Anti‐vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity

Mari Jeeva Sankar; Jhuma Sankar; Manisha Mehta; Vishnu Bhat; Renuka Srinivasan

doi:10.1002/14651858.CD009734.pub2

Fármacos anti‐factor de crecimiento endotelial vascular (FCEV) para el tratamiento de la retinopatía del prematuro

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References

References to studies included in this review

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awaiting assessment
additional references

Autrata R, Krejčířová I, Šenková K, Holoušová M, Doležel Z, Borek I. Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. European Journal of Ophthalmology 2012;22(5):687‐94. [PUBMED: 22669848]

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Mintz‐Hittner HA, Kennedy KA, Chuang AZ, BEAT‐ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. New England Journal of Medicine 2011;364(7):603‐15. [PUBMED: 21323540]

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Lepore D, Quinn GE, Molle F, Baldascino A, Orazi L, Sammartino M, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology 2014;121(11):2212‐9. [PUBMED: 25001158]

References to studies awaiting assessment

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included studies
additional references

Kong L, Bhatt AR, Demny AB, Coats DK, Li A, Rahman EZ, et al. Pharmacokinetics of bevacizumab and its effects on serum VEGF and IGF‐1 in infants with retinopathy of prematurity. Investigative Ophthalmology & Visual Science 2015;56(2):956‐61. [DOI: 10.1167/iovs.14‐15842; PUBMED: 25613938]

Moran S, O'Keefe M, Hartnett C, Lanigan B, Murphy J, Donoghue V. Bevacizumab versus diode laser in stage 3 posterior retinopathy of prematurity. Acta Ophthalmologica2014; Vol. 92, issue 6:e496‐7. [PUBMED: 24428792]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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awaiting classification

Autrata 2012

Methods	Randomised controlled trial
Participants	Preterm infants with stage 3+ ROP in Zone I or posterior zone II (n = 76); Single centre, university hospital, Brno ‐ Czech republic
Interventions	Intervention: intravitreal pegaptanib (0.3 mg in 0.02 ml of solution) combined with confluent laser therapy Control: conventional laser therapy
Outcomes	Primary: treatment success defined as absence of recurrence of stage 3+ ROP in one or both eyes by 55 weeks' postmenstrual age Secondary: time of regression and decrease of plus signs, development of peripheral retinal vessels after treatment, final structural/anatomic outcomes
Notes	We tried to contact the authors for additional information on methods and other outcomes (relevant to the review) but did not get any response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	How the random sequence was generated is not mentioned
Allocation concealment (selection bias)	Unclear risk	Not clear if the random allocation was concealed
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not clear if the clinical team was masked to the intervention group
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not clear if the outcome assessors were blinded to the group allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	No loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Not clear if all the outcomes were reported

BEAT‐ROP Trial 2011

Methods	Randomised controlled trial
Participants	Infants with birth weight 1500 g or less and gestational age of 30 weeks or less with stage 3+ ROP in zone I or zone II posterior in each eye (n = 150) Multi‐centre trial conducted at 15 hospitals in the United States of America
Interventions	Intervention: intravitreal bevacizumab monotherapy (0.625 mg in 0.025 ml of solution) Control: conventional laser therapy
Outcomes	Primary: treatment failure defined as recurrence of neovascularisation in one or both eyes and requiring re‐treatment by 54 weeks' postmenstrual age Secondary: structural outcomes of recurrence (macular dragging, retinal detachment), complications requiring intraocular surgery (cornea opacity requiring corneal transplant, lens opacity requiring cataract removal), mortality
Notes	We tried to contact the authors for additional information on other outcomes relevant to the review but did not get any response
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Secure computer‐generated randomisation schedule stratified on the basis of zone by a study group member who did not participate in enrolment
Allocation concealment (selection bias)	Low risk	Treatment assignments were revealed to the investigators only after the eligibility for enrolment had been confirmed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Study was controlled but not masked owing to the marks made by the laser therapy
Blinding of outcome assessment (detection bias) All outcomes	High risk	Retcam photographs to document recurrence by treating and confirming ophthalmologists without masking of treatment assignments, before deciding on additional treatment. Unmasked practicing paediatric ophthalmologists performed the cycloplegic retinoscopic refractions to assess the refractive errors at 30 months of age.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data of all infants who survived until 54 weeks' postmenstrual age were included in the analysis; about 17% of eligible infants were lost to follow‐up at 30 months of age (refractive outcomes)
Selective reporting (reporting bias)	Low risk	All outcomes mentioned in the protocol were reported
Other bias	Low risk	‐

