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Results from searching for studies for inclusion in the review.
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Figure 1

Results from searching for studies for inclusion in the review.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: 1 Anti‐vascular endothelial growth factor (anti‐VEGF) versus photocoagulation, outcome: 1.3 Visual acuity [logMAR].
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Figure 4

Forest plot of comparison: 1 Anti‐vascular endothelial growth factor (anti‐VEGF) versus photocoagulation, outcome: 1.3 Visual acuity [logMAR].

Forest plot of comparison: 2 Anti‐vascular endothelial growth factor (anti‐VEGF) plus surgery versus surgery alone or surgery plus sham or placebo, outcome: 2.3 Visual acuity [logMAR].
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Figure 5

Forest plot of comparison: 2 Anti‐vascular endothelial growth factor (anti‐VEGF) plus surgery versus surgery alone or surgery plus sham or placebo, outcome: 2.3 Visual acuity [logMAR].

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 1 Visual acuity.
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Analysis 1.1

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 1 Visual acuity.

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 2 Regression of proliferative diabetic retinopathy.
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Analysis 1.2

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 2 Regression of proliferative diabetic retinopathy.

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 3 Presence of vitreous or pre‐retinal haemorrhage.
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Analysis 1.3

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 3 Presence of vitreous or pre‐retinal haemorrhage.

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 4 Adverse effects.
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Analysis 1.4

Comparison 1 Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone, Outcome 4 Adverse effects.

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 1 Loss of 3 or more lines of ETDRS visual acuity.
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Analysis 2.1

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 1 Loss of 3 or more lines of ETDRS visual acuity.

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 2 Gain of 3 or more lines of ETDRS visual acuity.
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Analysis 2.2

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 2 Gain of 3 or more lines of ETDRS visual acuity.

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 3 Visual acuity.
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Analysis 2.3

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 3 Visual acuity.

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 4 Presence of vitreous or pre‐retinal haemorrhage.
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Analysis 2.4

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 4 Presence of vitreous or pre‐retinal haemorrhage.

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 5 Adverse effects.
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Analysis 2.5

Comparison 2 Bevacizumab with vitrectomy compared with vitrectomy alone, Outcome 5 Adverse effects.

Summary of findings for the main comparison. Anti‐VEGF with or without laser (panretinal photocoagulation; PRP) compared with PRP alone for proliferative diabetic retinopathy

Anti‐VEGF with or without laser (panretinal photocoagulation; PRP) compared with PRP alone for proliferative diabetic retinopathy

Patient or population: people with PDR

Settings: hospital

Intervention: anti‐VEGF with or without PRP

Comparison: PRP

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

PRP

Anti‐VEGF with or without PRP

Loss of3 lines of ETDRS visual acuity
Follow‐up: 12 months

300 per 1000

57 per 1000 (15 to 243)

RR 0.19 (0.05 to 0.81)

61 (1 study)

⊕⊝⊝⊝
very low1

Gain of3 lines of ETDRS visual acuity
Follow‐up: mean 12 months

10 per 1000

68 per 1000 (4 to 1260)

RR 6.78 (0.37 to 125.95)

61 (1 study)

⊕⊕⊝⊝
very low1

Visual acuity
logMAR

(logMAR scale value of 0 = 6/6 vision, higher score = worse vision)

Follow‐up: 12 months

The mean visual acuity ranged across control groups from
0.08 to 0.72 logMAR

The mean visual acuity in the intervention groups was
0.07 logMAR units lower
(0.12 to 0.02 lower)

373 (5 studies)

⊕⊕⊝⊝
low2

Regression of proliferative diabetic retinopathy (as measured by area of fluorescein leakage)

