Evidence reviews for the effectiveness and acceptability of intravitreal steroids, macular laser and anti-vascular endothelial growth factor agents for treating diabetic macular oedema

1.1.1. Introduction

People with diabetic retinopathy can develop macular oedema, a swelling or thickening of the macula. Diabetic macular oedema is a common complication of diabetic retinopathy and can lead to moderate to severe visual loss. Currently there are several treatment options for people with diabetic macular oedema including macular laser (standard threshold or subthreshold laser), anti-vascular endothelial growth factor agents (anti-VEGFs), intravitreal steroids, or combinations of these treatments. This review aims to compare all treatments to identify the most effective treatment strategy for people with diabetic macular oedema.

This evidence review informed recommendations in the NICE guideline on the management and treatment of diabetic retinopathy, which is a new NICE guideline in this area.

1.1.2. Summary of the protocol

Table 1

Effectiveness and acceptability of intravitreal steroids, macular laser and anti-vascular endothelial growth factor agents for treating diabetic macular oedema.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in (Appendix A) and the methods document.

Results were separated into two populations (people with central-involving macular oedema and people with non-central-involving macular oedema) and were reported at short-term and longer-term time points (12 months and 24 months or longer). As not all studies reported outcomes at these exact time points, it was decided that the 12-month data would include any results from 6 months to 18 months from the beginning of treatment, and 24 months would represent any results reported from 24 months onwards. Results for the primary outcomes of change in visual acuity from baseline and change in central retinal thickness were analysed using network meta-analyses (NMAs) where sufficient data was available. NMAs were therefore used to analyse:

• change in visual acuity from baseline for people with central-involving macular oedema at 12 months and at 24 months.
• change in central retinal thickness for people with central-involving macular oedema at 12 and at 24 months.

Insufficient data was available for an NMA for the other population groups of the primary outcomes, and so results were presented as pairwise meta-analysis for:

• change in visual acuity from baseline for people with non-central-involving macular oedema at 12 months. No data was available for this comparison at 24 months.

Subgroup analysis of the primary NMAs were used to assess the different effects of treatment for people with central retinal thickness greater, or less than, 400 micrometres at baseline. Sufficient data was available for NMAs for:

• change in visual acuity from baseline for people with central-involving macular oedema and central retinal thickness of 400 micrometres or more at 12 months and at 24 months
• change in central retinal thickness from baseline for people with central-involving macular oedema and central retinal thickness of 400 micrometres or more at 12 months.

Insufficient data was available for a network analysis for subgroup analysis of the other population groups, and so results were presented as meta-analysis for:

• change in central retinal thickness at 24 months for people with central-involving macular oedema and central retinal thickness of 400 micrometres or more
• all change in visual acuity and central retinal thickness outcomes for people with central-involving macular oedema and central retinal thickness less than 400 micrometres

All secondary outcomes were presented using meta-analysis as stated in the review protocol. These were performed according to the NICE methods stated in the methods document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

1.1.5. Summary of studies included in the effectiveness evidence

Table 2

Table of included studies. Studies from NICE additional searches

See Appendix D for full evidence tables.

Table 3

Summary of Cochrane reviews used for clinical effectiveness evidence.

Summary of included primary studies from Cochrane systematic review

Table 4

Randomised controlled trials (for full study details, see Virgili et al. 2022).

Table 5

Randomised controlled trials (for full study details, see Jorge et al. 2018).

Table 6

Randomised controlled trials (for full study details, see Mehta et al. 2018).

Table 7

Randomised controlled trials (for full study details, see Rittiphairoj et al. 2020).

1.1.6. Summary of the effectiveness evidence

Network meta-analysis

People with centre-involving macular oedema

Visual acuity

Whole population

Table 8

Visual acuity at 12 months relative to Standard threshold laser.

Table 9

Visual acuity at 24 months relative to Standard threshold laser.

Subgroup analysis: People with baseline central retinal thickness >400 micrometres

Table 10

Visual acuity at 12 months relative to Standard threshold laser.

Table 11

Visual acuity at 24. months relative to Standard threshold laser

Central retinal thickness

Whole population

Table 12

Central retinal thickness at 12 months relative to Standard threshold laser.

Table 13

Central retinal thickness at 24 months relative to Standard threshold laser.

Subgroup analysis: People with baseline central retinal thickness >400 micrometres

Table 14

Central retinal thickness at 12 months relative to Standard threshold laser.

Pairwise Meta-analysis

People with centre-involving macular oedema (whole population)

Anti-VEGFs vs standard threshold laser

Table 15

Anti-VEGF vs standard threshold laser: Visual Acuity: three or more lines improvement from baseline up to 12M.

Table 16

Anti-VEGF vs standard threshold laser: The mean number of treatments at 12 months.

Table 17

Anti-VEGF vs standard threshold laser: The mean number of treatments at 24 months.

Table 18

Anti-VEGF vs standard threshold laser: Adverse Events at 24 months.

Anti-VEGF vs Anti-VEGF

Table 19

Bevacizumab VS Ranibizumab.

Table 20

Aflibercept vs Ranibizumab.

Table 21

Brolucizumab vs Aflibercept.

Table 22

Faricimab vs Aflibercept.

Anti-VEGF plus standard threshold laser vs Anti-VEGF

Table 23

Ranibizumab vs Ranibizumab + standard threshold laser.

Table 24

Bevacizumab vs Bevacizumab + standard threshold laser.

Anti-VEGF vs sham

Table 25

Ranibizumab vs sham.

Anti-VEGFs + steroids vs Anti-VEGF

Table 26

Anti-VEGF and steroid versus anti-VEGF alone.

Steroids vs sham

Table 27

Intravitreal dexamethasone versus sham.

Table 28

Intravitreal fluocinolone acetonide implant versus sham.

Table 29

Intravitreal triamcinolone acetonide injection versus sham.

Steroids vs Anti-VEGFs

Table 30

Intravitreal dexamethasone versus intravitreal anti-VEGF.

Table 31

Intravitreal dexamethasone versus intravitreal anti-VEGF: The mean number of treatments at 12 months.

Table 32

Intravitreal dexamethasone versus intravitreal anti-VEGF: Adverse Events at 12 and 24 months.

Steroids vs Macular Laser

Table 33

Intravitreal triamcinolone acetonide versus macular laser.

Subthreshold laser vs standard threshold laser

Table 34

Number of patients meeting driving standards at month 24, n (%).

Table 35

Number of laser treatments used from baseline to month 24 in study eye, mean (SD).

People with non-centre-involving macular oedema

Comparisons vs standard threshold laser

Table 36

Comparisons vs standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Table 37

Change in central retinal thickness from baseline (mean difference) at 12 months.

Table 38

Change in visual acuity LogMAR at 24 months (mean difference).

Table 39

Change in central retinal thickness at 24 months (mean difference).

Anti-VEGFs vs sham

Table 40

Anti-VEGF vs sham: Change in visual acuity from baseline (logMAR) at 12 months.

Subgroup analysis: People with centre-involving diabetic macular oedema with a baseline central retinal thickness of less than 400 micrometres

Subthreshold vs standard threshold laser

Table 41

Subthreshold vs standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Anti-VEGFs vs Anti-VEGFs with standard threshold laser

Table 42

bevacizumab vs bevacizumab + standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Anti-VEGFs vs standard threshold laser

Table 43

Anti-VEGF vs standard threshold laser: Change in visual acuity LogMAR at 24 months (mean difference).

