactorily in all cases with topical therapy; significant progression of cataract was in one eye from each group; one case of infectious endophthalmitis in group 1

Masked semiquantitative grading of macular thickness was reduced by 1 grade or more in 75% group 2 versus 16% group 2, and oedema increased in 0 versus six such eyes, respectively; p = 0.0001) Foveal thickness decreased by 115 nm (95% CI, 69 to 161 mm) more in the treatment group than in the placebo group at the 3-month visit (p = 0.0001) Glaucoma medication 44% group 1 Improvement of five letters’ BCVA was found in 19 of 34 versus 3% group 2 (p = 0.0002); (56%) group 1, compared with nine of 35 (26%) group 2 cataract surgery 54% group 1 versus (p = 0.006) 0% group 2 (p = 0.0001); two trabeculectomies in group 1; one case of infectious endophthalmitis in group 2 Foveal thickness had decreased by 59 nm more in group 1 than in group 2, at 2 years (p = 0.009) The mean BCVA improvement at 26 weeks was significantly Proportion of eyes on treatment for higher in the 8 mg than in the 4 mg group (p = 0.047) glaucoma at 6 months was higher in group 3 than groups 1 and 2 (p = 0.05); no significant difference in the proportion of eyes with increased cataract grading and the average increase in grading between the three groups (p = 0.31 and 0.53, respectively) CMT decreased in all three groups, reaching a trough at 4–9 weeks, after which there was recurrence of oedema, especially groups 1 and 2 The mean CMT at all time points was not significantly different between the three dosage groups There was a significant trend towards a longer duration of There was a highly significant correlation between the number of diabetes and number of injections received; the mean improvement in VA after 24 months bore no correlation with injections received and the need for the no of injections received; VA improved in all groups at cataract surgery different times, and there was no significant trend towards progressive improvement of vision over the course of the study; no correlation between the number of injections received and absolute level of CMT; significant trend towards progressive improvement in CMT for groups 1 and 3 but not significant for groups 2 and 4 The probability of requiring glaucoma medication did not correlate with increasing numbers of injections (p = 0.43)

BCVA improved significantly at 4 and 9 weeks for group 2 but did not change significantly in the other 2 groups; no significant difference in BCVA was observed between the 3 groups at any time point

The proportion of patients with increased IOP .22 mm Hg was significantly higher in groups 2 and 3 (p = 0.002); increases in cataract scores between the three groups were not statistically significant (p = 0.10) Continued

1586



Review Table 3 Continued Author

No of eyes Intervention

Follow-up month


Audren et al33 34

Group 3: 4 mg IVTA with sequential grid laser about 1 month later (n = 36) Group 1: 4 mg IVTA 24 (n = 17)

Group 2: Fellow eye as control (n = 17)

Audren et al36 32

Ramezani et al34

20

Avitabile et al40

63

Kang et al41

86


Outcome

Comments/adverse events

Significant CMT reductions were noted in groups 2 and 3 at all follow-up visits (p = 0.01) but not in the laser group; the difference between the 3 groups was not significant at 6 months; the standardised change in CMT at 17 weeks was significantly greater in group 3 versus group 2 (p = 0.007), suggesting that combined treatment might prolong the effects of IVTA

24

Group 2: 2 mg IVTA (n = 16) 9 Each member of the group was given a sham injection, followed for 9 months, then given 4 mg of IVTA (n = 20)

Group 1: 4 mg IVTA 9 (n = 22) Group 2: Grid laser (n = 21) Group 3: 4 mg IVTA and laser at 3 months (n = 20) 6 Group 1: 4 mg IVTA followed by macular grid laser at 3 weeks (n = 48)

At 12 weeks, VA had improved by two or more lines in 10 eyes 58.8% in injected eyes versus four (23%) in the control group; the difference in changes between both groups was significant at 4, 12 and 24 weeks after injection; however, at 28 weeks, there was no difference Difference between CMT in both groups was significant at 4 weeks and 12 weeks (p = 0.003 and 0.008); at 24 weeks there was no significant difference between CMT in treated and untreated eyes In the two groups, ETDRS scores rose significantly 4 weeks after injection and were still significant at 12 weeks postinjection and at 24 weeks; the mean CMT decreased significantly from preinjection at 4 and 12 weeks in both groups; there was no significant difference between groups at each of these time points; At 24 weeks, diabetic macular oedema had recurred in most eyes of both groups, but CMT was still normal in 14% and 7% of groups 1 and 2 respectively

