Table 2.
Visual Acuity Per Presence or Absence of SRF and/or IRF
| Ref | Study Design | Bias Risk | Treatment/Protocol | Previous Treatment | N | Outcome | No Fluid | SRF | IRF | Both SRF and IRF | Key Points |
| Chatziralli et al 201627 | Interventional | Low | AFL Fixed dose |
PRN RAN | 431 | ETDRS letters (by presence of fluid at BL) P values adjusted for time | BL: 63.2 ± 13.5 Week 8: 61.9 ± 14.0 Week 16: 62.3 ± 14.7 Week 24: 61.0 ± 16.1 Week 48: 62.3 ± 17.2 |
BL: 70.8 ± 12.3 Week 8: 70.7 ± 14.1 Week 16: 70.9 ± 12.8 Week: 24: 70.1 ± 13.3 Week 48: 71.0 ± 12.8 P = 0.900 vs. no fluid |
BL: 61.2 ± 17.3 Week 8: 62.0 ± 17.4 Week 16: 62.0 ± 16.3 Week 24: 62.2 ± 17.1 Week 48: 60.6 ± 17.7 P = 0.049 vs. no fluid |
BL: 59.6 ± 15.4 Week 8: 59.3 ± 16.6 Week 16: 59.2 ± 18.1 Week 24: 60.4 ± 16.6 Week 48: 59.8 ± 17.7 P < 0.001 vs. no fluid |
At 12 months: No significant increase in VA from BL prog risk factors: age, increased CST, IRF, PED, subfoveal thickening |
| Ebneter et al 201536 | Observational | Mod | RAN Monthly |
Treatment-naive | 31 | Change in BCVA (ETDRS letters) | N/A | BL: 59.4 ± 13.3 3 months: 65.2 ± 9.1 |
BL: 50.0 ± 10.8 3 months: 55.3 ± 10.0 |
BL: 46.4 ± 18.4 3 months: 54.0 ± 14.1 |
Neither BL nor improvement of BCVA at Month 3 was statistically significant between the groups |
| Ersoy et al 201432 | Observational | Mod | RAN or BEV Physician discretion |
Mixed | 30 | Change in logMAR BCVA per response | Response defined as absence of IRF or SRF at any visit. After 3 injections: −0.07 ± 0.23 At last visit: 0.07 ± 0.32 |
Nonresponse defined as persistent SRF at all visits. After 3 injections: −0.06 ± 0.17 (P = 0.657 vs. response) At last visit: 0.08 ± 0.30 (P = 1.0 vs. response) |
N/A | N/A | Mean follow-up of 40.25 ± 13.5 months Eyes with SD-OCT phenotype + isolated PED and SRF often nonresponsive to anti-VEGF, different mechanism may be involved vs. AMD |
| Dervenis and Younis 201624 | Observational | Low | RAN PRN |
Treatment-naive | 62 | Mean ± SD ETDRS letters | No SRF BL: 0.62 ± 0.26 Month 4: 0.63 ± 0.52 Month 6: 0.65 ± 0.53 No IRF Baseline: 0.54 ± 0.22 Month 4: 0.36 ± 0.20 Month 6: 0.44 ± 0.29 |
BL: 0.59 ± 0.30 Month 4: 0.42 ± 0.39 Month 6: 0.48 ± 0.36 |
BL: 0.63 ± 0.30 Month 4: 0.62 ± 0.47* Month 6: 0.57 ± 0.45 *P = 0.045 vs. no IRF at baseline |
N/A | PED at presentation was associated with lower CMT RPE disruption was associated with worse VA at Month 6. IRF presence was associated with worse VA at Month 4 |
| Chakravarthy et al 202029 | Observational | Low | Mixed Mixed |
Mixed previous anti-VEGF | 321 eyes | Change in VA (ETDRS letters) | 5 letters gain (no SRF/IRF at ≥2 visits) | 3-Letter difference between groups P = 0.042 Sensitivity analysis: No association (P = 0.111) |
3-Letter difference between groups P = 0.006 Sensitivity analysis: Association (P = 0.036) |
N/A | At 12 months: Higher number of monitoring visits associated with absence of fluid correlate with better VA gain Significant association of IRF with VA |
| de Massougnes et al 201830 | Observational | Low | RAN or AFL Mixed |
Treatment-naive | 104 eyes | BCVA change (by presence of foveal SRF; ETDRS letters) | 1.8 ± 18.1 | 9.4 ± 11.8 P = 0.092 vs. no fluid | N/A | N/A | At 12 months: Visual improvement associated with VA at BL, foveal SRF, and female gender AFL favored (vs. RAN) for PED reduction |
| Inan et al 201925 | Observational | Low | RAN PRN |
Treatment-naive | 65 eyes | BCVA (logMAR) | No SRF BL: 0.95 ± 0.53 12 months: 0.77 ± 0.52 No IRF BL: 0.69 ± 0.4 12 months: 0.60 ± 0.4 |
