Switching to aflibercept among patients with treatment-resistant neovascular age-related macular degeneration: a systematic review with meta-analysis

Figures & data

Figure 1 Data sample extraction.

Abbreviation: PCV, polypoidal choroidal vasculopathy.

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 al^Citation25	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 al^Citation30	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 al^Citation42	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 al^Citation31	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 al^Citation22	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 al^Citation32	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 al^Citation24	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 al^Citation23	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 al^Citation43	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 al^Citation41	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 al^Citation33	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 al^Citation34	USA	Retrospective	67	Persistent exudation confirmed on OCT despite a minimum of 3 anti-VEGF injections	Nil retinal thickening due to subretinal fibrosis	24
Gerding^Citation45	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 al^Citation35	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 al^Citation26	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 al^Citation36	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 al^Citation46	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 al^Citation47	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 al^Citation37	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 al^Citation38	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 al^Citation48	USA	Retrospective	60	Persistent PED despite ≥2 prior anti-VEGF injections	No h/o CSR, glaucoma, or intraocular steroids	12
Mantel et al^Citation27	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 Muecke^Citation39	Australia	Retrospective	80	Persistent macular fluid after >12 months of ranibizumab treatment	Eyes excluded if they received prior PDT	12
Pinheiro-Costa et al^Citation44	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 al^Citation49	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 al^Citation28	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 al^Citation40	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 al^Citation29	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.