IOP increased .24 mm Hg in 9/17 eyes; the max IOP was 32 mm Hg; time to increase ranged from 2 days to 16 weeks No increase in cataract progression

Injector not blinded, but assessors blinded; five of the 16 eyes in group 1 and eight of the 16 eyes in group 2 had an increase in IOP .24 mm Hg; no difference in cataract development; one case CRVO and one vitreous haemorrhage secondary to PVD occurred

Blinded Comparison of VA changes between and within the two interventions (IVTA and sham injections) was not statistically significant

Comparison of CMT changes between the two interventions did not show any significant difference, except at one stage between 0 and 4 months (p = 0.014), which implied CMT reduction after IVT treatment in eyes which had been followed without any treatment for 9 months Groups 1 and 3 had a better VA and lower CMT than those 20% increase in IOP in IVTA groups receiving photocoagulation at all time points The triamcinolone effect regressed at 6 months

Differences in VA between two groups significant at 3 months (p = 0.02) and 6 months (p,0.001), better in group 1; significantly improved VA and CMT at 6 months sustained in group 1 only

Increased IOP in 40% both groups; one eye required trabeculectomy

Group 2: 4 mg IVTA (n = 38) BCVA, best-corrected visual acuity; CMT, central macular thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; IOP, intraocular pressure; IVTA, intravitreal triamcinolone; VA, visual acuity.

intravitreal pegaptanib or sham injections showed that treated eyes were more likely to have improvement in visual acuity of 10 letters or more (34% vs 10%, p = 0.03), macular thickness (p = 0.02) and need for focal laser treatment (p = 0.04) at 36 weeks.49 Serious infection occurred in one of 652 injections (0.15%) and was not associated with severe visual loss.49 Ranibizumab (Lucentis; Genentech, South San Francisco, California) is another anti-VEGF agent used for treatment of neovascular AMD.50 51 and may also be useful for DR and DMO.52 A phase 2 RCT (the RESOLVE study) is currently evaluating ranibizumab in DMO. Finally, bevacizumab (Avastin, Genentech) is an anti-VEGF agent similar to ranibizumab that is approved for the treatment of disseminated colorectal cancer and not licensed for intraocular use. However, bevacizumab Br J Ophthalmol 2008;92:1581–1590. doi:10.1136/bjo.2008.144550

appears to show a similar efficacy for treatment of neovascular AMD and may also be effective for DMO and proliferative DR.53–56 Bevacizumab has attracted interest because of its low cost, but systemic safety is a concern.57 The US National Eye Institute has recently reported a phase 2 trial comparing the effects of laser treatment, intravitreal bevacizumab, and combined intravitreal bevacizumab and laser or sham injection. Random assignment to one of five groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22) or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks 1587


Review Table 4 Antivascular endothelial growth factor therapy in diabetic macular oedema No of eyes in the study

Authors Cunningham et al

49

172

Follow-up weeks

Intervention Group 1: Intravitreous pegaptanib 0.3 mg (n = 44)

Median VA was better at week 36 with 0.3 mg Endophthalmitis occurred in one of 652 injections (20/50), as compared with sham (20/63) (p = 0.04) A larger proportion of those receiving 0.3 mg gained VAs of >10 letters (approximately 2 lines) (34% vs 10%, p = 0.003) and >15 letters (18% vs 7%, p = 0.12) Mean CMT decreased by 68 mm with 0.3 mg, versus an increase of 4 mm with sham (p = 0.02) Larger proportions of those receiving 0.3 mg had an absolute decrease of both >100 mm (42% vs 16%, p = 0.02) and >75 mm (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)

12

There were no meaningful differences between groups 2 and 3 in CMT reduction or VA improvement A CMT reduction .11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and five of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and nine of 18 (50%) eyes, respectively At baseline, the median CMT was 411 mm, and the median Snellen VA equivalent was 20/50; Compared with group 1, groups 2 and 3 had a greater reduction in CMT at 3 weeks and about one line better median VA over 12 weeks

Group 3: Intravitreous pegaptanib 3 mg (n = 42) Group 4: Sham injection (n = 42)

121 Diabetic Retinopathy Clinical Research Network Scott et al58

Group 2: Intravitreous bevacizumab 1.25 mg baseline and 6 weeks (n = 22)

