Table 1.

Characteristics of included studies in the meta-analysis

Study	Country	Study design	Sample size	Definition of treatment resistance	Inclusion/exclusion criteria	Mean follow-up (months)
Aghdam et al25	Germany	Prospective	22	Persistent fluid after >6 months of monthly ranibizumab therapy	No previous macular laser, PDT, or vitrectomy No history of RAP/PCV or presence of macular fibrosis scar	12
Arcinue et al30	USA	Retrospective	63	Persistent retinal fluid after the eyes have been dry following at least 3 injections every 4 weeks; or persistence of exudation or fibrovascular PED with IRF/SRF on OCT while on monthly ranibizumab or bevacizumab monotherapy	Excluded if they had received aflibercept elsewhere prior; macular hole, VMT, ERM, retinal detachment, PCV, macular dystrophy, or peripapillary CNV	12
Bakall et al42	USA	Retrospective	36	Persistent IRF/SRF despite monthly intravitreal injections with the same drug or a change from either bevacizumab or ranibizumab to the other 4 weeks apart	IRF/SRF present for minimum of 3 months prior to baseline Must be treated with minimum 3 aflibercept injections	6
Barthelmes et al31	Australia	Retrospective	384	Persistent exudation and loss of vision despite regular treatment	At least 12 months previously treated with ranibizumab and 12 months of follow-up after switch	12
Broadhead et al22	Australia	Prospective	43	Persistent IRF or SRF and PED on OCT for at least 6 months despite at least 4 intravitreal anti-VEGF injections in the past	BCVA of 35–90 letters (20/200–20/20) PED height >100 µm	12
Chan et al32	USA	Retrospective	189	Persistent or recurrent macular edema, SRF, hemorrhage, exudates, and/or PED to the same drugs during the time of drug transition to aflibercept	Received at least 3 consecutive injections of the same anti-VEGF prior (bevacizumab and/or ranibizumab) to baseline Must receive 3 loading doses and have 6 months of follow-up	6
Chang et al24	Australia	Prospective	49	Persistent IRF/SRF on OCT despite at least 4 anti-VEGF injections in the previous 6 months	BCVA of 35–90 letters (20/200–20/20) Excluded if: uncontrolled IOP >25 mmHg; h/o vitreous hemorrhage, inflammation, vitrectomy, PDT, or subfoveal atrophy; triamcinolone 180 days prior to baseline	6
Chang et al23	Australia	Prospective	49	Presence of IRF/SRF OCT despite at least 4 intravitreal injections of an anti-VEGF agent in the preceding 6 months	BCVA of 35–90 letters (20/200–20/20) Excluded if: uncontrolled IOP >25 mmHg; h/o vitreous hemorrhage, inflammation, vitrectomy, PDT, or subfoveal atrophy; triamcinolone 180 days prior to baseline	12
Chatziralli et al43	UK	Retrospective	447	Persisting or increasing SRF/IRF or PED on OCT or the presence of macular hemorrhage	Received at least 3 monthly ranibizumab injections over a period of no more than 4 months before switch No h/o vitrectomy, prior PDT, or laser treatment; uncontrolled glaucoma; or uveitis	12
Cho et al41	USA	Retrospective	28	Persistent IRF/SRF 28–35 days after a minimum of 6 ranibizumab and/or bevacizumab injections	Excluded if: OCT was dry at any time 3 months prior to baseline; OCT or FFA suggesting retinal tubulation without IRF/SRF or cystic degeneration	6
de Massougnes et al33	Switzerland	Retrospective	60	Presence of IRF/SRF at each visit 1 month after injection to ranibizumab treatment during 9 months leading to switch	PED height >150 µm Excluded if: PCV, or any other confounding retinal pathology	9
Eadie et al34	USA	Retrospective	67	Persistent exudation confirmed on OCT despite a minimum of 3 anti-VEGF injections	Nil retinal thickening due to subretinal fibrosis	24
Gerding45	Switzerland	Retrospective	40	The necessity of monthly ranibizumab injections, or OCT findings were worse within the last 6 months than previously under an equal or lower frequency of ranibizumab treatment	No other treatment for AMD. Completed 6 months of follow-up	6
Gharbiya et al35	Italy	Retrospective	31	Persistent IRF/SRF despite at least 6 consecutive monthly injections with ranibizumab	Interval between last injection and baseline not <4 weeks or exceeding 6 weeks Must have at least 6 months of follow up No prior PDT, PCV, RAP, or intraocular surgery except standard cataract surgery	6