Lepore 2014

Methods	Randomised controlled trial Randomised one eye of enrolled infants to conventional laser and the other eye to bevacizumab
Participants	Infants with type 1 ROP in zone I in both eyes and required treatment, according to ET‐ROP criteria (n = 13)
Interventions	'Intervention' eye: intravitreal bevacizumab monotherapy (0.5 mg in 0.02 ml of balanced salt solution) 'Control' eye: conventional laser therapy
Outcomes	Abnormailities on fluorescein angiography (FA) ‐ macular abnormalities (absence of foveolar avascular zone or hyperfluorescent lesion), capillary bed loss, linear choroidal filling pattern; complete retinal detachment (stage 5); mortality at three months of age
Notes	The eye assigned to conventional laser peripheral ablation was treated first. The eye randomized to receive bevacizumab was then prepared and 0.5 mg (0.02 ml) of bevacizumab was injected intravitreally
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... randomly selected using a random number series"
Allocation concealment (selection bias)	Unclear risk	Not clear if the random allocation was concealed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not possible because one eye is randomized to intervention while the other eye to control (laser)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not clear if the outcome assessors were blinded to the group allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	No loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Not clear if all the outcomes were reported (secondary outcomes not available in the published protocol)
Other bias	High risk	Because eyes were randomized, the eye randomized to control group would have been exposed to both anti‐VEGF agents and control treatment resulting in better outcomes if there was significant systemic absorption of bevacizumab

Characteristics of studies awaiting assessment [ordered by study ID]

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included studies

Kong 2015

Methods	Randomised controlled trial
Participants	Twenty‐four infants with type 1 ROP
Interventions	Twenty‐four infants with type 1 ROP were randomized into three treatment groups: intravitreal injection of bevacizumab (IVB) at 0.625 mg per eye per dose, IVB at 0.25 mg per eye per dose, and laser.
Outcomes	Blood samples were collected prior to treatment and on post‐treatment days 2, 14, 42, and 60. Weekly body weights were documented from birth until 60 days post treatment. Serum levels of bevacizumab, free VEGF, and IGF‐1 were measured with enzyme‐linked immunosorbent assay (ELISA).
Notes

Moran 2014

Methods	Prospective case–control study
Participants	Fourteen infants with symmetrical zone 1 or posterior zone 2 Stage 3 + ROP
Interventions	Comparing intravitreal bevacizumab in one eye to laser therapy in the fellow eye
Outcomes	"We observed rapid regression of ROP in all eyes injected with bevacizumab, as well as resolution of plus disease and flattening of the ridge by 48 hr post‐injection in all eyes. Further vascularization was noted with complete regression taking up to sixty weeks in some eyes. In our study, four of 14 eyes (28.6%) had recurrence of ROP; three eyes (21.42%) which had bevacizumab treatment and one eye (7.14%) with conventional laser therapy. There was a significant time delay to recurrence in the bevacizumab group compared with laser, with a mean age of 51 weeks PMA at time of recurrence in bevacizumab‐treated eyes compared with 37 weeks PMA in the laser‐treated eye." Moran 2014
Notes

Data and analyses

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Comparison 1. Anti‐VEGF vs cryo/laser therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Structural outcome ‐ partial or complete retinal detachment Show forest plot	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.21, 5.13]
Open in figure viewer Analysis 1.1 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 1 Structural outcome ‐ partial or complete retinal detachment.
1.1 Zone I	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.26]
1.2 Zone II posterior	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	5.13 [0.25, 103.45]
2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes) Show forest plot	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.50]
Open in figure viewer Analysis 1.2 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes).
3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes) Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.20]
Open in figure viewer Analysis 1.3 $Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes).$ Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes).
3.1 Zone I	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.30]
3.2 Zone II posterior	1	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.34]
4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes) Show forest plot	1	211	Mean Difference (IV, Fixed, 95% CI)	5.68 [4.33, 7.02]
Open in figure viewer Analysis 1.4 $Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).$ Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).
4.1 Zone I	1	87	Mean Difference (IV, Fixed, 95% CI)	6.93 [4.26, 9.60]
4.2 Zone II posterior	1	124	Mean Difference (IV, Fixed, 95% CI)	5.25 [3.69, 6.81]
5 Mortality before discharge from primary hospital Show forest plot	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.26, 8.75]
Open in figure viewer Analysis 1.5 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 5 Mortality before discharge from primary hospital.
5.1 Zone I	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.07, 15.80]
5.2 Zone II posterior	1	83	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.18, 20.71]
6 Mortality at 30 months of age Show forest plot	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.30, 2.45]
Open in figure viewer Analysis 1.6 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 6 Mortality at 30 months of age.
6.1 Zone I	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.16, 2.38]
6.2 Zone II posterior	1	83	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.26, 8.31]
7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes) Show forest plot	1	286	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.26]
Open in figure viewer Analysis 1.7 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes).
7.1 Zone I	1	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Zone II posterior	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.26]
8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes) Show forest plot	1	286	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.79]
Open in figure viewer Analysis 1.8 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes).
8.1 Zone I	1	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Zone II posterior	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.79]
9 Recurrence of ROP by 54 weeks PMA Show forest plot	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.08, 0.62]
Open in figure viewer Analysis 1.9 Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 9 Recurrence of ROP by 54 weeks PMA.
9.1 Zone I	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.04, 0.62]
9.2 Zone II posterior	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.08, 1.99]