Group 3: Intravitreous bevacizumab 2.5 mg baseline and 6 weeks (n = 24)

Group 4: Intravitreous 1.25 mg baseline and 6 weeks (n = 22) Group 5: Intravitreous 1.25 mg baseline and photocoagulation at 3

Comments

36

Group 2: Intravitreous pegaptanib 1 mg (n = 44)

Injections at weeks 0, 6 and 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks Group 1: Focal photocoagulation at baseline (n = 19)

Outcome

bevacizumab sham injection at

Endophthalmitis one subject Transient increase in intraocular pressure occurred one subject

Among the 107 subjects who received at least one bevacizumab injection, a myocardial infarction occurred in two and congestive heart failure in one

Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes

bevacizumab 6 weeks with weeks (n = 22)

CMT, central macular thickness; VA, visual acuity.

(n = 22). At baseline, median CST was 411 mm, and the median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about one line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction .11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and five of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and nine of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes.

CONCLUSION The ETDRS study was the first study to help clinically grade the severity of diabetic macular oedema.4 It defines clinically significant macular oedema when the following features are present: (1) thickening of the retina at or within 500–3000 mm of the centre of the macula; (2) hard exudates at or within 500 mm of the centre of the macula and associated with thickening of the adjacent retina; and (3) a zone of retinal thickening with a size of >1 disc area, any part of which is within 1 disc diameter of the centre of the macula.4 However, with the advent of optical coherence tomography and its almost universal use in clinical practice, even early signs of diabetic macular oedema can be identified.59 60 Furthermore, response to 1588

treatment can be quantified by changes in central macular thickness, which often predates improvements in visual acuity.59 60 Many of the studies in this report did not distinguish between diffuse macular oedema and cystoid macular oedema. The potential benefits of distinguishing between these types of oedema remain to be established. The authors recommend the following practice guidelines for diabetic macular oedema.

TREATMENT OF DIABETIC MACULAR OEDEMA IN PATIENTS WHO HAVE NOT HAD PREVIOUS TREATMENT Focal or grid laser is still a recommended first line in treatment (table 1). To date there is no trial which has had greater power in terms of patient numbers and design than the ETDRS study.4 5 Focal laser refers to a direct treatment of leaking microaneurysms in the oedematous retina within 3000 mm of the centre of the macula. Grid laser is recommended for areas of diffuse leakage with no defined focal leakage.4 5 If oedema is greater than 390 mm, then intravitreal triamcinolone to help reduce oedema prior to laser application 1 month later holds theoretical and proven benefit.41 42 However, combined treatment with bevacizumab and laser at 1 month does not appear to hold any advantage.58 If, after one trial of laser, there is no significant improvement in CMT (ie, greater than 100 mm change) then we recommend a Br J Ophthalmol 2008;92:1581–1590. doi:10.1136/bjo.2008.144550


Review trial of intravitreal triamcinolone or intravitreal antiangiogenic agents.39 49 Prior to commencing steroid treatment, we advise a trial of topical dexamethazone 0.1% four times a day for 4 weeks prior to intravitreal injections to identify steroid responders. We favour antiangiogenic agents in patients with ocular hypertension and glaucoma or those with a history of steroid response. In patients with cystoid macular oedema, evidence would support first-line treatment with intravitreal triamcinolone followed by grid laser at 3 months.40 There is no trial that has compared the effects of triamcinolone with those of the antiangiogenic agents. Though the antiangiogenic agents hold an ocular-specific advantage in terms of a low rate of ocular hypertension, there have been some concerns with regard to their possible systemic effects. Therefore, until a large prospective RCCT is published, the choice of intravitreal agent remains a subjective decision. Vitrectomy for diabetic macular oedema cannot be recommended on the basis of current available literature except where there is evidence of anatomical vitreomacular traction. Evidence-based medicine is accepted as an essential requirement in the delivery of optimal clinical care. This review has evaluated the role of laser, intravitreal triamcinolone, antiangiogenic agents and surgery in the treatment of diabetic macular oedema. This review provides the ophthalmologist with a management algorithm integrating recent advances in ophthalmology into their treatment regimes. We acknowledge that laser is still the mainstay in treatment based on evidence, but we feel that the literature now supports additional treatments if only in the short term. There are a number of trials ongoing that may shed further light on long-term outcomes and comparisons between each of the treatment modalities.

15.

Competing interests: None.

30.

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