Background
Methods
Search strategy
Inclusion criteria
Criteria
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Inclusion
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Exclusion
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Study design | Published and unpublished randomized controlled studies | Systematic or non-systematic reviews and meta-analyses |
Dose or frequency comparison studies | Preclinical studies, retrospective prognostic studies, and case reports | |
Ad-hoc analyses of randomized controlled study data | Editorials, commentaries, letters, and consensus reports | |
Crossover randomized controlled studies | Pilot studies (if phase not mentioned), phase I and II randomized controlled studies (to be included as second-level evidence, if primary evidence is unavailable) | |
Controlled observational studies (to be included as second-level evidence, if primary evidence is unavailable) | ||
Separate searches will be performed as required | ||
Single dose of intervention studies | ||
Studies of less than 3 months follow-up | ||
Population | Patients with DME | |
Interventions | Eylea/VEGF Trap-Eye/aflibercept | Systemic treatments (alone or in combination with intervention) |
Anti-VEGF treatments (any including ranibizumab/Lucentis, bevacizumab/Avastin, and pegaptanib/Macugen) | Surgery (alone or in combination with intervention) | |
Subtenon injections | ||
Intravitreal steroids (any including triamcinolone, fluocinolone acetonide/Iluvien, dexamethasone/Ozurdex, and implants) | ||
Laser treatments | ||
NOTE the intervention should be to treat the DME not to treat cataracts | ||
The above interventions can be included if combined with other treatments (e.g., eye drops) except the exclusions | ||
Comparators | Placebo, best standard care, masked control, sham, and eye drops | Systemic treatments (alone or in combination with intervention) |
Any intervention (from those listed as interventions) | Surgery (alone or in combination with intervention) | |
NOTE: this can be a single treatment/implant | ||
Clinical Outcomes | Number of injections/visits/assessments | |
BCVA (mean change from baseline, mean average change from baseline, as measured by ETDRS score or Snellen equivalent) | ||
Loss of ≤ 15, ≥ 15, ≥ 30 ETDRS letters | ||
Gain of ≥ 0, 10, 15, 30 ETDRS letters | ||
20/40 vision or better (Snellen chart) | ||
20/200 or worse (Snellen chart) | ||
Reduction in laser use | ||
Anatomical changes (e.g., change in CNV and lesion area, central foveal thickness, and fluid on OCT) | ||
Health-related quality of life (EQ-5D, NEI VFQ-25, and other scales) | ||
Treatment discontinuations | ||
Serious AE (all serious AE, all ocular serious AE, death, endophthalmitis, uveitis, retinal tear, diabetic macular/retinal edema, reduced visual acuity, vitreous hemorrhage, corneal abrasion, and any others) | ||
AE (all AE, all ocular AE, all non-ocular AE, retinal detachment, retinal ischemia, lens damage, all grades of ocular inflammation, eye pain, increased ocular pressure, retinal degradation, macular edema, cataract, neovascularization, and any others) | ||
Serious non-ocular AE (all, non-fatal cardiac infarction, non-fatal stroke, non-ocular hemorrhage, hypertension, serious systemic events, arterial thrombotic events, and venous thrombotic events) | ||