Open in table viewer

Comparison 2. Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Structural outcome ‐ retinal detachment (unit of analysis: eyes) Show forest plot	1	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.12, 0.55]
Open in figure viewer Analysis 2.1 Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 1 Structural outcome ‐ retinal detachment (unit of analysis: eyes).
2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes) Show forest plot	1	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.24, 1.56]
Open in figure viewer Analysis 2.2 Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes).
3 Recurrence of ROP by 55 weeks PMA Show forest plot	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.70]
Open in figure viewer Analysis 2.3 Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 3 Recurrence of ROP by 55 weeks PMA.

Figure 1

Study flow diagram.

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Figure 2

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

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Analysis 1.1

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 1 Structural outcome ‐ partial or complete retinal detachment.

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Analysis 1.2

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes).

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$Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes).$

Analysis 1.3

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes).

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$Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).$

Analysis 1.4

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).

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Analysis 1.5

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 5 Mortality before discharge from primary hospital.

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Analysis 1.6

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 6 Mortality at 30 months of age.

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Analysis 1.7

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes).

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Analysis 1.8

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes).

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Analysis 1.9

Comparison 1 Anti‐VEGF vs cryo/laser therapy, Outcome 9 Recurrence of ROP by 54 weeks PMA.

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Analysis 2.1

Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 1 Structural outcome ‐ retinal detachment (unit of analysis: eyes).

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Analysis 2.2

Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes).

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Analysis 2.3

Comparison 2 Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy, Outcome 3 Recurrence of ROP by 55 weeks PMA.

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Summary of findings for the main comparison. Intravitreal anti‐VEGF therapy compared to conventional laser/cryotherapy in preterm infants with type 1 ROP

Intravitreal anti‐VEGF therapy compared to conventional laser/cryotherapy in preterm infants with type 1 ROP
Patient or population: preterm infants with type 1 ROP Settings: Intervention: intravitreal anti‐VEGF therapy Comparison: conventional laser/cryotherapy
Outcomes*	Illustrative comparative risks^# (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	conventional laser/cryotherapy	intravitreal anti‐VEGF therapy
Structural outcome ‐ retinal detachment	Study population		RR 1.04 (0.21 to 5.13)	143 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2,3
	27 per 1000	28 per 1000 (6 to 141)
Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes)	Study population		RR 0.06 (0.02 to 0.2)	211 (1 RCT)	⊕⊕⊝⊝ LOW ^1,4
	416 per 1000	25 per 1000 (8 to 83)
Mortality before discharge from primary hospital	Study population		RR 1.5 (0.26 to 8.75)	150 (1 RCT)	⊕⊕⊝⊝ LOW ^2,3,5
	27 per 1000	40 per 1000 (7 to 233)
Mortality at 30 months of age	Study population		RR 0.86 (0.3 to 2.45)	150 (1 RCT)	⊕⊕⊝⊝ LOW ^2,3,5
	93 per 1000	80 per 1000 (28 to 229)
Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes)	Study population		RR 0.34 (0.01 to 8.26)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2,3,4
	7 per 1000	2 per 1000 (0 to 57)
Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes)	Study population		RR 0.15 (0.01 to 2.79)	286 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2,3,4
	21 per 1000	3 per 1000 (0 to 57)
Recurrence of ROP by 54 weeks PMA	Study population		RR 0.22 (0.08 to 0.62)	143 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹
	260 per 1000	57 per 1000 (21 to 161)
Only the outcomes for which data are available are reported here; ^#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;
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.
¹Outcome assessment not blinded ²95% CI around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm ³Number of events too small ⁴Serious risk of bias in analysis (unit of analysis error) ⁵Outcome assessment not blinded but outcome is objective

Summary of findings for the main comparison. Intravitreal anti‐VEGF therapy compared to conventional laser/cryotherapy in preterm infants with type 1 ROP

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Summary of findings 2. Anti‐VEGF combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 ROP