Table 2 Clinical characteristics of included studies in the meta-analysis

Study	Mean age in years (range)	Number of injections prior to conversion (range)	Time between last anti-VEGF treatment and conversion (range)	Mean number of aflibercept injections (range)	Treatment regimen
Aghdam et al^Citation25	73.95±10.65 (56–91)	9.55±6.91 (6–30)	Not <4 weeks or >6 weeks	7.27±1.98 (4–12)	Loading phase of aflibercept every 4 weeks for 3 months followed by PRN
Arcinue et al^Citation30	81.00 (IQR 76–87)	13.00 (IQR 7–22)	Median 6 weeks (range 4–18)	Those treated every 8 weeks =4 (4–6) 21 eyes were switched to every 4-weekly treatment	8 weekly aflibercept injections without loading phase In case of persistent fluid regimen, changed to every 4 weeks
Bakall et al^Citation42	79.00 (60–88)	25.60 (6–74) 10.6 for ranibizumab group 15.0 for bevacizumab group	4 weeks	5.72 (in 9 eyes treatment was stopped prior to 6 months: in 8 patients after the fifth injection and in 1 patient after the fourth injection)	Loading phase of aflibercept every 4–6 weeks for 3 months, followed by PRN
Barthelmes et al^Citation31	N/A	N/A	N/A	6.60	N/A
Broadhead et al^Citation22	78.70	34.80	N/A	8.00	Loading phase of aflibercept every 4 weeks for 3 months, followed by 8 weekly injections
Chan et al^Citation32	83.40	Bevacizumab group: 4.80 over 6 months prior to switch Ranibizumab group: 8.60 over 6 months prior to switch Mixed group: 4.90 over 6 months prior to switch	N/A	5.40 5.40 bevacizumab group 5.50 ranibizumab group 5.50 mixed group	3 monthly loading doses, and then treat- and-observe strategy
Chang et al^Citation24	77.80±7.50	34.90±16.10	>30 days	5.00	Loading phase of 3 monthly injections plus mandatory injection at weeks 16 and 24
Chang et al^Citation23	77.80±7.50	34.90±16.10	36 days	8.00	Loading phase of 3 monthly injections plus mandatory injection every 2 months at months 4, 6, 8, 10, and 12
Chatziralli et al^Citation43	78.60±8.20	7.00±4.50 (3–36)	N/A	6.80	8 weekly aflibercept injections. No loading dose
Cho et al^Citation41	81.00 (62–95)	20.20±7.60 (7–37)	28–35 days	4.40 (3–6)	Loading phase of 3 monthly injections, and then every 6–8 weeks for 21 eyes (75%)
de Massougnes et al^Citation33	78.80±7.10	26.10±12.00	N/A	N/A	3 monthly loading doses, and then treat-and -observe strategy
Eadie et al^Citation34	79.90	3–38	5.88 weeks (4–10)	5.53 (2–11)	Treat + extend approach, or every 4 weeks due to persistent exudation
Gerding^Citation45	80.60±7.70 (60.9–100)	21.50±11.70 (9–54)	46.5 days	4.01±1.14 (2–6)	PRN
Gharbiya et al^Citation35	70.10±8.10 (60–86)	34.40±11.90 (15–50)	4.90±0.80 weeks (4–6)	4.50±1.30 (3–6)	Loading dose of 3 injections and retreatment according to following factors: 1) VA loss of at least 5 letters with OCT evidence of fluid, 2) persistent or recurrent IRF/SRF on OCT, and 3) new SR hemorrhage from CNV
Grewal et al^Citation26	80.70±4.50	29.80±17.10 (6–70)	Not <28 days	10.20±1.20 (10–12)	Loading phase of 3 monthly injections plus bimonthly injections in case of resolution of the edema or monthly in case of edema
Hall et al^Citation36	80.40±1.45	14.90±2.01 (2–53)	N/A	6.27±0.37 (4–11) (6-month follow-up: 30 patients received 4.50±0.11 injections; 9 month follow-up: 26 patients received 6.00±0.23; 12-month follow-up: 22 patients received 7.17±0.38)	In the presence of SRF at the time of the switch: loading phase of 3 monthly injections, and then treat-and-extend regimen. In absence of SRF at the time of the switching: treat-and -extend regimen
Hariri et al^Citation46	81.00 (60–97)	18.00	35.80±5.04 days (28–42)	N/A	N/A
He et al^Citation47	82.90±8.15	17.46±10.07 (3–46)	N/A	7.51±1.65	82 eyes: standard therapy: 3 monthly loading doses and bimonthly doses thereafter 34 eyes: Rx with less than standard therapy, undergoing injections further apart 26 eyes: Rx with more than standard: monthly or every 6 week injections
Kanesa-Thasan et al^Citation37	80.70±4.38	25.70±20.10 (6–70)	N/A	15.10±2.47 18 months (12–19)	Minimum 3 monthly aflibercept, and then switched to a bimonthly interval if complete resolution of SRF or IRF, or kept at an interval at which complete resolution was maintained, based on treat–and -extend approach
Kumar et al^Citation38	79.00±8.00 (72–84)	28.60±20.10 (IQR 11–43)	34.40±5.00 days (IQR 32–37)	5.30±0.60 (IQR 5–6)	Loading phase of 3 monthly injections followed by PRN treatment
Major et al^Citation48	81.20 (60–95)	24.80 (2–66)	36 days (27–65)	N/A	N/A
Mantel et al^Citation27	76.00	20.70 Group A (aflibercept n=10 eyes): 21.30 Group R (ranibizumab n=11 eyes): 20.10	N/A	10.70 Group A (aflibercept): 10.70 Group R (ranibizumab): 10.70	3 monthly injections and then observe-and -extend regimen for 12 months
Narayan and Muecke^Citation39	83.20±7.00	N/A	N/A	7.58	48 eyes (60%): 8 weekly; 25 eyes (31%): 6 weekly; 6 eyes (7.5%): 4 weekly; 1 eye: initially 4 weekly extended to 12 weekly
Pinheiro-Costa et al^Citation44	76.60 (61–92)	12.40 16.50 (6–24) bevacizumab group 8.90 (3–39) ranibizumab group	N/A	5.10±1.70 (range 3–9) Bevacizumab group: 4.50±1.60 Ranibizumab group: 5.60±1.60	Treat and extend
Ricci et al^Citation49	79.00 (59–93) PRN group 77 (52–85) fixed regimen group	5.00 (4.5–7.50) PRN group 6.50 (4–9.5) fixed regimen group	N/A	3.50±1.60 (1–7) PRN group 7.00 fixed regimen group	36 eyes (50%): PRN regimen; 36 eyes (50%): loading dose of 3 monthly injections followed by fixed bimonthly injection
Sarao et al^Citation28	78.30±8.20	15.20±1.90	N/A	3.50±1.80	Initial injection of aflibercept and then reviewed every 4 weeks. Rx at investigators’ discretion
Thorell et al^Citation40	76.20±8.70	30.70±15.50	N/A	4.50±1.00	Treat-and -extend strategy, starting from every 4-week treatment
Wykoff et al^Citation29	77.80 (55–95)	42.00 (19–67)	33.30 days (28–68)	5.60	Loading phase of 3 monthly injections, one mandatory dose at month 4 and PRN doses at months 3 and 5

Abbreviations: CNV, choroidal neovascularization; IQR, interquartile range; IRF, intraretinal fluid; N/A, not available; OCT, optical coherence tomography; PRN, pro re nata; Rx, treatment; SRF, subretinal fluid; SR, subretinal; VA, visual acuity; VEGF, vascular endothelial growth factor.