Language | Any | |
Additional criteria necessary for inclusion in indirect and mixed treatment analysis | Studies that were connected by one arm only and did not form a closed network, unless they included comparators of interest | |
Studies that formed loops but did not lie along the path between IVT-AFL 2q8 versus comparators of interest (IVR 0.5 mg PRN, or implants of dexamethasone 0.7 mg or fluocinolone acetonide 0.2 μg/day) | ||
Studies that did not report 12-month outcomes |
Data extraction and quality assessment
Statistical analyses
Results
Feasibility assessments
Efficacy outcomes: IVT-AFL 2q8 versus IVR 0.5 mg PRN
Reference
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Phase
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Design
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Randomized patients (n)
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Inclusion
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Interventions
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Baseline ETDRS score, mean (SD)
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Follow-up (months)
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Primary outcome
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Mean change in BCVA (letters) at Month 12
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VIVID-DME [13] | III | Randomized, double-blind, multicenter | 136 135 135 | Patients with DME secondary to diabetes mellitus. BCVA ETDRS letter score between 24 and 73 in the study eye | IVT-AFL 2q4* IVT-AFL 2q8* Laser* | 60.8 (10.7) 58.8 (11.2) 60.8 (10.6) | 12 | Mean change in BCVA (ETDRS letters score) at Week 52 | +10.5 +10.7 +1.2 |
VISTA-DME [13] | III | Randomized, double-blind, multicenter | 156 154 156 | Patients with DME secondary to diabetes mellitus. BCVA ETDRS letter score between 24 and 73 in the study eye | IIVT-AFL 2q4* IVT-AFL 2q8* Laser* | 58.9 (10.8) 59.4 (10.9) 59.7 (11.0) | 12 | Mean change in BCVA (ETDRS letters score) at Week 52 | +12.5 +10.7 +0.2 |
IBETA [29] Abstract | III | Randomized, open, single center | 23 21 20 | Clinically significant DME. Snellen logarithm of minimum angle of 20/40 or worse | Laser fixed → PRN IVB 1.5 mg + laser IVTA 4 mg + laser | NR NR NR | 12 | Outcomes included BCVA, OCT-CMT at Week 52 | +9.5 +11.5 +12.5 |
RESTORE [15] | III | Randomized, double-blind, multicenter | 111 116 118 | Focal or diffuse DME. BCVA letter score between 39 and 78 | Laser fixed q4 → PRN* IVR 0.5 mg q4 → PRN* IVR 0.5 mg + laser | 62.4 (11.1) 64.8 (10.1) 63.4 (10.0) | 12 | Mean average change in BCVA from baseline to Month 1 through 12 | +0.8 +6.1 +5.9 |
REVEAL [16] Abstract | III | Randomized, double-blind, multicenter | 133 132 131 | Focal or diffuse DME. BCVA letter score between 39 and 78 | IVR 0.5 mg q4 → PRN* IVR 0.5 mg + laser Laser fixed q4 → PRN* | NR NR NR | 12 | Mean average change in BCVA from baseline to Month 1 through 12 | +6.6 +6.4 +1.8 |
III | Randomized, double-blind, multicenter | 85 43 | DME | IVR 0.5 mg + prompt laser Laser fixed q4 → PRN* | NR NR | 12 | Changes in BCVA, OCT-CRT, and FA | +6.5 +1.4 | |
DRCR.net Protocol I [32] | III | Randomized, double-blind, multicenter | 293 187 188 186 | DME. BCVA letter score between 24 and 78 | Laser fixed q4 → PRN* IVR 0.5 mg + prompt laser IVR 0.5 mg + deferred laser IVTA 4 mg + laser | NR NR NR NR | 12 (maximum 36) | Mean change in BCVA at month 12 | +3 +9 +9 +4 |