Follow‐up: 12 months

In 1 trial, people who received bevacizumab in addition to PRP had more regression of PDR, as measured by area of fluorescein leakage at 6 months compared with people who had PRP alone (MD ‐8.13 mm2, 95% CI ‐10.94 mm2 to ‐5.32 mm2, 19 participants). In another trial, people who received ranibizumab in addition to PRP had more regression of PDR, as measured by change in area of fluorescein leakage between baseline and 12 months compared with people who had PRP alone, however, the size of the effect was smaller and the CIs were compatible with no effect, or less regression (MD ‐1.0 mm2, 95% CI ‐5.3 mm2 to 3.3 mm2, 20 participants)

Presence of vitreous/pre‐retinal haemorrhage

Follow‐up: 12 months

150 per 1000

48 per 1000 (24 to 98)

RR 0.32 (95% CI 0.16 to 0.65)

342 (3 studies)

⊕⊕⊝⊝
low3

Quality of life

No data reported on quality of life

Adverse effects

Adverse effects were reported in 3 studies: 1 study of bevacizumab plus PRP compared with PRP alone and followed up to 3 months (61 participants); 1 study of ranibizumab compared with saline (both groups received PRP if indicated) and followed up to 4 months (261 participants); 1 study of ranibizumab plus PRP compared with PRP alone and followed up to 12 months (31 participants)

  • Neovascular glaucoma: RR 1.09 (95% CI 0.07 to 17.21; 1 RCT, 261 participants)

  • Retinal detachment: RR 0.99 (95% CI 0.44 to 2.25; 1 RCT, 261 participants)

  • Cataract: RR 0.32 (95% CI 0.01 to 7.63; 1 RCT, 61 participants)

  • Raised intraocular pressure: 2 different estimates from 2 trials: RR 0.11 (95% CI 0.01 to 1.92; 1 RCT, 61 participants) and RR 0.92 (95% CI 0.49 to 1.70; 1 RCT, 261 participants)

  • Cerebrovascular accident: RR 3.26 (95% CI 0.13 to 79.34; 2 RCTs, 322 participants)

  • Endophthalmitis: RR 0.36 (95% CI 0.01 to 8.82; 1 RCT, 261 participants) ‐ but unusual trial as control group received injection of saline, only case of endophthalmitis

  • Arterial hypertension: RR 0.47 (95% CI 0.12 to 1.76; 1 RCT, 261 participants)

  • Pain score: MD ‐56.1 (95% CI ‐71.9 to ‐40.3; 1 RCT, 31 participants) in favour of ranibizumab compared with PRP

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ETDRS: Early Treatment Diabetic Retinopathy Study; MD: mean difference; PDR: proliferative diabetic retinopathy; PRP: panretinal photocoagulation; RR: risk ratio; VEGF: vascular endothelial growth factor.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded for risk of bias (‐1) (study at high risk of selective reporting bias) imprecision (‐1) (wide CIs) and indirectness (‐1) (study reported gain/loss of ≥ 2 lines at 3 months only).
2 Downgraded for risk of bias (‐1) (3 studies at high risk of bias in ≥ 1 domains) and downgraded for indirectness (‐1) (only 1 of the studies followed up to 12 months).

3 Downgraded for risk of bias (‐1) (2 studies at high risk of bias in ≥ 1 domain) and downgraded for indirectness (‐1) (no study reported at 12 months).

Figures and Tables -
Summary of findings for the main comparison. Anti‐VEGF with or without laser (panretinal photocoagulation; PRP) compared with PRP alone for proliferative diabetic retinopathy
Summary of findings 2. Bevacizumab before or during vitrectomy compared with vitrectomy alone

Bevacizumab before or during vitrectomy compared with vitrectomy alone

Patient or population: people undergoing vitrectomy for PDR

Settings: hospital

Intervention: bevacizumab before or during vitrectomy

Comparison: vitrectomy alone or vitrectomy with sham injection

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Surgery

Anti‐VEGF plus surgery

Loss of3 lines of ETDRS visual acuity

Follow‐up: 12 months

60 per 1000

29 per 1000
(5 to 188)

