Visual Outcome and Treatment Frequency of Anti-VEGF Therapy Using the Treat-and-Extend and Treatment Cessation Regimen for Exudative Age-Related Macular Degeneration and Pachychoroid Neovasculopathy

Figures & data

Table 1 Baseline Demographic Data of the 101 Studied Patients

	All Participants (n = 101)	tnAMD (n = 28)	PCV without Pachychoroid (n = 36)	RAP (n = 9)	PN (n = 28)	P value
Age, year	74.4 (10.0)	74.8 (10.2)	74.6 (9.5)	82.9 (6.9)	71.0 (10.2)	0.018*
Sex, No. (%) Men	67 (66.3)	21 (75.0)	24 (66.7)	4 (44.4)	18 (64.3)	0.403^†
BCVA, logMAR	0.42 (0.41)	0.70 (0.35)	0.44 (0.48)	0.66 (0.45)	0.32 (0.34)	0.215*
Current smoking, No. (%)	7 (6.9)	2 (1.98)	5 (4.95)	0 (0.0)	0 (0.0)	0.171^†
Eyes with BCVA ≥ 20/40	58 (57.4)	16 (57.1)	20 (55.6)	2 (22.2)	20 (71.4)	0.078^†
Eyes with BCVA ≤ 20/200	15 (14.9)	3 (10.7)	6 (16.7)	3 (33.3)	3 (10.7)	0.337^†
Lesion size, mm^2	6.5 (6.23)	4.3 (3.22)	8.6 (8.48)	8.3 (5.38)	5.5 (4.47)	0.070*
Lens status, No.(%), pseudophakia	27 (26.7)	6 (21.4)	7 (19.4)	6 (66.7)	8 (28.6)	0.049^†
Central retinal thickness, μm	390.6 (188.1)	365.1 (121.9)	392.6 (210.3)	485.1 (145.7)	382.9 (207.7)	0.178*
Subfoveal choroidal thickness, μm	206.1 (100.8)	160.8 (74.6)	191.3 (80.4)	118.4 (42.4)	306.4 (94.5)	<0.001*
IRF, No. (%)	25 (24.8)	7 (25.0)	5 (13.9)	9 (100)	4 (24.8)	<0.001^†
SRF, No. (%)	79 (78.2)	24 (85.7)	28 (77.8)	6 (66.7)	21 (75.0)	0.585^†
PED, No. (%)	38 (37.6)	5 (17.9)	21 (58.3)	4 (44.4)	8 (28.6)	0.005^†
Vitreoretinal adhesion, No. (%)	20 (19.8)	5 (17.9)	6 (16.7)	0 (0.0)	9 (32.1)	0.189^†
Subretinal hyperreflective material, No. (%)	25 (24.8)	10 (35.7)	7 (19.4)	2 (22.2)	6 (21.4)	0.499^†

Notes: Data are presented as mean (SD) unless otherwise specified. *Kruskal–Wallis analysis. ^†Fisher’s exact test.

Abbreviations: tnAMD, typical neovascular age-related macular degeneration; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; PN, pachychoroid neovasculopathy; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelial detachment.

Table 2 Visual Outcome, Central Retinal Thickness, and Treatment Frequency in Different Disease Types

	All Participants (n = 101)	tnAMD (n = 28)	PCV without Pachychoroid (n = 36)	RAP (n = 9)	PN (n = 28)	P value
Follow-up period, months	49.9 (26.9)	52.2 (25.5)	50.9 (24.7)	41.4 (31.9)	49.0 (30.4)	0.740*
TAE regimen, No. (%), prompt TAE	62 (60.4)	9 (32.1)	29 (80.6)	7 (77.8)	17 (60.7)	0.002^†
Change in BCVA at year 1, logMAR	−0.048 (0.331)	−0.076 (0.266)	−0.016 (0.418)	−0.091 (0.253)	−0.048 (0.282)	0.349*
Change in BCVA at the last visit, logMAR	0.010 (0.364)	0.030 (0.343)	0.020 (0.447)	−0.014 (0.391)	−0.018 (0.255)	0.947*
Change in CRT at year 1, μm	−125.6 (164.1)	−108.4 (107.3)	−108.3 (147.1)	−200.4 (129.9)	−139.6 (226.5)	0.107*
Change in CRT at the last visit, μm	−122.8 (180.9)	−121.0 (138.2)	−97.2 (194.7)	−189.4 (150.8)	−136.1 (209.3)	0.253*
Maintained vision at the last visit^‡, n (%)	83 (82.2)	23 (82.1)	29 (80.6)	6 (66.7)	25 (89.3)	0.484^†
Improved vision at the last visits, n (%)**	13 (12.9)	3 (10.7)	4 (11.1)	3 (33.3)	3 (10.7)	0.297^†
BCVA ≥ 20/40 at the last visit, n (%)	54 (53.5)	17 (60.7)	18 (50.0)	1 (11.1)	18 (64.3)	0.034^†
BCVA ≤ 20/200 at the last visits, n (%)	14 (13.9)	4 (14.3)	6 (16.7)	3 (33.3)	1 (3.6)	0.116^†
Total injection number	21.1 (16.4)	20.0 (16.9)	21.4 (16.1)	19.2 (17.3)	22.4 (16.9)	0.883*
Injection number in the first year	6.8 (2.33)	5.8 (2.43)	7.1 (2.32)	7.8 (2.49)	6.9 (1.95)	0.038*
Estimated annual injection number	5.5 (2.86)	4.8 (2.78)	5.7 (3.16)	6.4 (3.38)	5.7 (2.29)	0.324*
Eyes treated frequently at the last visits^††	29 (28.7)	6 (21.4)	13 (36.1)	1 (11.1)	9 (32.1)	0.390^†
Eyes treated less frequently at the last visits^‡‡	48 (47.5)	16 (57.1)	18 (50.0)	3 (33.3)	11 (39.3)	0.478^†
Eyes under treatment cessation at the last visits, n (%)	27 (26.7)	9 (32.1)	10 (27.8)	3 (33.3)	5 (17.9)	0.617^†
Successful treatment cessation during the study period	56 (55.4)	18 (64.3)	17 (47.2)	4 (44.4)	17 (60.7)	0.453^†
Number of recurrences	3.0 (3.7)	3.1 (4.4)	3.3 (3.7)	0.8 (1.0)	3.2 (3.4)	0.070*