Baseline: 1.02 ± 0.55 (P = 0.66 vs. no SRF) 12 months: 0.87 ± 0.54 (P = 0.43 vs. no SRF) |
Baseline: 1.17 ± 0.5 (P<0.001 vs. no IRF) 12 months: 0.97 ± 0.5 (P = 0.01 vs. no IRF) |
N/A | At 12 months: Anatomic improvement and increased VA observed in groups with and without PED, IRC, and SRF Inverse correlation between pretreatment CMT, IRC and posttreatment IRC, and final BCVA |
| Jaffe et al 201637 (VIEW 1 and 2) | RCT post hoc | Low | RAN or AFL Q4W (RAN4/AFL4) or Q8W (AFL8) |
Treatment-naive | 1,815 eyes | ETDRS letters LS mean change from baseline | RAN4: 9.5 AFL4: 8.9 AFL8: 9.8 (without IRF or SRF at all 4 initial visits) |
N/A | N/A | RAN4: 8.5 AFL4: 11.7 AFL8: 7.5 (IRF or SRF at all 4 initial visits) |
At 12 months: Pattern of visual outcomes was similar regardless of fluid type Eyes with persistent early fluid may benefit from AFL4 vs. AFL8 or RAN4 |
| Jaffe et al 201313 NCT00593450 (CATT) |
RCT post hoc | Low | RAN or BEV Monthly or PRN |
Treatment-naive | 1,185 | Mean ± SE VA (ETDRS letters) | No SRF 68 No IRF 71.2 ± 0.7 |
Foveal SRF: 71 Extrafoveal SRF: 70 P = 0.051 |
Foveal IRF: 62.4 ± 1.3 Extrafoveal IRF: 67.2 ± 1.0 P < 0.0001 |
N/A | At 12 months: Little association between fluid type and VA At all time points residual IRF, especially foveal IRF, correlated with worse VA vs. no IRF |
| Kodjikian et al 201819 NCT01170767 |
RCT post hoc | Low | RAN or BEV PRN |
Not reported | 404 | Fluid as predictor of BCVA (letters) on multivariate analysis | N/A | Change in BCVA SRF at BL No: 3.5 ± 1.8 Yes: 3.8 ± 0.9 (P = 0.90) |
Change in BCVA IRF at BL No: 6.4 ± 1.4 Yes: 0.9 ± 1.2 (P < 0.01) |
N/A | At 12 months: IRF was associated with lower BCVA score, less improvement in BCVA, and poor prognosis |
| Lin et al 202038 | Observational | Low | BEV or RAN PRN |
Treatment-naive | 77 eyes | Extended remission (absence of hemorrhage, IRF/SRF, and leakage for 52 weeks after cessation of anti-VEGFs) | N/A | N/A | Extended remission achieved earlier in eyes with isolated IRF at BL HR 2.05; 95% CI 1.929–4.520; P = 0.045 vs. eyes with IRF + SRF |
N/A | At 12 months: Extended remission achieved earlier in eyes with isolated IRF at presentation |
| Ogasawara et al 201831 | Observational | Low | AFL Fixed |
Treatment-naive | 107 (109 eyes) | Association of VA loss and fluid | N/A | Univariate standardized β: −0.103 P = 0.501 Multivariate standardized β: −0.203 P = 0.039 |
Univariate standardized β: 0.195 P = 0.189 Multivariate N/A |
N/A | At 12 months: Highest gains in BCVA were associated with no PED, SRF, and poor BCVA at BL |
| Pokroy et al 201826 | Observational | Mod | BEV PRN |
Treatment-naive | 73 eyes | Mean ± SD BCVA LogMAR | No SRF BL: 0.87 ± 0.66 Month 12: 0.93 ± 0.67 No IRF BL: 0.43 ± 0.43 Month 12: 0.47 ± 0.45 |
BL: 0.61 ± 0.51 Month 12: 0.66 ± 0.59 P = 0.01 vs. no SRF |
BL: 0.88 ± 0.59 Month 12: 0.95 ± 0.67 P < 0.001 vs. no IRF |
N/A | At 12 months: BL IRF was prognostic for poorer VA Supports use of SHRM as a prognostic biomarker |
| Regillo et al 201517 NCT00891735 (HARBOR) |
RCT | Low | RAN Monthly or PRN |
Treatment-naive | 500 | BCVA of ≥20/40 at Month 12 | N/A | SRF at BL Yes: 56% No: 40% |
N/A | N/A | At 12 months: Presence of SRF at BL was predictive of improved VA outcomes |
| Ritter et al 201418 NCT00433017 (MONT BLANC) |
RCT | NI | RAN or RAN + PDT PRN |
Treatment-naive | 255 | BCVA (ETDRS letters) | N/A | SRF at BL No significant effect on BCVA (P = 0.704) |