Steroids vs sham

Table 44

Steroids vs sham: Change in visual acuity LogMAR at 24 months (mean difference).

Anti-VEGF vs Anti-VEGF

Table 45

Brolucizumab vs aflibercept: Change in visual acuity LogMAR at 24 months (mean difference).

Table 46

Anti VEGF vs Anti VEGF: Change in visual acuity LogMAR at 24 months (mean difference).

Steroids vs Anti-VEGFs

Table 47

Dexamethasone vs bevacizumab: Change in visual acuity LogMAR at 24 months (mean difference).

Steroids vs standard threshold laser

Table 48

Triamcinolone vs standard threshold laser: Change in visual acuity LogMAR at 24 months (mean difference).

Combination treatments vs standard threshold laser

Table 49

Combination treatment vs sham + standard threshold laser: Change in visual acuity LogMAR at 24 months (mean difference).

Combination treatments vs Anti-VEGFs

Table 50

Change in visual acuity LogMAR at 24 months (mean difference).

Table 51

Change in visual acuity from baseline (logMAR) at 12 months.

Anti-VEGFs vs standard threshold laser

Table 52

Aflibercept vs standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Table 53

Aflibercept vs standard threshold laser: Change in visual acuity (logMAR) at 24 months.

Table 54

Aflibercept vs standard threshold laser: Change in central retinal thickness at 12 months (mean difference).

Table 55

Aflibercept vs standard threshold laser: Change in central retinal thickness at 24 months.

Steroids vs standard threshold laser

Table 56

Triamcinolone vs standard threshold laser: Change in visual acuity LogMAR at 24 months (mean difference).

Combination treatments vs standard threshold laser

Table 57

Combination treatment vs standard threshold laser: Change in central retinal thickness from baseline (mean difference).

Subgroup analysis: People with centre-involving diabetic macular oedema with a baseline central retinal thickness of 400 micrometres or more

Table 58

Aflibercept vs standard threshold laser.

Subgroup analysis: People with non-centre-involving diabetic macular oedema and baseline central retinal thickness of less than 400 micrometres

Table 59

Comparisons vs standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Table 60

Comparisons vs standard threshold laser: Change in central retinal thickness from baseline (mean difference) at 12 months.

Subgroup analysis: People with non-centre-involving diabetic macular oedema and baseline central retinal thickness of 400 micrometres or more

Table 61

Comparisons vs standard threshold laser: Change in visual acuity from baseline (logMAR) at 12 months.

Table 62

Ranibizumab vs standard threshold laser: Change in central retinal thickness from baseline (mean difference) at 12 months.

Table 63

Bevacizumab vs sham.

Table 64

Ranibizumab vs standard threshold laser: Change in central retinal thickness from baseline (mean difference) at 12 months.

Table 65

Comparisons vs standard threshold laser: Change in visual acuity LogMAR at 24 months (mean difference).

Table 66

Comparisons vs standard threshold laser: Change in central retinal thickness from baseline to 24 months.

See Appendix G for full GRADE tables.

1.1.7. Economic evidence

A literature search was conducted to identify published economic evaluations to answer this question. Additionally, any relevant economic analyses conducted for published technology appraisals were reviewed for use in discussion around model conceptualisation and validation for the de novo economic model developed for this review question. The following technology appraisals in treatments for DMO were reviewed: TA824, TA820, TA799, TA346, TA953, TA274.

1.1.8. Summary of included economic evidence

Table 67

Economic evidence profile.

1.1.9. Economic model

A de novo Markov economic model was conducted from the perspective of UK NHS and personal social services (PSS) for this review question.

Due to the heterogeneity of the population and associated treatments for diabetic macular oedema (DMO), the model results have been separated by the following populations:

• All centre involving DMO
• Centre involving DMO with a central retinal thickness (CRT) ≥400µm

Due to a lack of data to be able to form an NMA, it was not possible to generate model results for the subpopulations of “centre involving DMO with a CRT<400µm” and “non-centre involving DMO”.

The model was a lifetime cost-utility analysis comparing nine treatments along with no treatment for DMO: standard threshold laser; subthreshold laser; aflibercept; ranibizumab (Lucentis); ranibizumab plus standard threshold laser; bevacizumab; bevacizumab plus standard threshold laser; brolucizumab; and faricimab. In addition, ranibizumab biosimilar (Ongavia) was considered as a scenario assuming the same efficacy, safety and resource use as ranibizumab.

Intravitreal steroids are also treatments of interest in DMO, namely: dexamethasone (TA824) and fluocinolone (TA953). Intravitreal steroids are predominantly used as second line therapies and are only considered as first line treatments for patients in whom other first line treatments are not suitable or who had not responded to previous treatments (mainly laser), which would be a different population to that considered in this economic analysis. Therefore, intravitreal steroids were not included in the economic model. Consequently, the focus of this economic analysis was first line therapies only. Combination treatment of intravitreal steroids plus anti-VEGF agents was also not considered a comparator of interest as the committee felt it was unlikely that the combination would be used over either type of treatment alone.

Clinical inputs in the model were based on the literature, while the results of an NMA informed the mean difference in visual acuity. Main outputs were costs, health outcomes (in quality-adjusted life-years; QALYs), incremental cost-effectiveness ratios (ICERs) and net monetary benefits (NMBs).

All centre involving diabetic macular oedema

In the base-case probabilistic analysis using list prices for the anti-VEGF therapies, subthreshold laser had the lowest ICER of £1,248 compared with no treatment. The probabilistic base-case fully incremental results are presented in Table 68. Macular laser treatments are not suitable for all people with centre involving macular oedema, for example people with thicker retinas, and for this reason the probabilistic base-case results compared with no treatment are also presented in Table 69. Whilst subthreshold laser treatment still had the lowest ICER compared with no treatment (and standard threshold laser had the second lowest ICER), bevacizumab monotherapy also had an ICER below £20,000 which is the opportunity cost used by NICE for decision making. It should be noted that these results were not used by the committee when drafting recommendations for this review question, as they do not take into account the confidential discounts associated with each of the anti-VEGF treatments.

The committee was also presented with the results of the probabilistic base-case and scenario analyses when the confidential Patient Access Scheme (PAS) discounts were applied in the model and these results were used as the basis for their recommendations. These results cannot be presented here because they are commercially sensitive. When these discounts were applied, subthreshold laser remained the treatment with the lowest ICER, and standard threshold laser had the second lowest ICER. Subthreshold laser was the treatment with the lowest ICER in most scenario analyses, but the difference was very small between the two macular laser types. Both bevacizumab and brolucizumab had ICERs below £20,000 per QALY in people for whom laser treatments are not suitable. In the scenario where the confidential prices and the ranibizumab biosimilar (Ongavia) were considered, all treatments had ICERs below £25,000 per QALY. It should be noted that the NICE reference case uses an opportunity cost of £20,000 per QALY gained, but consideration can be given to therapies with an ICER between £20,000 and £30,000, for example when there are few other treatments available for a population or if the strategy is likely to reduce health inequalities.

Table 68

Economic model results (list price) fully incremental analysis.