Notes: Data are presented as mean (SD) unless otherwise specified. Changes in BCVA or CRT at year 1 and at last visit were determined as BCVA or CRT at year 1 and last visit subtracted from those at baseline. *Kruskal–Wallis analysis. ^†Fisher’s exact test. ^‡Loss of BCVA < 0.3 logMAR. **Gain of BCVA > 0.3 logMAR. ^††Eyes treated with a treatment interval of < 8 weeks. ^‡‡Eyes treated with a treatment interval of ≥ 12 weeks or under treatment cessation.

Abbreviations: tnAMD, typical neovascular age-related macular degeneration; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; PN, pachychoroid neovasculopathy; TAE, treat-and-extend; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; CRT, central retinal thickness.

Figure 1 Temporal changes in the best-corrected visual acuity (BCVA). Compared with the baseline BCVA, the BCVA significantly improved at 12 weeks, but not at year 1 and the last visit. Error bars indicate standard errors. *p = 0.004, ^†p = 0.067, ^‡p = 1.000.

Table 3 Multivariate Regression Analysis for Determinants That Could Affect the Estimated Annual Number of Injections

	B	SE	Lower Bound of 95% CI	Upper Bound of 95% CI	P value
Constant	4.870	0.816	3.249	6.490
Disease type tnAMD	−0.034	0.697	−1.418	1.350	0.961
PCV without pachychoroid	−0.464	0.661	−1.776	0.848	0.484
RAP	0.694	0.974	−1.241	2.629	0.478
PN	0
SRF at baseline	1.251	0.614	0.031	2.471	0.045
PED at baseline	−0.260	0.548	−1.348	0.827	0.636
Vitreomacular adhesion at baseline	1.124	0.644	−0.155	2.403	0.084
Use of ranibizumab in the loading phase	1.017	0.536	−0.048	2.082	0.061
Deferred TAE	−2.535	0.567	−3.661	−1.408	<0.001

Notes: Six possible clinically relevant variables were selected as independent variables, considering the results of previous studies to prevent overfitting in the regression model.

Abbreviations: B, unstandardized coefficients; SE, standard error; CI, confidence interval; tnAMD, typical neovascular age-related macular degeneration; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; PN, pachychoroid neovasculopathy; SRF, subretinal fluid; PED, pigment epithelial detachment; TAE, treat-and-extend.

Figure 2 Summary of the treatment course using two treat-and-extend (TAE) regimens. The numbers of eyes are shown in parentheses. Regarding eyes with post-cessation recurrences, the median treatment-free periods between treatment cessation and recurrences are shown in parentheses next to the number of eyes. Among 62 eyes treated with the prompt TAE regimen, 24 (39.3%) eyes achieved treatment cessation. Among them, 12 (50.0%) eyes were treatment-free at the last visit, with a median treatment-free period of 53 weeks. Twelve (50.0%) eyes had recurrences after a median treatment-free period of 41 weeks. Among the 39 eyes treated with the deferred TAE regimen, 10 (25.6%) eyes lacked additional injections after the three loading injections until the last visit, with a median treatment-free period of 165 weeks. Twelve (30.7%) eyes reached treatment cessation after TAE following recurrence. Among them, 5 eyes were under treatment cessation at the last visit, with a median treatment-free period of 166 weeks.