IRF at BL Significantly reduced BCVA gain (P = 0.006) |
N/A | At 12 months: IRC had a strong negative predictive value for visual improvement in both groups |
| Waldstein et al 201612 NCT00637377 NCT00509795 (VIEW 1 and 2) |
RCT post hoc | Low | RAN or AFL Q4W (RAN4/AFL4) or Q8W (AFL8) |
Treatment-naive | 1,815 | Change in BCVA (ETDRS letters) ± SE vs. no fluid | Index | 2.11 ± 0.89 P = 0.018 vs. no SRF | −2.77 ± 0.73 P < 0.001 vs. no IRF | N/A | At 12 months: Greater fluid resolution in all compartments with AFL4 vs. ALF8 or RAN4 IRC was associated with lower BL VA and poorer VA outcomes |
| Waldstein et al 20166 NCT00275821 (EXCITE) |
RCT post hoc | Low | RAN Monthly or quarterly |
Treatment-naive | 353 | Change in BCVA per BL fluid status | No SRF at BL Freq: 11.3 letters Infreq: −1.0 letters |
SRF at BL Freq: 6.3 letters Infreq: 5.4 letters |
N/A | N/A | At 12 months: BL SRF was predictive of BCVA gains |
| Wickremasinghe et al 201222 | Interventional | NI | RAN or BEV PRN |
Treatment-naive | 214 eyes | BCVA (logMAR) | N/A | BL: 0.55 12 months: 0.54 (P = 0.07 vs. IRF) |
BL: 0.79 (P = 0.006 vs. SRF alone) 12 months: 0.78 |
N/A | At 12 months: Dry eyes/eyes with SRF had improved BCVA vs. eyes with residual IRF; BL IRF confers significantly worse prognosis for visual outcome |
| Wickremasinghe et al 201623 | Observational | Mod | RAN T&E |
Treatment-naive | 103 eyes | Mean ± SD BCVA (ETDRS letters) | 59.4 ± 12.9 | 61.2 ± 11.9 | 54.6 ± 17.8* P < 0.001 vs. no fluid/SRF | N/A | At 20.8 months (mean): New occurrence of IRF/SRF more likely to lead to BCVA loss vs. dry eyes or persistent IRF/SRF |
| Kim et al 201728 | Observational | Mod | RAN or BEV N/A |
Treatment-naive | 35 | BCVA (logMAR) | N/A | BL: 0.95 ± 0.23 24 months: 1.34 ± 0.38 (P = 0.03) |
IRF with or without SRF BL: 1.06 ± 0.19 24 months: 1.79 ± 0.60 (P value not provided) |
N/A | At 24 months: Presence of IRF was associated with worse visual prognosis |
| Schmidt-Erfurth et al 202020 (HARBOR) | RCT post hoc | Low | RAN Monthly or PRN |
Treatment-naive | 1,095 | Correlation of fluid location and quantification with BCVA Association of 100 nL increase in fluid in central 1 mm with function |
N/A | Weak prognostic effect on vision +1.10 letters; P = 0.0046 |
Volume-dependent negative effect on vision −4.00 letters; P < 0.0001 |
N/A | At 24 months: Volume-dependent negative impact of IRF on vision and a weak positive prognostic effect of SRF Dosage and regimen parameters directly correlated with resulting fluid volumes |
| Sharma et al 201614 (CATT) | RCT | Low | RAN or BEV Monthly or PRN |
Treatment-naive | 1,185 | Mean ± SE BCVA (ETDRS letters) | No foveal SRF/IRF: 69.7 ± 1.2 (P = 0.049 vs. any type of foveal or extrafoveal fluid) |
No SRF: 66.6 ± 0.7 Foveal SRF: 72.8 ± 1.5 Extrafoveal SRF: 69.6 ± 1.2 (P = 0.0005 foveal SRF vs. extrafoveal SRF or no SRF) |
No IRF: 72.2 ± 0.8 Foveal IRF: 59.3 ± 1.5 Extrafoveal IRF: 65.3 ± 0.9 (P < 0.0001 for both groups vs. no IRF) |
N/A | At 24 months: Foveal IRF, abnormally thin retina, greater thickness of the subretinal tissue complex, and subfoveal geographic atrophy or scar had the worst VA Foveal SRF had better VA than no SRF |
| Ying et al 20149 (CATT) | RCT | Low | RAN or BEV Monthly or PRN |
Treatment-naive | 1,030 | Sustained VA loss Yes: n = 61 No: n = 969 |
N/A | Sustained VA loss Yes: 19.2% No: 36.8% (P = 0.006) |
Sustained VA loss Yes: 82.5% No: 51.0% (P < 0.001) |
N/A | At 24 months: Higher proportions of IRF seen in eyes with sustained VA loss |