RR 0.49
(0.08 to 3.14)

94
(3 studies)

⊕⊕⊝⊝
low1

Gain of3 lines of ETDRS visual acuity

Follow‐up: 12 months

500 per 1000

810 per 1000
(600 to 1000)

RR 1.62
(1.2 to 2.17)

94
(3 studies)

⊕⊕⊝⊝
low 1

Visual acuity

logMAR
(logMAR scale value of 0 = 6/6 vision, higher score = worse vision)

Follow‐up: 12 months

The mean visual acuity ranged across control groups from
0.51 to 1.46 logMAR units

The mean visual acuity in the intervention groups was
0.24 logMAR units lower
(0.50 lower to 0.01 higher)

335
(6 studies)

⊕⊕⊝⊝
low3

Regression of PDR (as measured by area of fluorescein leakage)

Follow‐up: 12 months

No data reported on regression of PDR

Presence of vitreous/pre‐retinal haemorrhage

Follow‐up: 12 months

500 per 1000

150 per 1000 (90 to 260)

RR 0.30 (0.18 to 0.52)

393 (7 studies)

⊕⊕⊝⊝
low4

Quality of life

No data reported on quality of life

Adverse effects

Neovascular glaucoma: RR 2.33 (95% CI 0.28 to 19.17; 1 RCT, 368 participants)

Retinal detachment: RR 0.56 (95% CI 0.11 to 2.86; 3 RCTs, 182 participants)

Cataract: RR 0.68 (95% CI 0.38 to 1.23; 2 RCTs, 137 participants)

Raised intraocular pressure: RR 0.31 (95% CI 0.01 to 7.47; 1 RCT, 68 participants)

Myocardial infarction: no events in 2 trials (175 participants)

Cerebrovascular accident: no events in 2 trials (175 participants)

Endophthalmitis: none of the studies reported endophthalmitis

Arterial hypertension: none of the studies reported arterial hypertension

Pain: none of the studies reported pain

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ETDRS: Early Treatment Diabetic Retinopathy Study; PDR: proliferative diabetic retinopathy; RR: risk ratio; VEGF: vascular endothelial growth factor.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded for imprecision (‐1) (wide CIs) and downgraded for indirectness (‐1) (only 1 trial reported at 12 months and only 1 (other) trial reported loss of ≥ 3 lines).
2 Downgraded for indirectness (‐1) (only 1 trial reported at 12 months and only 1 (other) trial reported gain of ≥ 3 lines) and downgraded for inconsistency (‐1) (I2 = 73%).

3Downgraded for risk of bias (‐1) (2 studies at high risk of bias in ≥ 1 domains) and downgraded for inconsistency (‐1) (I2 = 66%).

4 Downgraded for risk of bias (‐1) (2 studies at high risk of bias in ≥ 1 domains, 3 studies at unclear risk of bias in ≥ 3 domains) and downgraded for indirectness (‐1) (only 1 study reported at 12 months).

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Summary of findings 2. Bevacizumab before or during vitrectomy compared with vitrectomy alone
Table 1. ETDRS classification of diabetic retinopathy

Mild

Presence of at least 1 microaneurysm

Moderate

Haemorrhages or microaneurysms (or both) more than standard photo 2A, presence of soft exudates, venous beading, IRMA definitively present

Severe

Haemorrhages or microaneurysms (or both) more than standard photo 2A in all 4 quadrants, or venous beading in ≥ 2 quadrants, or IRMA more than standard photo 8A in at least 1 quadrant

Very severe

Any ≥ 2 of the changes seen in severe NPDR

Early PDR

Presence of new vessels

High‐risk PDR

Any of the following: NVD more than one‐third to one‐quarter disc diameter, NVD less than one‐third to one‐quarter disc diameter with vitreous or pre‐retinal haemorrhage, new vessels elsewhere with vitreous or pre‐retinal haemorrhage

ETDRS: Early Treatment Diabetic Retinopathy Study; IRMA: intraretinal microaneurysm; NPDR: non‐proliferative diabetic retinopathy; NVD: new vessels at optic disc; PDR: proliferative diabetic retinopathy.