Table 69

Economic model results (list price) compared with no treatment.

Centre involving diabetic macular oedema with a CRT≥400µm

In the base-case probabilistic analysis using list prices for the anti-VEGF therapies, subthreshold laser had the lowest ICER of £1,442 compared with no treatment. The probabilistic base-case fully incremental results are presented in Table 70 and the results compared with no treatment are presented in Table 71. Whilst subthreshold laser treatment still had the lowest ICER compared with no treatment (and standard threshold laser had the second lowest ICER), for people in whom laser therapy is not suitable bevacizumab monotherapy also had an ICER below £20,000 which is the opportunity cost used by NICE for decision making. It should be noted that these results were not used by the committee when drafting recommendations for this review question, as they do not take into account the confidential discounts associated with each of the anti-VEGF treatments.

The committee was also presented with the results of the probabilistic base-case and scenario analyses when the confidential PAS discounts were applied in the model and these results were used as the basis for their recommendations comparing anti-VEGFs with macular laser therapies. These results cannot be presented here because they are commercially sensitive. When these discounts were applied, subthreshold laser remained treatment with the lowest ICER, while standard threshold laser remained the treatment with the second lowest ICER. The difference was very small between the two macular laser types, and it should be noted that the efficacy for subthreshold laser was assumed equivalent to standard threshold laser due to a lack of data for this population which would explain the very small differences. When the confidential prices were considered, all treatments had ICERs below £25,000 per QALY.

Table 70

Economic model results (list price) fully incremental analysis.

Table 71

Economic model results (list price) compared with no treatment.

1.1.10. Unit costs

The list prices of the drugs for this review question are presented in Table 72. It should be noted that aflibercept, ranibizumab, brolucizumab, faricimab and bevacizumab are recommended by NICE only if the manufacturer provides them with the agreed confidential patient access scheme discount.

Table 72

List prices for treatments included in the recommendations.

1.1.11. Economic evidence statements

Ten published cost-utility analyses were identified:

• Regnier et al (2015) compared intravitreal ranibizumab treatment (as needed and treat and extend regimens) with intravitreal aflibercept for the treatment of DMO. This study found that over a lifetime horizon both of the intravitreal ranibizumab treatment regimens were more effective and less costly compared with aflibercept. This analysis was from an NHS perspective and was informed by the RESTORE clinical trial.
• Mitchell et al (2012) compared intravitreal ranibizumab monotherapy, intravitreal ranibizumab in combination with laser therapy and laser monotherapy for the treatment of DMO from an NHS perspective. This study found over a 15-year time horizon ranibizumab monotherapy could be considered cost effective assuming a willingness-to-pay threshold of £30,000 per QALY.
• Pochopien et al (2019) compared the cost effectiveness of fluocinolone acetonide (FAc) implant with dexamethasone and usual care (mixture of laser treatment and anti-VEGF treatments ranibizumab, bevacizumab and aflibercept) for the treatment of vision impairment in people with DMO which has not responded to previous treatment and who have Pseudophakic lens. The authors also compared the cost effectiveness of FAc compared with usual care for eyes with phakic lens. This study found that over 15 years FAc could be considered cost effective for the population with Pseudophakic lens based on an ICER of £14,070 for FAc compared with dexamethasone and an ICER of £16,609 for FAc compared with usual care.
• Haig et al (2016) compared the cost effectiveness of intravitreal ranibizumab monotherapy and intravitreal ranibizumab in combination with laser therapy with laser monotherapy for the treatment of DMO from a Canadian healthcare system perspective. The authors considered both ranibizumab monotherapy and ranibizumab in combination with laser to be cost effective over a period of 36 months compared with laser monotherapy for the treatment of visual impairment in people with DMO assuming QALYs are valued at CA$50,000. However, this study was only considered partially applicable due to the Canadian study setting and the different ICER thresholds.
• Holekamp et al (2020) compared the cost effectiveness of intravitreal ranibizumab and intravitreal aflibercept for the treatment of DMO. This study found over 10 years aflibercept could not be considered cost effective compared to ranibizumab for the treatment of DMO. However, this study was only partially applicable due to the US study setting which is very different to the NHS, and the study had serious limitations with how the analysis was conducted and reported.
• Brown et al (2015) compared the cost effectiveness of intravitreal ranibizumab compared with the sham arm from RIDE and RISE clinical trials for the treatment of DMO. This study found over 14 years that the ICER incorporating all direct costs from a third-party insurer perspective was $4,587 (£3,186) per QALY. However, this study was only partially applicable due to the US study setting, which is very different to the NHS and the study had serious limitations with how the analysis was conducted and reported.
• Stein et al (2013) compared the cost-effectiveness of immediate laser treatment plus ranibizumab, delayed laser treatment plus ranibizumab, immediate laser treatment plus bevacizumab, and delayed laser treatment plus bevacizumab with laser monotherapy for the treatment of DMO. This study found that over 25 years delayed laser treatment was considered cost effective compared to laser treatment with an ICER of $11,138 (£7,774) per QALY and dominated immediate laser plus bevacizumab because deferred laser plus bevacizumab both increased QALYs and had lower costs. Neither immediate laser plus ranibizumab or delayed laser plus ranibizumab would not be considered cost effective with an ICER of $89,903 (£62,752) and $71,271 (£49,747) respectively per QALY. However, this study was only partially applicable due to the US study setting, which is very different to the NHS.
• Sharma et al (2000) compared the cost-effectiveness of laser photocoagulation with no treatment in people with DMO. The study estimated over a 40-year life expectancy laser treatment could be considered cost effective compared to no treatment for improving vision in DMO based on a QALY being valued at $20,000. However, this study was only partially applicable due to the US study setting, which is very different to the NHS and the study had serious limitations with how the analysis was conducted and reported.
• Lois et al (2022) compared the cost-effectiveness of subthreshold micro pulse laser compared with standard threshold laser treatment in adults with centre involving DMO with either a CRT between 300µm and 400µm or CRT<300µm and subretinal fluid was present in the central subfield. Over the two-year DIAMOND clinical trial duration, the study estimated that subthreshold laser could be considered equivalent to standard threshold laser in terms of both costs and clinical benefits and considered both treatments to be cost-effective treatments in people for whom laser treatment is suitable and have a CRT<400µm.
• Hutton et al (2023) compared the cost-effectiveness of aflibercept monotherapy with bevacizumab as first line treatment followed by aflibercept if needed. The study estimated bevacizumab as first line treatment followed by aflibercept if needed to be a cost saving treatment without any changes in visual acuity gains across the two-year clinical trial duration. Aflibercept monotherapy was not considered to be cost effective compared with bevacizumab as first line treatment.

1.1.12. The committee’s discussion and interpretation of the evidence

1.1.13. Other factors the committee took into account

The committee were aware of other recommendations about when to assess response to anti-VEGFs. They highlighted how the NHS Framework Agreement for the supply of Medical Retinal Vascular Treatments states that one approach to this is to assess response after 6 months of anti-VEGF treatment. However, they noted that these decisions were based primarily on the effectiveness of anti-VEGF treatments and steroids, and not the additional adverse events associated with steroids. As such, they thought that their decision to recommend a review of response to anti-VEGF treatment after 12 months was appropriate for most people.