| Shin et al 201339 | Observational | Low | Mixed Mixed |
Mixed | 20 | Mean BCVA | N/A | 20/100 | 20/1,000 | N/A | Mean follow-up 31.5 months: VA outcomes were worse for eyes with IRF vs. SRF BEV-refractory patients with IRF may respond to RAN; patients with SRF may be refractory to BEV and RAN |
| Gianniou et al 201540 | Observational | Low | RAN Q4W |
Persistent SRF or IRF | 76 eyes | Mean VA (letters) change from baseline | N/A | Refractory SRF BL: 65.3 (11.9) 12 months: +10.4 (13.3) 24 months: +8.2 (14.4) 36 months: +8.6 (11.6) |
Refractory IRF BL: 53.7 (17.2) 12 months: +7.0 (13.8) 24 months: +7.5 (17.0) 36 months: +7.4 (17.4) |
N/A | At 12, 24 and 36 months, VA increased with RAN Higher risk of fibrosis, atrophy, or VA loss with refractory cysts vs. refractory SRF |
| Guymer et al 201911 NCT01972789 |
RCT post hoc | Low | RAN T&E |
Treatment-naive | 349 | Mean change from baseline in BCVA | “Intensive” not tolerating SRF 12 months: 4.0 ± 14.4 24 months: 3.0 ± 16.3 |
“Relaxed” tolerating SRF 12 months: 4.3 ± 12.7 (P = 0.63 vs. intensive) 24 months: 2.6 ± 16.3 (P = 0.99 vs. intensive) |
N/A | N/A | At 24 months: Relaxed treatment was noninferior to intensive treatment Patients on relaxed treatment had fewer injections, and significantly more extended/maintained 12-week treatment intervals vs. patients on intensive treatment |
| Jang et al 201541 | Observational | Low | RAN Monthly |
Treatment for ≥12 months | 44 (45 eyes) | Mean VA change | N/A | Treatment-refractory SRF BL: 65.3 letters 12 months: +10.4 letters 24 months: +8.2 letters 36 months: +8.6 letters |
N/A | N/A | Across 36 months: RAN retreatment in nAMD with refractory SRF may still allow good and maintained visual improvement |
| Jaffe et al 201910 (CATT) | RCT | Low | RAN or BEV Physician discretion |
Treatment-naive | 523 | Mean VA | N/A | No SRF: 61 letters Extrafoveal SRF: 57 letters Foveal SRF: 68 letters (P = 0.02) |
No IRF: 68 letters Extrafoveal IRF: 57 letters (P < 0.001) Foveal IRF: 44 letters (P < 0.001) |
N/A | At 5 years: 60% of eyes had IRF and 38% of eyes had SRF IRF was significantly associated with worse VA and VA loss from baseline to year 5 |
| Ying et al 201821 (CATT) | RCT | Low | RAN or BEV Physician discretion |
Treatment-naive | 647 | Mean VA and change from BL | N/A | BL SRF None: −9.1 (2.3) Extrafoveal: −2.4 (1.3) Foveal: −2.2 (1.4) P = 0.03 |
Not significant on multivariate analysis | N/A | At 5 years: Absence of BL SRF was associated with worse VA and more VA loss vs. presence of SRF |
AFL, aflibercept; AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; BEV, bevacizumab; BL, baseline; CI, confidence interval; CMT, central macular thickness; CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; Freq, frequent; HR, hazard ratio; Infreq, infrequent; IRC, intraretinal cyst; IRF, intraretinal fluid; LogMAR, logarithm of the minimum angle of resolution; LS, least squares; Mod, moderate; N/A, not applicable; nAMD, neovascular age-related macular degeneration; NI, no information; PDT, photodynamic therapy; PED, pigment epithelial detachment; PRN, pro re nata; Q4W, every 4 weeks; Q8W, every 8 weeks; RAN, ranibizumab; RCT, randomized controlled trial; RPE, retinal pigment epithelium; SD, standard deviation; SD-OCT, spectral-domain optical coherence tomography; SE, standard error; SHRM, subretinal hyperreflective material; SRF, subretinal fluid; T&E, treat-and-extend; VA, visual acuity; VEGF, vascular endothelial growth factor.