Table 4 Comparison of Variables Between Eyes Under Continuous Treatment and Treatment Cessation

	At the Last Visit			During the Study Period
	Eyes Under Continuous Treatment (n = 74)	Eyes Under Treatment Cessation (n = 27)	P value	Not Achieved the Successful Cessation (n = 45)	Achieved the Successful Cessation (n = 56)	P value
Age, year	75.0 (9.1)	72.7 (12.3)	0.620*	75.6 (8.8)	73.4 (10.9)	0.436*
Sex, No. (%) Men	51 (68.9)	16 (59.3)	0.476^†	13 (28.9)	21 (37.5)	0.403^†
Baseline BCVA, logMAR	0.35 (0.34)	0.59 (0.55)	0.067*	0.30 (0.31)	0.51 (0.46)	0.026*
Lesion size, mm^2	6.4 (5.9)	6.8 (7.1)	0.820*	7.0 (6.7)	6.1 (5.9)	0.341*
Lens status at baseline, No.(%), pseudophakia	21 (28.4)	6 (22.2)	0.618^†	15 (33.3)	12 (21.4)	0.263
Central retinal thickness at baseline, μm	395.7 (192.8)	376.4 (159.8)	0.939*	438.5 (219.2)	352.0 (140.3)	0.070*
Subfoveal choroidal thickness at baseline, μm	212.6 (101.1)	189.8 (101.9)	0.380*	202.2 (80.0)	209.7 (112.9)	0.809*
IRF at baseline, No. (%)	17 (23.0)	8 (29.6)	0.329^†	10 (22.2)	15 (26.8)	0.649^†
SRF at baseline, No. (%)	62 (83.8)	17 (63.0)	0.032^†	37 (82.2)	42 (75.0)	0.470^†
PED at baseline, No. (%)	26 (35.1)	12 (31.6)	0.265^†	22 (48.9)	16 (8.6)	0.041^†
Vitreoretinal adhesion at baseline, No. (%)	16 (21.6)	4 (14.8)	0.325^†	12 (26.7)	8 (14.3)	0.138^†
Subretinal hyperreflective material at baseline, No. (%)	14 (18.9)	11 (40.7)	0.036^†	8 (17.8)	17 (30.4)	0.17^†
Anti-VEGF agent used for loading phase, No. (%) aflibercept	49 (66.2)	14 (51.9)	0.139^†	11 (24.4)	27 (48.2)	0.022^†
Disease activity at 12 weeks, No. (%), absent	39 (52.7)	23 (85.2)	0.002^†	20 (44.4)	42 (75.0)	0.002^†
Number of recurrences during the study period	3.9 (4.0)	0.8 (1.3)	<0.001*	4.5 (4.9)	1.9 (1.9)	0.002*
Follow-up period, months	48.8 (27.2)	53.0 (26.8)	0.468*	44.0 (26.8)	54.4 (26.4)	0.053*

Notes: Data were presented as mean (SD) unless otherwise specified. *Mann–Whitney U-test. ^†Fisher’s exact test.

Abbreviations: BCVA, best corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; IRF, intraretinal fluid; SRF, subretinal fluid; PED, pigment epithelial detachment; VEGF, vascular endothelial growth factor.

Table 5 Multivariate Logistic Regression Analysis of Factors Associated with Successful Treatment Cessation at the Last Visits and Successful Treatment Cessation During the Study Period

Independent Variable	Odds Ratio	Lower 95% Confidence Interval	Upper 95% Confidence Interval	P value
Dependent variable; successful cessation at the last visits (27 eyes)
Disease activity at 12 weeks, absent	6.650	1.750	25.300	0.005
Number of recurrences	0.377	0.235	0.607	<0.001
Dependent variable; successful treatment cessation during the study period (56 eyes)
Disease activity at 12 weeks, absent	2.530	0.936	6.860	0.067
Number of recurrences	0.688	0.545	0.868	0.002
Using aflibercept in the loading phase	3.970	1.380	11.400	0.011
PED at baseline, present	0.291	0.106	0.803	0.017

Notes: In the upper model, absence of disease activity at 12 weeks and the recurrence number during the follow-up period were entered as independent variables to fulfill the study objectives and prevent overfitting in the regression model. The results were similar even with the inclusion of SRF and subretinal hyperreflective material presence at baseline in the regression model using the stepwise method. Similarly, four independent variables were selected in the lower model.

Abbreviation: PED, pigment epithelial detachment.

Figure 3 Receiver operating characteristic (ROC) curve for predicting successful treatment cessation at the last visits. ROC analysis showed that the area under the curve was 0.841. The curve was closest to the upper-left corner with a sensitivity and specificity of 0.718 and 0.778, respectively, when the cut-off value for the recurrence number was set to ≤1.