DRCR.net Protocol J [33] | III | Randomized, double-blind, multicenter | 123 113 109 | DME and presence of severe NPDR or PDR. ETDRS letter score ≥ 24 | Laser fixed* IVR 0.5 mg + laser IVTA 4 mg + laser | NR NR NR | 12 | Mean change in visual acuity from baseline to Week 14 | −6 −4 −5 |
LUCIDATE [34] Abstract | IV | Randomized, open, single center | 11 11 | DME. BCVA letter score between 55 and 79 | IVR 0.5 mg q4 → PRN Laser fixed → PRN | NR NR | 11 | BCVA ETDRS VA, FA, OCT, microperimetry, full-field and multifocal ERG at Week 48 | +6.0 −0.9 |
Maia et al. (2009) [35] | II/III | Randomized, single-blind, single center | 22 22 | DR and CSME. ETDRS severity level 65 | Laser fixed → PRN IVTA 4 mg + laser | NR NR | 12 | Changes in BCVA, CMT, and TMV | +3** +16** |
PLACID [36] | II | Randomized, double-blind, multicenter | 126 127 | Diffuse DME. BCVA letter score between ≥ 34 and ≤ 70 | Dexamethasone fixed → PRN Laser fixed → PRN* | 57 (9.4) 57.5 (9.5) | 12 | Proportion who gained ≥ 10 letters from baseline to Month 12 | NA |
Direct and indirect analyses
(A)
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MTC
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Studies (n)
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FE: effect size [95% CrI]
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RE: effect size [95% CrI]
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BCVA mean change from baseline | 10 studies (n = 3060)* | MD = 4.67 [2.45–6.87] | MD = 4.67 [1.85–7.52] |
Gain ≥ 10 ETDRS letters | 6 studies (n = 2810)** | RR = 1.32 [0.98–1.78] | RR = 1.19 [0.90–1.57] |
OR = 1.64 [0.97–2.78] | OR = 1.59 [0.75–3.35] | ||
Loss ≥ 10 ETDRS letters | 6 studies (n = 2810)** | RR = 0.27 [0.07–0.90] | RR = 0.28 [0.06–1.29] |
OR = 0.27 [0.07–0.90] | OR = 0.26 [0.05–1.31] | ||
Gain ≥ 15 ETDRS letters | 6 studies (n = 2810)** | RR = 1.78 [0.96–3.29] | RR = 1.42 [0.93–2.24] |
OR = 1.90 [0.95–3.75] | OR = 1.87 [0.87–4.16] | ||
Loss ≥ 15 ETDRS letters | 6 studies (n = 2810)** | RR = 0.13 [0.004–1.35] | RR = 0.14 [0.007–1.52] |
OR = 0.13 [0.004–1.35] | OR = 0.14 [0.006–1.53] | ||
(B)
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Bucher
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Studies (n)
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FE: effect size [95% CI]
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RE: effect size [95% CI]
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BCVA mean change from baseline | 4 studies (n = 1611)*** | MD = 4.82 [2.52–7.11] | MD = 4.82 [2.52–7.11] |
Gain ≥ 10 ETDRS letters | 4 studies (n = 1611)*** | RR = 0.993 [0.65–1.52] | RR = 1.00 [0.60–1.66] |
OR = 1.32 [0.74–2.35] | OR = 1.32 [0.65–2.68] | ||
Loss ≥ 10 ETDRS letters | 4 studies (n = 1611)*** | RR = 0.31 [0.09–1.04] | RR = 0.31 [0.09–1.09] |
OR = 0.28 [0.08–0.99] | OR = 0.27 [0.08–0.94] | ||
Gain ≥ 15 ETDRS letters | 4 studies (n = 1611)*** | RR = 1.49 [0.78–2.85] | RR = 1.49 [0.78–2.85] |
OR = 1.74 [0.83–3.65] | OR = 1.74 [0.83–3.65] | ||
Loss ≥ 15 ETDRS letters | 4 studies (n = 1611)*** | RR = 0.24 [0.03–1.90] | RR = 0.26 [0.03–2.11] |
OR = 0.23 [0.03–1.86] | OR = 0.23 [0.03–1.86] |
Efficacy outcomes: IVT-AFL 2q8 versus dexamethasone 0.7 mg implants