The committee discussed how people may have different pathologies in each eye. They stressed the importance of treating diabetic retinopathy on a per-eye basis. This will ensure that individuals receive the most effective treatment which addresses the specific active issues in each eye, rather than focusing solely on one eye with more severe disease. Treating both eyes individually is essential because it reduces the risk of progression in either eye, ultimately lowering the chances of severe consequences like vision loss.

1.1.14. Recommendations supported by this evidence review

This evidence review supports recommendations 1.3.1 and 1.6.1 to 1.6.11.

1.1.15. References – included studies

1.1.14.1. Effectiveness

Included studies from NICE search

• Callanan, David G, Gupta, Sunil, Boyer, David S et al. (2013) Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 120(9): 1843–51 [PubMed: 23706947]

• Chen, Y.-X., Li, X.-X., Yoon, Y.H. et al. (2020) Intravitreal aflibercept versus laser photocoagulation in asian patients with diabetic macular edema: The VIVID-east study. Clinical Ophthalmology 14: 741–750 [PMC free article: PMC7069586] [PubMed: 32210527]

• Faghihi, H, Esfahani, MR, Harandi, ZA et al. (2010) Intravitreal bevacizumab vs. combination of intravitreal bevacizumab plus macular photocoagulation in clinically significant diabetic macular edema: 6 months results of a randomized clinical trial. Iranian journal of ophthalmology 22(1): 21–26

• Fouda, S.M. and Bahgat, A.M. (2017) Intravitreal aflibercept versus intravitreal ranibizumab for the treatment of diabetic macular edema. Clinical Ophthalmology 11: 567–571 [PMC free article: PMC5367610] [PubMed: 28356711]

• Gillies, Mark C, Simpson, Judy M, Gaston, Christine et al. (2009) Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology 116(11): 2182–7 [PubMed: 19796823]

• Lam, Dennis S C, Chan, Carmen K M, Mohamed, Shaheeda et al. (2007) Intravitreal triamcinolone plus sequential grid laser versus triamcinolone or laser alone for treating diabetic macular edema: six-month outcomes. Ophthalmology 114(12): 2162–7 [PubMed: 17459479]

• Shaggily, Cemal and Duru, Necati (2020) COMPARISON OF INTRAVITREAL DEXAMETHASONE IMPLANT AND AFLIBERCEPT IN PATIENTS WITH TREATMENT-NAIVE DIABETIC MACULAR EDEMA WITH SEROUS RETINAL DETACHMENT. Retina (Philadelphia, Pa.) 40(6): 1044–1052 [PubMed: 30950970]

• Vader, Maartje J C, Schauwvlieghe, Ann-Sofie M E, Verbraak, Frank D et al. (2020) Comparing the Efficacy of Bevacizumab and Ranibizumab in Patients with Diabetic Macular Edema (BRDME): The BRDME Study, a Randomized Trial. Ophthalmology. Retina 4(8): 777–788 [PubMed: 32362552]

Included studies from Cochrane review: Virgili et al-2022

• Azad 2012

  Azad R, Sain S, Sharma YR, Mahajan D. Comparison of intravitreal bevacizumab, intravitreal triamcinolone acetonide, and macular grid augmentation in refractory diJuse diabetic macular edema: A prospective, randomized study. Oman Journal of Ophthalmology 2012;5(3):166–70. [PMC free article: PMC3574512] [PubMed: 23439853]

• Baker 2019 Baker 2019 {published data only}

  Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, et al. EJect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA 2019;321(19):1880–94. [PMC free article: PMC6537845] [PubMed: 31037289]

• BOLT 2010 (Michaelides 2010)

  Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010;117(6):1078–86. [PubMed: 20416952]
  Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Archives of Ophthalmology 2012;130(8):972–9. [PubMed: 22491395]
  Sivaprasad S, Crosby-Nwaobi R, Esposti S, Peto T, Rajendram R, Michaelides M, et al. Structural and functional measures of eJicacy in response to bevacizumab monotherapy in diabetic macular oedema: exploratory analyses of the BOLT Study (Report 4). PloS ONE 2013;8(8):e72755 [PMC free article: PMC3754932] [PubMed: 24013651]

• Brown 2015

  Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, Heier JS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD, JaJe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Zeitz O, Metzig C, Korobelnik JF. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology 2015;122(10):2044–52. [PubMed: 26198808]

• Brown 2020

  Brown DM, Emanuelli A, Bandello F, Barranco JJ, Figueira J, Souied E, et al. KESTREL and KITE: 52-week results from two Phase III pivotal trials of brolucizumab for diabetic macular edema. American Journal of Ophthalmology 2022;238:157–72 [PubMed: 35038415]

• Chatzirallis 2020

  Chatzirallis A, Theodossiadis P, Droutsas K, Koutsandrea C, Ladas I, Moschos MM. Ranibizumab versus aflibercept for diabetic macular edema: 18-month results of a comparative, prospective, randomized study and multivariate analysis of visual outcome predictors. Cutaneous and Ocular Toxicology 2020;39:317–22 [PubMed: 32722955]

• DA VINCI 2011 (Do 2012)

  Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R, et al. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119(8):1658–65. [PubMed: 22537617]
  Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, et al. The DAVINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology 2011;118(9):1819–26 [PubMed: 21546089]

• DRCRnet 2010

  Anonymous. Erratum: Patient-reported visual function outcomes improve aGer ranibizumab treatment in patients with vision impairment due to diabetic macular edema: Randomized clinical trial (JAMA Ophthalmology (2013) 131:10 (1339-1347) DOI: 10.1001/jamaophthalmol.2013.4592). JAMA Ophthalmology 2013;131(12):1652. [PubMed: 23974915]
  Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year aGer treatment for diabetic [PMC free article: PMC3543147] [PubMed: 22965591]
  Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, et al. Exploratory analysis of the eJect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmology 2013;131(8):1033–40. [PMC free article: PMC4162127] [PubMed: 23807371]
  Dewan V, Lambert D, Edler J, Kymes S, Apte RS. CosteJectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2012;119(8):1679–84. Diabetic Retinopathy Clinical Research Network, [PMC free article: PMC3612959] [PubMed: 22503301]
  Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117(6):1064–77. [PMC free article: PMC2937272] [PubMed: 20427088]
  Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118(4):609–14. [PMC free article: PMC3096445] [PubMed: 21459214]
  Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 2012;119(11):2312–8. [PMC free article: PMC3490003] [PubMed: 22999634]

• DRCRnet 2015

  Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. New England Journal of Medicine 2015;372(13):1193–203. [PMC free article: PMC4422053] [PubMed: 25692915]
  Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative eJectiveness randomized clinical trial. Ophthalmology 2016;123(6):1351–9. [PMC free article: PMC4877252] [PubMed: 26935357]

• Ekinci 2014

  Ekinci M, Ceylan E, Cakici O, Tanyildiz B, Olcaysu O, Cagatay HH. Treatment of macular edema in diabetic retinopathy: Comparison of the eJicacy of intravitreal bevacizumab and ranibizumab injections. Expert Review of Ophthalmology 2014;9(2):139–43

• Ishibashi 2014

  Ishibashi T, Yuzawa M, Yoshimura N, Ohji M, Ishida S, Isogawa N, et al. Japan phase 3 study of pegaptanib sodium in patients Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis (Review) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 38 For Preview Only Cochrane Library Trusted evidence. Informed decisions. Better health. Cochrane Database of Systematic Reviews with diabetic macular edema. Nippon Ganka Gakkai Zasshi 2014;118(9):773–82. [PubMed: 25318186]