Grewal et al26	USA	Prospective	21	Persistent IRF/SRF or PED despite >6 months of monthly anti-VEGF treatment	Previously treated with at least 6 anti-VEGF 12 injections No PCV, CSR, RPE tear, PDT (3 months prior to baseline), subfoveal fibrosis, or prior triamcinolone (within 6 months prior to baseline); intraocular Sx within 2 months prior to baseline; h/o vitrectomy, inflammation, and subretinal hemorrhage	12
Hall et al36	USA	Retrospective	30	Central macular edema or submacular fluid despite a mean of 19.1±0.06 prior to anti-VEGF injections	Received 2 anti-VEGF injections prior to baseline, and had to be followed for 6 months after the switch	12
Hariri et al46	USA	Retrospective	142	Refractory fluid to other anti-VEGF therapies	At least 3 injections in the previous 12 months prior to Baseline No DMO, CRVO, ERM, CSR, previous inflammation, or PDT	12
He et al47	USA	Retrospective	142	Refractory fluid to other anti-VEGF therapies	At least 3 injections in the previous 12 months prior to baseline No DMO, CRVO, ERM, CSR, previous inflammation, PDT	12
Kanesa-Thasan et al37	USA	Retrospective	11	Persistent PED, IRF/SRF, and/or sub-RPE fluid with adjacent SRF or IRF after at least 6 months of monthly anti-VEGF treatment	No PDT, subfoveal fibrosis, h/o vitrectomy, active inflammation, vitreous hemorrhage, subretinal hemorrhage involving at least 1 disc area of central fovea, previous RPE tear, or PCV and CSR	18
Kumar et al38	USA	Retrospective	34	Persistent IRF/SRF or subfoveal sub-RPE fluid with adjacent IRF/SRF fluid on OCT despite at least 3 consecutive injections with ranibizumab	Had consecutive anti-VEGF therapy in 6 months prior to baseline (3 being ranibizumab) Interval between the last ranibizumab injection and baseline not exceeding 42 days	6
Major et al48	USA	Retrospective	60	Persistent PED despite ≥2 prior anti-VEGF injections	No h/o CSR, glaucoma, or intraocular steroids	12
Mantel et al27	Switzerland	Prospective	21	Presence of IRF/SRF despite monthly retreatment with ranibizumab	Previous ranibizumab Rx for 2 years and still had persistent fluid BCVA between 20/25 and 20/400 Max lesion size 12 DD	12
Narayan and Muecke39	Australia	Retrospective	80	Persistent macular fluid after >12 months of ranibizumab treatment	Eyes excluded if they received prior PDT	12
Pinheiro-Costa et al44	Portugal	Retrospective	82	Persistent IRF/SRF after ≥3 consecutive monthly bevacizumab injections	Minimum 3 anti-VEGF before Baseline Received at least 3 aflibercept with follow-up	8.3
Ricci et al49	Italy	Retrospective	72	Persistent IRF/SRF after at least 3 monthly consecutive ranibizumab injections as evaluated by OCT	Exclusion criteria: Prior vitrectomy, trabulectomy, surgery in the study eye within 3 months of baseline, uncontrolled glaucoma, uveitis, or other ocular disease to confound the results	12
Sarao et al28	Italy	Prospective	92	Persistent or recurrent IRF/SRF on OCT after at least 4 intravitreal ranibizumab injections during the previous 6 months	BCVA <70 ETDRS No RAP, PCV, RPE tear, active inflammation, or infection	12
Thorell et al40	USA	Retrospective	73	Persistent or recurrent IRF/SRF on OCT despite at least 12 months of intravitreal bevacizumab or ranibizumab	Received at least 12 months of anti-VEGF therapy prior to baseline No concomitant retinal pathology	6
Wykoff et al29	USA	Prospective	46	Recalcitrant fluid despite monthly or near-monthly anti-VEGF therapy	Previously treated on 2-year SAVE trial No subretinal fibrosis or GA	6

Abbreviations: AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; CNV, choroidal neovascularization; CRVO, central retinal vein occlusion; CSR, central serous retinopathy; DD, disc diameters; DMO, diabetic macular edema; ERM, epiretinal membrane; ETDRS, Early Treatment Diabetic Retinopathy Study; GA, geographic atrophy; FFA, fundus fluorescein angiogram; h/o, history of; IOP, intraocular pressure; IRF, intraretinal fluid; OCT, optical coherence tomography; PCV, polypoidal choroidal vasculopathy; PDT, photodynamic therapy; PED, pigment epithelial detachment; RAP, retinal angiomatous proliferation; RPE, retinal pigment epithelium; Rx, treatment; SRF, subretinal fluid; Sx, surgery; VEGF, vascular endothelial growth factor; VMT, vitreomacular traction.