Diversity when interpreting evidence in network meta-analyses (NMAs) on similar topics: an example case of NMAs on diabetic macular oedema

Wu, Jing; Adams, Clive; He, Xiaoning; Qi, Fang; Xia, Jun

doi:10.1186/s13643-023-02349-4

Systematic Reviews

Table 1 Summary of Included NMAs

From: Diversity when interpreting evidence in network meta-analyses (NMAs) on similar topics: an example case of NMAs on diabetic macular oedema

			Study ID^a
			Korobelnik 2015 [13]	Régnier 2014 [14]	Zhang 2016 [15]	Muston 2018 [16]	Virgili 2018 [17]
Protocol identified			x	x	x	x	√
Search	Cochrane		√	√	√	√	√
	EMBASE		√	√	√	√	√
	MEDLINE		√^b	√^b	√^c	√^b	√
	Others		^d	^e	^f	^g	^h
	Date		01/2013	02/2014	08/2015	12/2016	04/2017
Number of studies			11	8	21	13	24
Statistics	Network model		Bayesian	Bayesian	Bayesian	Bayesian	Frequentist
	Sensitivity analysis		Heterogeneous studies; ethnic group	Ethnic group		Heterogeneous studies; ethnic group	Studies at higher risk of biasⁱ
	Covariates		Baseline BCVA and/or CRT	Baseline BCVA and/or CRT		Baseline BCVA and/or CRT
	Others					Some IPD
Participants	Diabetic macular oedema		√	√	√	√	√
Participants	Diabetic macular oedema		Significant, focal or diffuse; DME secondary to diabetes involving the centre of the macula; Retinal thickening due to DME/clinically significant macula oedema with DR	Baseline BCVA and CRT varied—24–78 letters	Non-specific	As for Korobelnik 2015	Baseline visual acuity between 20/200 and 20/40; Previously received central/peripheral laser or treatment naïve included
Interventions^k	Aflibercept		2q4 or 2q8	2 mg; bimonthly	Intravitreal	2q8	2 mg^j
	Aflibercept	+ Laser	√			√
	Ranibizumab		0.5 mg, PRN	0.5 mg, PRN	Intravitreal	0.5 mg PRN or 0.5 mg T&E or 0.3 mg q4	0.5 mg or 0.3 mg
		+ Laser	√	√		√	Deferred
		+ Laser	√	√		√	Prompt
	Dexamethasone (continued)		Implants		Implants
	Bevacizumab				Intravitreal	1.25 mg	1.25 mg
	Bevacizumab	+ Laser	√		√	√
	Triamcinolone acetonide				Intravitreal	4 mg q4/PRN or 4 mg q4
	Triamcinolone acetonide	+ Laser	√		√	√
	Pegaptanib						0.3 mg
	Laser		√	√	√		√
	Laser	+ Sham injection	√
	Sham			√			√
Outcomes	Binary	ETDRS letters in BCVA	> 10 and > 15 gain; > 10 and > 15 loss	> 10 gain		> 10 and > 15 gain; > 10 and > 15 loss	> 15 gain
	Binary	AEs	√		√		√
	Continuous (average change)	In BCVA using ETDRS charts	√		√	√	√
	Continuous (average change)				CMT		CRT measured using OCT
Conclusions			Studies of IVT-AFL 2q8 showed improved 12-month visual acuity measures compared with studies of IVR 0.5 mg PRN and dexamethasone 0.7 mg implants based on indirect comparisons	Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser	Our analysis confirms that intravitreal aflibercept is the most favourable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection	This NMA, which incorporated IPD to improve analytic robustness, showed evidence of the superiority of IVT-AFL 2q8 to laser and ranibizumab 0.5 mg PRN. These results were irrespective of adjustment for baseline BCVA	Anti-VEGF drugs given by injection into the eye improve vision in people with diabetic macular oedema as compared to no average improvement with laser photocoagulation. One of these drugs, aflibercept, probably works slightly better after 1 year. There did not appear to be important harms from any of these drugs
Key results			There was an increase in the mean best-corrected visual acuity (BCVA) with IVT-AFL 2q8 over IVR 0.5 mg PRN. IVT-AFL 2q8 doubled the proportion of patients gaining ≥ 10 Early Treatment Diabetic Retinopathy Study letters at 12 months compared with dexamethasone 0.7 mg implants. There were no significant differences in safety outcomes between IVT-AFL 2q8 and IVR 0.5 mg PRN or dexamethasone 0.7 mg implants	The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept. Ranibizumab and aflibercept were statistically superior to laser monotherapy. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser	Intravitreal ranibizumab improved BCVA most significantly in 6 months and intravitreal aflibercept in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly in 6 months and intravitreal aflibercept in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved	IVT-AFL 2q8 was superior to laser in all analyses. IVT-AFL 2q8 showed strong evidence of superiority (95% credible interval [CrI] did not cross null) versus ranibizumab 0.5 mg PRN for the mean change in BCVA, ≥ 15 ETDRS letter gain, and ≥ 10 ETDRS letter loss. IVT-AFL 2q8 was not superior to ranibizumab 0.5 mg T&E for mean change in BCVA	All three anti-VEGF drugs prevent visual loss and improve vision in people with DMO (high-certainty evidence) People receiving ranibizumab were probably slightly less likely to improve vision compared with aflibercept at 1 year after the start of treatment (moderate-certainty evidence). Approximately three in 10 people improve vision by 3 or more lines with ranibizumab, and one in 10 additional people can achieve this with aflibercept. People receiving ranibizumab and bevacizumab probably have a similar visual outcome at 1 year after the start of treatment (moderate certainty evidence). Aflibercept, ranibizumab, and bevacizumab are similar for common and serious systemic harms (such as any disease leading to hospitalisation, disability, or death) (moderate- or high-certainty evidence) but is less certain for arterial thromboembolic events (mainly stroke, myocardial infarction, and vascular death) and death of any cause (very low-certainty evidence)

AE Adverse event, BCVA Best-corrected visual acuity, CI Credible/confidence interval, CMT Central macular thickness, CRT Central retinal thickness, DME Diabetic macular oedema, DR Diabetic retinopathy, ETDRS Early Treatment Diabetic Retinopathy Study, IPD Individual patient data, NI No information, NMA Network meta-analysis, OCT Optical coherence tomography, PRN Pro re nata, q4 Every 4 weeks, T&E Treat-and-extend, 2q8 2 mg every 8 week
^aSorted by search date, empty spaces indicate that the content was not part of the NMA
^bIncluding in-process citations and daily update
^cPubMed
^dThe bibliographies of identified research and review articles. Any abstracts for any unpublished studies at the time of literature review were provided by Bayer HealthCare (Berlin, Germany)
^eHand searching of abstracts from ophthalmology congresses (Association for Research in Vision and Ophthalmology [ARVO], American Academy of Ophthalmology [AAO], and European Society of Retina Specialists [EURETINA]), the ClinicalTrials.gov registry, and data on file at Novartis
^fClinicalTrials.gov (from January 2015 to December 2016)
^gThe reference lists of published meta-analyses of DME treatment
^hInternational Clinical Trials Registry Platform, ISRCTN registry, LILACS; Novartis Clinical Trials database, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, and World Health Organization
ⁱPost hoc
^jRegarding drug dose and monitoring/retreatment regimen, Virgili et al. (2018) [17] included schemes that are either on-label or commonly used in clinical practice (such as monthly, bimonthly, PRN, T&E)
^kNo included NMAs included RCTs which investigated conbercept during our search dates (June 2020)

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ISSN: 2046-4053

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