• Korobelnik 2014 (1)

  Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014;121(11):2247–54. [PubMed: 25012934]

• Li 2019

  Li X, Dai H, Li X, Han M, Li J, Suhner A, et al. EJicacy and safety of ranibizumab 0.5 mg in Chinese patients with visual impairment due to diabetic macular edema: results from the 12-month REFINE study. Graefe’s Archive for Clinical and Experimental Ophthalmology 2019;257(3):529–41. [PubMed: 30645696]

• Liu 2022

  Liu K, Wang H, He W, Ye J, Song Y, Wang Y, et al. Intravitreal conbercept for diabetic macular oedema: 2-year results from a randomised controlled trial and open-label extension study. British Journal of Ophthalmology 2021 17 May [Epub Ahead of Print]. [DOI: 10.1136/bjophthalmol-2020-318690 [PMC free article: PMC9510409] [PubMed: 34001667] [CrossRef]

• Prunte 2016

  Prünte C, Fajnkuchen F, Mahmood S, Ricci F, Hatz K, Studnička J, et al. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. British Journal of Ophthalmology 2016;100(6):787–95. [PMC free article: PMC4893084] [PubMed: 26453639]

• LUCIDATE 2014 (Comyn 2014)

  Comyn O, Sivaprasad S, Peto T, Neveu MM, Holder GE, Xing W, et al. A randomized trial to assess functional and structural eJects of ranibizumab versus laser in diabetic macular edema (the LUCIDATE study). American Journal of Ophthalmology 2014;157(5):960–70. [PubMed: 24531025]

• Macugen 2005

  Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D’Amico DJ, et al. A phase II randomized doublemasked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112(10):1747–57. [PubMed: 16154196]

• Macugen 2011 (Sultan 2011)

  LoGus JV, Sultan MB, Pleil AM, Macugen 1013 Study Group. Changes in vision and health-related quality of life in patients with diabetic macular edema treated with pegaptanib sodium or sham. Investigative Ophthalmology and Visual Science 2011;52(10):7498–505. [PubMed: 21896838]
  * Sultan MB, Zhou D, LoGus J, Dombi T, Ice KS, Macugen 1013 Study Group. A phase 2/3, multicenter, randomized, doublemasked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology 2011;118(6):1107–18 [PubMed: 21529957]

• Nepomuceno 2013

  Nepomuceno AB, Takaki E, Paes de Almeida FP, Peroni R, Cardillo JA, Siqueira RC, et al. A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. American Journal of Ophthalmology 2013;156(3):502–10 [PubMed: 23795985]

• READ2 2009 (Nguyen 2009)

  Do DV, Nguyen QD, Khwaja AA, Channa R, Sepah YJ, Sophie R, et al. Ranibizumab for edema of the macula in diabetes study: 3- year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmology 2013;131(2):139–45. [PubMed: 23544200]
  Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, et al. Primary end point (six months) results of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2009;116(11):2175–81. [PubMed: 19700194]
  Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2010;117(11):2146–51. [PubMed: 20855114]

• RELATION 2012

  CRFB002DD13. A 12-month, two-armed, randomized, doublemasked, multicenter, phase IIIb study assessing the eJicacy and safety of laser photocoagulation as adjunctive to ranibizumab intravitreal injections vs. laser photocoagulation monotherapy in patients with visual impairment due to diabetic macular edema followed by a 12 month follow up period. Novartis clinical trial results database www​.novctrd.com/ctrdWebApp​/clinicaltrialrepository​/public/login.jsp (accessed 2 June 2014).
  NCT01131585. A 12-month, two-armed, randomized, doublemasked, multicenter, phase IIIb study assessing the eJicacy and safety of laser photocoagulation as adjunctive to ranibizumab intravitreal injections vs. laser photocoagulation monotherapy in patients with visual impairment due to diabetic macular edema followed by a 12 month follow up period. clinicaltrials.gov/show/NCT01131585 (first received 25 May 2010).

• RESOLVE 2010 (Massin 2010)

  CRFB002D2201. A randomized, double-masked, multicenter, phase II study assessing the safety and eJicacy of two concentrations of ranibizumab (intravitreal injections) compared with non-treatment control for the treatment of diabetic macular edema with center involvement. Novartis clinical trial results database www​.novctrd.com/ctrdWebApp​/clinicaltrialrepository​/public/login.jsp (accessed 2 June 2014).
  Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, et al. Safety and eJicacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010;33(11):2399–405 [PMC free article: PMC2963502] [PubMed: 20980427]

• RESPOND 2013

  Berger A, Sheidow T, Li R, Rehel B, De Takacsy F, Courseau AS. A Canadian 12-month, phase IIIb study of ranibizumab combination or monotherapy in visual impairment due to diabetic macular edema: Preliminary analysis (“RESPOND”). In: 16th Annual Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism Professional Conference and Annual Meetings; 2013 Oct 17-19; Montreal. 2013. CRFB002DCA05.
  A Canadian 12-month, prospective, randomized, open-label, multicenter, phase IIIb study assessing the eJicacy, safety and cost of ranibizumab as combination and monotherapy in patients with visual impairment due to diabetic macular edema. Novartis clinical trial results database www​.novctrd.com/ctrdWebApp​/clinicaltrialrepository​/public/login.jsp (accessed 2 June 2014).

• RESTORE 2011 (Mitchell 2011)

  Anonymous. Erratum: Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Three year randomized trial results (Ophthalmology 2012;119:2312-8). Ophthalmology 2014;121(3):805. [PMC free article: PMC3490003] [PubMed: 22999634]
  Lang GE, Berta A, Eldem BM, Simader C, Sharp D, Holz FG, et al. Two-year safety and eJicacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study. Ophthalmology 2013;120(10):2004–12. [PubMed: 23725735]
  Mitchell P, Annemans L, Gallagher M, Hasan R, Thomas S, Gairy K, et al. Cost-eJectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment: evidence from the RESTORE trial. British Journal of Opthalmology 2012;96(5):688–93. [PMC free article: PMC3329632] [PubMed: 22399690]
  Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118(4):615–62. [PubMed: 21459215]
  Mitchell P, Bressler N, Tolley K, Gallagher M, Petrillo J, Ferreira A, et al. Patient-reported visual function outcomes improve aGer ranibizumab treatment in patients with vision impairment due to diabetic macular edema: randomized clinical trial. JAMA Ophthalmology 2013;131(10):1339–47. [PubMed: 23974915]
  Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabeticmacular edema: the RESTORE extension study. Ophthalmology2014;121(5):1045–53 [PubMed: 24491642]

• REVEAL 2015 (Ishibashi 2015)

  Ishibashi T, Li X, Koh A, Lai TY, Lee FL, Lee WK, et al. The REVEAL Study: ranibizumab monotherapy or combined with laser versus laser monotherapy in asian patients with diabetic macular edema. Ophthalmology 2015;122(7):1402–15 [PubMed: 25983216]

• RISE-RIDE (Nguyen 2012)