Anti‐VEGF combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 ROP
Patient or population: preterm infants with type 1 ROP Settings: Intervention: anti‐VEGF combined with laser/cryotherapy Comparison: laser/cryotherapy
Outcomes*	Illustrative comparative risks^# (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	laser/cryotherapy	anti‐VEGF combined with laser/cryotherapy
Structural outcome ‐ retinal detachment (unit of analysis: eyes)	Study population		RR 0.26 (0.12 to 0.55)	152 (1 RCT)	⊕⊕⊝⊝ LOW ^1,2,3
	393 per 1000	102 per 1000 (47 to 216)
Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes)	Study population		RR 0.62 (0.24 to 1.56)	152 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^1,2,3,4
	143 per 1000	89 per 1000 (34 to 223)
Recurrence of ROP by 55 weeks' PMA	Study population		RR 0.29 (0.12 to 0.7)	76 (1 RCT)	⊕⊕⊝⊝ LOW ^1,3
	500 per 1000	145 per 1000 (60 to 350)
Only the outcomes for which data are available are reported here; ^#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;
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.
¹Outcome assessment not blinded ²Serious risk of bias in analysis (unit of analysis error) ³Unclear risk of selection bias ⁴95% CI around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm

Summary of findings 2. Anti‐VEGF combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 ROP

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Comparison 1. Anti‐VEGF vs cryo/laser therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Structural outcome ‐ partial or complete retinal detachment Show forest plot	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.21, 5.13]

1.1 Zone I	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.26]
1.2 Zone II posterior	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	5.13 [0.25, 103.45]
2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes) Show forest plot	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.50]

3 Refractive error ‐ very high myopia ‐ at 30 months of age (unit of analysis: eyes) Show forest plot	1	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.02, 0.20]

3.1 Zone I	1	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.30]
3.2 Zone II posterior	1	124	Risk Ratio (M‐H, Fixed, 95% CI)	0.05 [0.01, 0.34]
4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes) Show forest plot	1	211	Mean Difference (IV, Fixed, 95% CI)	5.68 [4.33, 7.02]

4.1 Zone I	1	87	Mean Difference (IV, Fixed, 95% CI)	6.93 [4.26, 9.60]
4.2 Zone II posterior	1	124	Mean Difference (IV, Fixed, 95% CI)	5.25 [3.69, 6.81]
5 Mortality before discharge from primary hospital Show forest plot	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.26, 8.75]

5.1 Zone I	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.07, 15.80]
5.2 Zone II posterior	1	83	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.18, 20.71]
6 Mortality at 30 months of age Show forest plot	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.30, 2.45]

6.1 Zone I	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.16, 2.38]
6.2 Zone II posterior	1	83	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.26, 8.31]
7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes) Show forest plot	1	286	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.26]

7.1 Zone I	1	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Zone II posterior	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.26]
8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes) Show forest plot	1	286	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.79]

8.1 Zone I	1	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Zone II posterior	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.79]
9 Recurrence of ROP by 54 weeks PMA Show forest plot	1	143	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.08, 0.62]

9.1 Zone I	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.04, 0.62]
9.2 Zone II posterior	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.08, 1.99]

Comparison 1. Anti‐VEGF vs cryo/laser therapy

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Comparison 2. Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Structural outcome ‐ retinal detachment (unit of analysis: eyes) Show forest plot	1	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.12, 0.55]

2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes) Show forest plot	1	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.24, 1.56]

3 Recurrence of ROP by 55 weeks PMA Show forest plot	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.70]

Comparison 2. Anti‐VEGF plus cryo/laser therapy vs cryo/laser therapy

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References

References to studies included in this review

Autrata 2012 {published data only (unpublished sought but not used)}

BEAT‐ROP Trial 2011 {published data only (unpublished sought but not used)}

Lepore 2014 {published data only}

References to studies awaiting assessment

Kong 2015 {published data only}

Moran 2014 {published data only}

Additional references

Aiello 1995

American Academy of Pediatrics 2006

Andersen 1999

Ashton 1953

Ashton 1954

Committee for Classification of ROP 1984

Deeks 2011

ET‐ROP Group 2003

Gilbert 2005

Gilbert 2008

GRADEpro GDT [Computer program]

Higgins 2003

Higgins 2011

Higgins 2011a

Higgins 2011b

Kong 2008

Lashkari 2000

Law 2010

Mantagos 2009

Micieli 2009

Mintz‐Hittner 2008

Palmer 1997

RevMan 2014 [Computer program]

Schünemann 2011

Shah 2007

Smith 2003

Sterne 2011

Tasman 2006

Ueta 2009

Wong 2015

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of studies awaiting assessment [ordered by study ID]

Data and analyses

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