Figure 2 Forest plot of 19 studies reporting results of best-corrected visual acuity 6 months after the switch to aflibercept.

Note: Best-corrected visual acuity was divided by 10 for better visualization of the forest plot.
Abbreviation: CI, confidence interval.

Figure 3 Forest plot of 15 studies reporting results of best-corrected visual acuity 12 months after the switch to aflibercept.

Note: Best-corrected visual acuity was divided by 10 for better visualization of the forest plot.
Abbreviation: CI, confidence interval.

Table 3 Subgroup analysis of pooled BCVA means (95% confidence intervals) in ETDRS letters

6 months
Previous anti-VEGF injections (n)	<12 injections 3.83 (0.06–7.59)	12–23 injections 1.45 (−2.24 to 5.13)	≥24 injections −0.05 (−1.60 to 1.50)
Aflibercept injections (n)	<4 injections 2.97 (0.29–5.64)	≥4 injections 0.49 (−1.40 to 2.38)
Dosing	Loading + 2q8 1.42 (−4.71 to 7.56)	Loading + PRN 2.20 (−2.01 to 6.40)	Loading + T&E 0.21 (−3.09 to 3.52)	2q8 0.22 (−0.58 to 1.03)	PRN 3.47 (1.91–5.03)	T&E −1.20 (−4.97 to 2.57)
Study design	Prospective 3.96 (0.72–7.19)	Retrospective 0.25 (−1.26 to 1.75)
12 months
Aflibercept injections (n)	<8 injections 0.53 (−0.53 to 1.59)	≥8 injections 1.05 (−1.48 to 3.57)
Dosing	Loading + 2q8 2.37 (0.34–4.40)	Loading + PRN 13.41 (6.10–20.72)	Loading + T&E −0.73 (−1.32 to −0.14)	2q8 −0.29 (−1.82 to 1.24)	PRN −0.81 (−2.83 to 1.22)
Study design	Prospective 2.79 (−0.12 to 5.70)	Retrospective 0.11 (−0.87 to 1.08)

Note: n represents number, and 2q8 represents bimonthly injections.

Abbreviations: BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; PRN, pro re nata; T&E, treat and extend; VEGF, vascular endothelial growth factor.

Figure 4 Forest plot of 17 studies reporting results of central retinal thickness 6 months after the switch to aflibercept.

Note: Central retinal thickness was divided by 100 for better visualization of the forest plot.
Abbreviation: CI, confidence interval.

Figure 5 Forest plot of 11 studies reporting results of central retinal thickness 12 months after the switch to aflibercept.

Note: Central retinal thickness was divided by 100 for better visualization of the forest plot.
Abbreviation: CI, confidence interval.

Table 4 Subgroup analysis of pooled CRT means (95% confidence intervals) in µm

6 months
Previous anti-VEGF injections (n)	<12 injections −52.20 (−104.60 to 0.10)	≥12 injections −66.10 (−86.60 to −45.50)
Aflibercept injections (n)	<4 injections −66.90 (−114.00 to −19.90)	≥4 injections −63.10 (−85.00 to −41.10)
Dosing	Loading + 2q8 −44.20 (−85.80 to −2.60)	Loading + PRN −103.20 (−173.60 to −32.80)	Loading + T&E −38.40 (−70.40 to −6.30)	2q8 −62.50 (−117.60 to −7.40)	PRN −75.10 (−132.00 to −18.20)	T&E −47.50 (−106.80 to 11.80)
Study design	Prospective −70.00 (−107.80 to −32.10)	Retrospective −58.30 (−75.00 to −41.50)
12 months
Aflibercept injections (n)	<8 injections −49.00 (−63.20 to −34.80)	≥8 injections −53.20 (−100.10 to −6.20)
Dosing	Loading + 2q8 −25.90 (−40.50 to 11.30)	Loading + PRN −95.40 (−136.30 to −54.50)	Loading + T&E −24.00 (−27.60 to −20.30)	2q8 −69.40 (−142.50 to 3.70)	PRN −53.00 (−90.70 to −15.20)
Study design	Prospective −85.00 (−119.30 to −50.70)	Retrospective −38.80 (−53.10 to −24.60)

Note: n represents number, and 2q8 represents bimonthly injections.

Abbreviations: CRT, central retinal thickness; PRN, pro re nata; T&E, treat and extend; VEGF, vascular endothelial growth factor.

Figure 6 Forest plot of 8 studies reporting results of pigment epithelial detachment height 6 months after the switch to aflibercept.

Note: Pigment epithelium detachment values were divided by 100 for better visualization of the forest plot.
Abbreviation: CI, confidence interval.

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