  Bressler NM, Varma R, Suñer IJ, Dolan CM, Ward J, Ehrlich JS, et al. Vision-related function aGer ranibizumab treatment for diabetic macular edema: results from RIDE and RISE. Ophthalmology 2014;121(12):2461–72. [PubMed: 25148789]
  Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120(10):2013–22. [PubMed: 23706949]
  Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term eJects of ranibizumab on diabetic retinopathy severity and progression. Archives of Ophthalmology 2012;130(9):1145–52. [PubMed: 22965590]
  Mieler WF, Kim JE, Yau L, Ehrlich JS. Earlier treatment is important in diabetic macular edema: Outcomes from phase III trials of intravitreal ranibizumab. In: 73rd Scientific sessions of the American Diabetes Association; 2013 Jun 21-25; Chicago. 2013.
  Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119(4):789–801 [PubMed: 22330964]

• Soheilian 2007

  Soheilian M, Garfami KH, Ramezani A, Yaseri M, Peyman GA. Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. Retina 2012;32(2):314–21. [PubMed: 22234244]
  Soheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 2007;27(9):1187–95. [PubMed: 18046223]
  * Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 2009;116(6):1142–50 [PubMed: 19376585]

• Turkoglu 2015

  Turkoglu EB, Celık E, Aksoy N, Bursalı O, Ucak T, Alagoz G. Changes in vision related quality of life in patients with diabetic macular edema: ranibizumab or laser treatment? Journal of Diabetes and its Complications 2015;29(4):540–3. [PubMed: 25817172]

• Wykoff 2022

  WykoJ CC, Abreu F, Adamis AP, Basu K, Eichenbaum DA, Haskova Z, et al. EJicacy, durability, and safety of intravitreal faricimab withextended dosing up to every 16 weeks in patients withdiabetic macular oedema (YOSEMITE and RHINE):two randomised, double-masked, phase 3 trials. Lancet 2022;399(10326):741–55 [PubMed: 35085503]

Included studies from Cochrane review: Rittiphairoj et al-2020

• BEVORDEX 2014 {published data only}

  Alessandrello EM, Hodgson LA, McAuley AK, Fraser-Bell S, Gillies MC, Lim LL, et al. Retinal vascular calibre changes in the bevordex randomised clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular oedema. Clinical and Experimental Ophthalmology 2015;43:117–8.
  Cornish, E E, Teo, K Y C, Gillies, M C, Lim, L L, McAllister, I, Sanmugasundram, S, Nguyen, V, Wickremasinghe, S, Mehta, H, Fraser-Bell, S. Five year outcomes of the bevordex study (a multicenter randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone). Investigative Ophthalmology and Visual Science 2018;59(9).
  Gillies MC, Lim Ll, Campain A, Quin G, Salem W, Li J, et al. A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study. Ophthalmology 2014;121(12):2473–81. [PubMed: 25155371]
  Gillies MC, Lim Ll, Campain A, Quin G, Salem W, Li J, et al. BEVORDEX—a multicentre randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for persistent diabetic macular oedema. Investigative Ophthalmology and Visual Science 2014;55(13):ARVO E-abstract 5053. [PubMed: 25155371]

• Callanan 2017 {published data only}

  Callanan DG, Loewenstein A, Patel SS, Massin P, Corcóstegui B, Li XY, et al. A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema. Graefe’s Archive for Clinical and Experimental Ophthalmology 2017;255(3):463–73. [PubMed: 27632215]

• DRCR​.net 2008 {published data only}

  Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris F, et al. Factors associated with improvement and worsening of visual acuity 2 years aQer focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2010;117(5):946–53. [PMC free article: PMC2864322] [PubMed: 20122739]
  Bressler NM, Edwards AR, Beck RW, Flaxel CJ, Glassman AR, Ip MS, et al. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Archives of Ophthalmology 2009;127(12):1566–71. [PMC free article: PMC2872985] [PubMed: 20008708]
  Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115(9):1447–9. [PMC free article: PMC2748264] [PubMed: 18662829]
  Diabetic Retinopathy Clinical Research Network (DRCRnet), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Archives of Ophthalmology 2009;127(3):245–51. [PMC free article: PMC2754047] [PubMed: 19273785]
  Ip MS, Bressler SB, Antoszyk AN, Flaxel CJ, Kim JE, Friedman SM, et al. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: baseline features. Retina 2008;28(7):919–30. [PMC free article: PMC2796075] [PubMed: 18698292]
  Ip MS. A randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for diabetic macular edema (DME): study design and baseline characteristics. Investigative Ophthalmology and Visual Science 2008:ARVO Eabstract 3468.
  Lauer AK, Bressler NM, Edwards AR, Diabetic Retinopathy Clinical Research Network. Frequency of intraocular pressure increase within days aQer intravitreal triamcinolone injections in the Diabetic Retinopathy Clinical Research Network. Archives of Ophthalmology 2011;129(8):1097–9. [PMC free article: PMC4164019] [PubMed: 21825200]
  WykoJ CC, Hariprasad SM. DRCR protocol-T: reconciling 1- and 2-year data for managing diabetic macular edema. Ophthalmic Surgery Lasers and Imaging Retina 2016;47(4):308–12. [PubMed: 27065368]

• FAME 2011 {published data only}

  Campochiaro PA, Brown DM, Pearson A, Ciulla T, Boyer D, Holz FG, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 2011;118(4):626–35. [PubMed: 21459216]
  Dempe C, Scholl S, Augustin A. Fluocinolone acetonide (FAc) intravitreal implants improve visual acuity in chronic diabetic macular edema (DME) for up to 36 months. In: Acta Ophthalmologica. Conference: 40th Nordic Congress of Ophthalmology, Helsinki, Finland. 2012.

• Kriechbaum 2014 {published data only}

  Deak GG, Lammer J, Prager S, Mylonas G, Bolz M, Schmidt-Erfurth U. Refractive changes aQer pharmacologic resolution of diabetic macular edema. Ophthalmology 2014;121:1054–8. [PubMed: 24439462]
  Kriechbaum K, Prager S, Mylonas G, Scholda C, Rainer G, Funk M, et al. Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: one-year results. Eye 2014;28(1):9–15. [PMC free article: PMC3890767] [PubMed: 24336297]
  Prager SG, Lammer J, Mitsch C, Hafner J, Pemp B, Scholda C, et al. Analysis of retinal layer thickness in diabetic macular oedema treated with ranibizumab or triamcinolone. Acta Ophthalmologica 2018;96:e195–200. [PubMed: 29063703]

• Lim 2012 {published data only}

  Lim JW, Lee HK, Shin MC. Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: a randomized clinical trial. Ophthalmologica 2012;227(2):100–6. [PubMed: 21997197]

Included studies from Cochrane review: Mehta et al-2018

• DRCRnet U 2018 {published data only}

  Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM, et al. EFect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR network phase 2 randomized clinical trial. JAMA Ophthalmology 2018;136(1):29–38. [PMC free article: PMC5833605] [PubMed: 29127949]
  NCT01945866. Phase II combination steroid and anti-VEGF for persistent DME [Short-term evaluation of combination corticosteroid+anti-VEGF treatment for persistent central involved diabetic macular edema following anti-VEGF therapy]. clinicaltrials.gov/ct2/show/NCT01945866 (first received 19 September 2013).