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Table 1. ETDRS classification of diabetic retinopathy
Table 2. ICDRDS scale

Non‐apparent retinopathy

No abnormalities

Mild NPDR

Microaneurysms only

Moderate NPDR

More than just microaneurysms but less than severe NPDR

Severe NPDR

Any of the following: > 20 intraretinal haemorrhages in each of 4 quadrants; definite venous beading in 2 quadrants; prominent intraretinal microvascular abnormalities in 1 quadrant and no signs of proliferative retinopathy

Proliferative diabetic retinopathy

≥ 1 of the following: neovascularisation, vitreous or pre‐retinal haemorrhage

ICDRDS: International Clinical Diabetic Retinopathy Disease Severity scale; NPDR: non‐proliferative diabetic retinopathy.

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Table 2. ICDRDS scale
Comparison 1. Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Visual acuity Show forest plot

5

373

Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.12, ‐0.02]

1.1 Pegaptanib

1

16

Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.22, 0.10]

1.2 Bevacizumab

2

80

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.11, 0.09]

1.3 Ranibizumab

2

277

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.16, ‐0.03]

2 Regression of proliferative diabetic retinopathy Show forest plot

2

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

3 Presence of vitreous or pre‐retinal haemorrhage Show forest plot

3

342

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.16, 0.65]

3.1 Bevacizumab

1

61

Risk Ratio (M‐H, Fixed, 95% CI)

0.11 [0.01, 1.92]

3.2 Pegaptanib

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.01, 3.70]

3.3 Ranibizumab versus control

1

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.18, 0.81]

4 Adverse effects Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Neovascular glaucoma

1

261

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.07, 17.21]

4.2 Retinal detachment

1

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.44, 2.25]

4.3 Cataract

1

61

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 7.63]

4.4 Raised intraocular pressure

2

322

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.42, 1.36]

4.5 Cerebrovascular accident

2

322

Risk Ratio (M‐H, Fixed, 95% CI)

3.26 [0.13, 79.34]

4.6 Endophalmitis

1

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 8.82]

4.7 Arterial hypertension

1

261

Risk Ratio (M‐H, Fixed, 95% CI)

0.47 [0.12, 1.76]

Figures and Tables -
Comparison 1. Anti‐vascular endothelial growth factor (anti‐VEGF) with or without panretinal photocoagulation (PRP) versus PRP alone
Comparison 2. Bevacizumab with vitrectomy compared with vitrectomy alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Loss of 3 or more lines of ETDRS visual acuity Show forest plot

3

94

Risk Ratio (M‐H, Fixed, 95% CI)

0.49 [0.08, 3.14]

2 Gain of 3 or more lines of ETDRS visual acuity Show forest plot

3

94

Risk Ratio (M‐H, Fixed, 95% CI)

1.62 [1.20, 2.17]

3 Visual acuity Show forest plot

6

335

Mean Difference (IV, Random, 95% CI)

‐0.24 [‐0.50, 0.01]

4 Presence of vitreous or pre‐retinal haemorrhage Show forest plot

7

393

Risk Ratio (M‐H, Random, 95% CI)

0.30 [0.18, 0.52]

5 Adverse effects Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Neovascular glaucoma

1

107

Risk Ratio (M‐H, Random, 95% CI)

2.33 [0.28, 19.17]

5.2 Retinal detachment

3

182

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.11, 2.86]

5.3 Cataract

2

137

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.38, 1.23]

5.4 Raised intraocular pressure

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.01, 7.47]

5.5 Myocardial infarction

2

175

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5.6 Cerebrovascular accident

2

175

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

5.7 Arterial hypertension

0

0

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 2. Bevacizumab with vitrectomy compared with vitrectomy alone