Outcome
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Studies (n)
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FE: effect size [95% CI]
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RE: effect size [95% CI]
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---|---|---|---|
Gain ≥ 10 ETDRS letters | 3 studies (n = 1123)* | RR = 2.10 [1.29–3.40] | RR = 2.10 [1.21–3.66] |
OR = 3.51 [1.79–6.88] | OR = 3.52 [1.60–7.72] |
Safety outcomes
Outcome
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Studies (n)
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FE: effect size [95% CrI]
|
RE: effect size [95% CrI]
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---|---|---|---|
All AEs | 5 studies (n = 1739)* | RR = 0.79 [0.55–1.10] | RR = 0.88 [0.64–1.15] |
OR = 0.61 [0.29–1.26] | OR = 0.58 [0.18–1.82] | ||
All serious AEs | 5 studies (n = 1739)* | RR = 0.76 [0.47–1.26] | RR = 0.82 [0.47–1.42] |
OR = 0.71 [0.39–1.32] | OR = 0.74 [0.31–1.72] | ||
All serious ocular AEs | 5 studies (n = 1739)* | RR = 0.28 [0.06–1.24] | RR = 0.30 [0.05–2.49] |
OR = 0.27 [0.05–1.25] | OR = 0.28 [0.05–2.58] | ||
All serious non-ocular AEs | 4 studies (n = 1343)** | RR = 0.60 [0.32–1.14] | RR = 0.67 [0.29–1.66] |
OR = 0.53 [0.24–1.17] | OR = 0.53 [0.12–2.11] | ||
All ocular AEs | 4 studies (n = 1343)** | RR = 0.75 [0.54–1.05] | RR = 0.85 [0.58–1.25] |
OR = 0.60 [0.32–1.09] | OR = 0.58 [0.16–1.87] | ||
All non-ocular AEs | 3 studies (n = 1215)*** | RR = 1.09 [0.87–1.40] | RR = 1.03 [0.80–1.56] |
OR = 1.27 [0.65–2.42] | OR = 1.22 [0.23–6.18] | ||
Eye pain | 4 studies (n = 1343)** | RR = 0.98 [0.38–2.70] | RR = 0.96 [0.23–3.91] |
OR = 0.97 [0.34–2.94] | OR = 0.95 [0.17–4.75] | ||
Cataract | 3 studies (n = 1215)*** | RR = 3.93 [0.77–32.74] | RR = 3.83 [0.52–43.72] |
OR = 4.09 [0.76–34.86] | OR = 4.16 [0.49–50.98] | ||
Hypertension | 4 studies (n = 1343)** | RR = 0.95 [0.44–2.07] | RR = 0.95 [0.37–2.55] |
OR = 0.95 [0.40–2.22] | OR = 0.94 [0.28–3.14] | ||
All causes of mortality | 3 studies (n = 1215)*** | RR = 2.90 [0.20–50.4] | RR = 2.76 [0.13–79.02] |
OR = 3.06 [0.18–60.01] | OR = 2.83 [0.11–85.27] |
Outcome
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Studies (n)
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FE: effect size [95% CI]
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RE: effect size [95% CI]
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---|---|---|---|
Macular edema | 2 studies (n = 657)* | RR = 0.22 [0.03–1.67] | RR = 0.22 [0.03–1.64] |
OR = 0.21 [0.03–1.69] | OR = 0.21 [0.03–1.70] | ||
Reduced visual acuity | 3 studies (n = 1123)** | RR = 0.64 [0.24–1.67] | RR = 0.64 [0.17–2.40] |
OR = 0.61 [0.21–1.77] | OR = 0.61 [0.21–1.77] | ||
Vitreous hemorrhage | 3 studies (n = 1123)** | RR = 0.30 [0.07–1.39] | RR = 0.18 [0.02–1.65] |
OR = 0.28 [0.06–1.38] | OR =0.16 [0.02–1.54] | ||
Eye pain | 3 studies (n = 1123)** | RR = 0.80 [0.29–2.21] | RR = 0.78 [0.27–2.21] |
OR = 0.79 [0.26–2.38] | OR = 0.76 [0.24–2.38] | ||
Increased intraocular pressure | 3 studies (n = 1123)** | RR = 0.08 [0.02–0.42] | RR = 0.13 [0.01–1.79] |
OR = 0.07 [0.01–0.37] | OR = 0.11 [0.01–1.54] | ||
Cataract | 3 studies (n = 1123)** | RR = 0.42 [0.13–1.39] | RR = 0.43 [0.12–1.63] |
OR = 0.40 [0.11–1.40] | OR = 0.41 [0.10–1.64] |