• Lim 2012 {published data only}

  Lim JW, Lee HK, Shin MC. Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: a randomized clinical trial. Ophthalmologica 2012;227(2):100–6. [PubMed: 21997197]

• Maturi 2015 {published and unpublished data}

  Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW. A 12- month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema aKer multiple anti-VEGF Injections to assess the Efficacy of the dexamethasone delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina 2015;35(8):1604–14. [PubMed: 25829346]

• Neto 2017 {published data only}

  NCT00737971. Efficacy study of triamcinolone and bevacizumab intravitreal for treatment of diabetic macular edema (ATEMD) [Multicenter, randomized clinical trial to assess the Effectiveness of intravitreal Injections of bevacizumab, triamcinolone, or their combination in the treatment of diabetic macular edema]. clinicaltrials.gov/ct2/show/NCT00737971 (first received 20 August 2008).
  Neto HO, Regatieri CV, Nobrega MJ, Muccioli C, Casella AM, Andrade RE, et al. Multicenter, randomized clinical trial to assess the eFectiveness of intravitreal injections of bevacizumab, triamcinolone, or their combination in the treatment of diabetic macular edema. Ophthalmic Surgery, Lasers and Imaging Retina 2017;48(9):734–40. [PubMed: 28902334]

• Riazi-Esfahani 2017 {published data only}

  Riazi-Esfahani M, Riazi-Esfahani H, Ahmadraji A, Karkhaneh R, Mahmoudi A, Roohipoor R, et al. Intravitreal bevacizumab alone or combined with 1 mg triamcinolone in diabetic macular edema: a randomized clinical trial. International Ophthalmology 2017;37:1–14. [PubMed: 28349504]

• Shoeibi 2013 {published data only}

  Ahmadieh H, Ramezani A, Shoeibi N, Bijanzadeh B, Tabatabaei A, Azarmina M, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefe’s Archive for Clinical and Experimental Ophthalmology 2008;246(4):483–9. [PubMed: 17917738]
  Shoeibi N, Ahmadieh H, Entezari M, Yaseri M. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema: long-term results of a clinical trial. Journal of Ophthalmic and Vision Research 2013;8(2):99–106. [PMC free article: PMC3740475] [PubMed: 23943683]

• Soheilian 2012 {published data only}

  Soheilian M, Garfami KH, Ramezani A, Yaseri M, Peyman GA. Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. Retina 2012;32(2):314–21. [PubMed: 22234244]
  Soheilian M, Ramezani A, Obudi A, Bijanzadeh B, Salehipour M, Yaseri M, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology 2009;116(6):1142–50. [PubMed: 19376585]
  Yaseri M, Zeraati H, Mohammad K, Soheilian M, Ramezani A, Eslani M, et al. Intravitreal bevacizumab injection alone or combined with triamcinolone versus macular photocoagulation in bilateral diabetic macular edema; application of bivariate generalized linear mixed model with asymmetric random Effects in a subgroup of a clinical trial. Journal of Ophthalmic and Vision Research 2014;9(4):453–60. [PMC free article: PMC4329706] [PubMed: 25709771]

• Synek 2011 {published data only}

  Synek S, Vesely P. Intravitreal Bevacizumab with or without triamcinolone for refractory diabetic macular oedema. Collegium Antropologicum 2011;35(3):841–5. [PubMed: 22053565]

Included studies from Cochrane review: Jorge et al-2018

• B Bandello 2005 {published data only}

  Bandello F, Polito A, Del Borrello M, Zemella N, Isola M. “Light” versus “classic” laser treatment for clinically significant diabetic macular oedema. British Journal of Ophthalmology 2005;89(7):864–70. [PMC free article: PMC1772712] [PubMed: 15965168]

• Blankenship 1979 {published data only}

  Blankenship GW. Diabetic macular edema and argon laser photocoagulation: a prospective randomized study. Ophthalmology 1979;86(1):69–78. [PubMed: 530565]

• Casson 2012 {published data only}

  Casson RJ, Raymond G, Newland HS, Gilhotra JS, Gray TL. Pilot randomized trial of a nanopulse retinal laser versus conventional photocoagulation for the treatment of diabetic macular oedema. Clinical and Experimental Ophthalmology 2012;40(6):604–10. [PubMed: 22300292]

• Casswell 1990 {published data only}

  Casswell AG, Canning CR, Gregor ZJ. Treatment of diNuse diabetic macular oedema: a comparison between argon and krypton lasers. Eye 1990;4(Pt 5):668–72. [PubMed: 2282940]

• DRCRNET 2007 {published data only}

  Browning DJ, Apte RS, Bressler SB, Chalam KV, Danis RP, Davis MD, et al. Association of the extent of diabetic macular edema as assessed by optical coherence tomography with visual acuity and retinal outcome variables. Retina 2009;29(3):300–5. [PMC free article: PMC2657814] [PubMed: 19174719]
  Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, et al. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Archives of Ophthalmology 2007;125(4):469–80. [PMC free article: PMC2536574] [PubMed: 17420366]

• ETDRS 1985 {published data only}

  Anonymous. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research group. Ophthalmology 1991;98(5 Suppl):766–85. [PubMed: 2062512]
  Anonymous. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment eNect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Archives of Ophthalmology 1995;113(9):1144–55. [PubMed: 7661748]
  Anonymous. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report No. 4. Early Treatment Diabetic Retinopathy Research group. International Ophthalmology Clinics 1987;27(4):265–72. [PubMed: 3692708]
  Anonymous. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Archives of Ophthalmology 1985;103(12):1796–806. [PubMed: 2866759]

• Figueira 2009 {published data only}

  Figueira J, Khan J, Nunes S, Sivaprasad S, Rosa A, de Abreu JF, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. British Journal of Ophthalmology 2009;93(10):1341–4. [PubMed: 19054831]

• Freyler 1990 {published data only}

  Freyler H. Laser therapy of diabetic maculopathy. A comparative study of the argon green laser and dye red laser. Klinische Monatsblätter für Augenheilkunde 1990;197(2):176–81. [PubMed: 2243481]

• Ladas 1993 {published data only}

  Ladas ID, Theodossiadis GP. Long-term eNectiveness of modified grid laser photocoagulation for diNuse diabetic macular edema. Acta Ophthalmologica 1993;71(3):393–7. [PubMed: 8362641]

• Laursen 2004 {published data only}

  Laursen ML, Moeller F, Sander B, Sjoelie AK. Subthreshold micropulse diode laser treatment in diabetic macular oedema. British Journal of Ophthalmology 2004;88(9):1173–9. [PMC free article: PMC1772323] [PubMed: 15317711]

• Lavinsky 2011 {published data only}

  Lavinsky D, Cardillo JA, Melo LA Jr, Dare A, Farah ME, Belfort R Jr. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Investigative Ophthalmology and Visual Science 2011;52(7):4314–23. [PubMed: 21345996]

• Olk 1986 {published data only}

  Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diNuse diabetic macular edema. Ophthalmology 1986;93(7):938–50. [PubMed: 3763140]

• Olk 1990 {published data only}

  Olk, RJ. Argon green (514 nm) versus krypton red (647 nm) modified grid laser photocoagulation for diNuse diabetic macular edema. Ophthalmology 1990;97(9):1101–12. [PubMed: 2234840]

• Pei-Pei 2015 {published data only}

  Pei-Pei W, Shi-Zhou H, Zhen T, Lin L, Ying L, Jiexiong O. Randomised clinical trial evaluating best-corrected visual acuityandello 2005 [PMC free article: PMC4366477] [PubMed: 25697457]

• Tewari 1998 {published data only}

  Tewari HK, Gupta V, Kumar A, Verma L. ENicacy of diode laser for managing diabetic macular oedema. Acta Ophthalmologica Scandinavica 1998;76(3):363–6. [PubMed: 9686856]

• Venkatesh 2011 {published data only}

  Venkatesh P, Ramanjulu R, Azad R, Vohra R, Garg S. Subthreshold micropulse diode laser and double frequency neodymium: YAG laser in treatment of diabetic macular edema: a prospective, randomized study using multifocal electroretinography. Photomedicine and Laser Surgery 2011;29(11):727–33. [PubMed: 21612513]

• Vujosevic 2010 {published data only}

  Vujosevic S, Bottega E, Casciano M, Pilotto E, Convento E, Midena E. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 2010;30(6):908–16. [PubMed: 20168272]

• Xie 2013 {published data only}

  Xie TY, Guo QQ, Wang Y, Wang Q, Chen XY. Randomized, controlled clinical trial comparison of SDM laser versus argon ion laser in diabetic macular edema [阈下微脉冲激光与氩离 ⼦激光治疗糖尿病性⻩斑⽔肿的临床随机对照研究(英⽂)]. International Eye Science 2013;13(12):2370–2.

1.1.14.2. Economic

• Brown, Gary C, Brown, Melissa M, Turpcu, Adam et al. (2015) The Cost-Effectiveness of Ranibizumab for the Treatment of Diabetic Macular Edema. Ophthalmology 122(7): 1416–25 [PubMed: 25935787]

• Haig, Jennifer; Barbeau, Martin; Ferreira, Alberto (2016) Cost-effectiveness of ranibizumab in the treatment of visual impairment due to diabetic macular edema. Journal of medical economics 19(7): 663–71 [PubMed: 26882365]

• Holekamp, Nancy, Duff, Steven B, Rajput, Yamina et al. (2020) Cost-effectiveness of ranibizumab and aflibercept to treat diabetic macular edema from a US perspective: analysis of 2-year Protocol T data. Journal of medical economics 23(3): 287–296 [PubMed: 31502893]

• Hutton, D.W., Glassman, A.R., Liu, D. et al. (2023) Cost-effectiveness of Aflibercept Monotherapy vs Bevacizumab First Followed by Aflibercept If Needed for Diabetic Macular Edema. JAMA ophthalmology [PMC free article: PMC9896372] [PubMed: 36729431]

• Lois, Noemi, Campbell, Christina, Waugh, Norman et al. (2022) Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT. Health technology assessment (Winchester, England) 26(50): 1–86 [PMC free article: PMC9791463] [PubMed: 36541393]

• Mitchell, Paul, Annemans, Lieven, Gallagher, Meghan et al. (2012) Cost-effectiveness of ranibizumab in treatment of diabetic macular oedema (DME) causing visual impairment: evidence from the RESTORE trial. The British journal of ophthalmology 96(5): 688–93 [PMC free article: PMC3329632] [PubMed: 22399690]

• Pochopien, Michal, Beiderbeck, Annette, McEwan, Phil et al. (2019) Cost-effectiveness of fluocinolone acetonide implant (ILUVIEN R) in UK patients with chronic diabetic macular oedema considered insufficiently responsive to available therapies. BMC health services research 19(1): 22 [PMC free article: PMC6327492] [PubMed: 30626376]

• Regnier, S.A., Malcolm, W., Haig, J. et al. (2015) Cost-effectiveness of ranibizumab versus aflibercept in the treatment of visual impairment due to diabetic macular edema: A UK healthcare perspective. ClinicoEconomics and Outcomes Research 7: 235–247 [PMC free article: PMC4427067] [PubMed: 25999748]

• Sharma, S, Brown, G C, Brown, M et al. (2000) The cost-effectiveness of grid laser photocoagulation for the treatment of diabetic macular edema: results of a patient-based cost-utility analysis. Current opinion in ophthalmology 11(3): 175–9 [PubMed: 10977223]

• Stein, Joshua D, Newman-Casey, Paula Anne, Kim, David D et al. (2013) Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema. Ophthalmology 120(9): 1835–42 [PMC free article: PMC3737388] [PubMed: 23642372]

1.1.14.3. Other

• National Institute for Health and care Excellence (NICE). British National Formulary (BNF). Published 2023. Accessed February, 2023. https://bnf​.nice.org.uk/

• National Institute for Health and Care Excellence (NICE). TA824: Dexamethasone intravitreal implant for treating diabetic macular oedema. 2022. Available from: https://www​.nice.org.uk/guidance/ta824

• Czoski-Murray, C., Carlton, J., Brazier, J., Young, T., Papo, N. L., & Kang, H. K. (2009). Valuing condition-specific health states using simulation contact lenses. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 12(5), 793–799. 10.1111/j.1524-4733.2009.00527.x [PubMed: 19490557] [CrossRef]

Search design and peer review

NICE information specialists conducted the literature searches for the evidence review. The searches were run in October 2022. Update searches were run in Feb 2023. This search report is compliant with the requirements of PRISMA-S.

The MEDLINE strategy below was quality assured (QA) by a trained NICE information specialist. All translated search strategies were peer reviewed to ensure their accuracy. Both procedures were adapted from the 2016 PRESS Checklist.

The principal search strategy was developed in MEDLINE (Ovid interface) and adapted, as appropriate, for use in the other sources listed in the protocol, taking into account their size, search functionality and subject coverage.

Review Management

The search results were managed in EPPI-Reviewer v5. Duplicates were removed in EPPI-R5 using a two-step process. First, automated deduplication is performed using a high-value algorithm. Second, manual deduplication is used to assess ‘low-probability’ matches. All decisions made for the review can be accessed via the deduplication history.

Limits and restrictions

English language limits were applied in adherence to standard NICE practice and the review protocol.

Limits to exclude, conference abstract or conference paper or “conference review” were applied in adherence to standard NICE practice and the review protocol. The limit to remove animal studies in the searches was the standard NICE practice, which has been adapted from: Dickersin, K., Scherer, R., & Lefebvre, C. (1994). Systematic Reviews: Identifying relevant studies for systematic reviews. BMJ, 309(6964), 1286. [PMC free article: PMC2541778] [PubMed: 7718048]

Search filters

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Limits and restrictions

English language limits were applied in adherence to standard NICE practice and the review protocol.

Limits to exclude, comment or letter or editorial or historical articles or conference abstract or conference paper or “conference review” or letter or case report were applied in adherence to standard NICE practice and the review protocol.

The limit to remove animal studies in the searches was the standard NICE practice, which has been adapted from: Dickersin, K., Scherer, R., & Lefebvre, C. (1994). Systematic Reviews: Identifying relevant studies for systematic reviews. BMJ, 309(6964), 1286. [PMC free article: PMC2541778] [PubMed: 7718048]

Search filters

Download PDF (223K)

Clinical evidence

Table

- Study does not contain a relevant intervention - Full text paper not available

Economic evidence

Table

Pharmacoeconomic review report Pharmacoeconomic review report