Purpose
To compare long-term vision and anatomic effects of ranibizumab with prompt or deferred laser vs laser or triamcinolone + laser with very deferred ranibizumab in diabetic macular edema (DME).
Design
Randomized clinical trial.
Methods
Eight hundred and twenty-eight study eyes (558 [67%] completed the 5-year visit), at 52 sites, with visual acuity 20/32 to 20/320 and DME involving the central macula were randomly assigned to intravitreous ranibizumab (0.5 mg) with either (1) prompt or (2) deferred laser; (3) sham injection + prompt laser; or (4) intravitreous triamcinolone (4 mg) + prompt laser. The latter 2 groups could initiate ranibizumab as early as 74 weeks from baseline, for persistent DME with vision impairment. The main outcome measures were visual acuity, optical coherence central subfield thickness, and number of injections through 5 years.
Results
At 5 years mean (± standard deviation) change in Early Treatment Diabetic Retinopathy Study visual acuity letter scores from baseline in the ranibizumab + deferred laser (N = 111), ranibizumab + prompt laser (N = 124), laser/very deferred ranibizumab (N = 198), and triamcinolone + laser/very deferred ranibizumab (N = 125) groups were 10 ± 13, 8 ± 13, 5 ± 14, and 7 ± 14, respectively. The difference (95% confidence interval) in mean change between ranibizumab + deferred laser and laser/very deferred ranibizumab and triamcinolone + laser/very deferred ranibizumab was 4.4 (1.2–7.6, P = .001) and 2.8 (−0.9 to 6.5, P = .067), respectively, at 5 years.
Conclusions
Recognizing limitations of follow-up available at 5 years, eyes receiving initial ranibizumab therapy for center-involving DME likely have better long-term vision improvements than eyes managed with laser or triamcinolone + laser followed by very deferred ranibizumab for persistent thickening and vision impairment.
As previously reported by the Diabetic Retinopathy Clinical Research Network ( DRCR.net ), the ranibizumab plus prompt or deferred laser groups were more effective than laser alone, or intravitreous triamcinolone plus prompt laser, for diabetic macular edema (DME) treatment. In this study, the ranibizumab plus prompt or deferred laser groups were continued on their original structured re-treatment algorithm through 5 years, at which time the visual acuity and optical coherence tomography (OCT) outcomes identified at 2 years were maintained.
Based on the 1-year trial results, study participants originally assigned to sham injections plus prompt laser (“laser”) or triamcinolone plus prompt laser (“triamcinolone + laser”) were given an opportunity to initiate very deferred (between 1.5 and 3 years following enrollment) intravitreous ranibizumab plus continued focal/grid laser (if indicated). This report compares visual acuity and OCT outcomes through 5 years among eyes assigned to the ranibizumab plus deferred laser group to the laser/very deferred ranibizumab and the triamcinolone + laser/very deferred ranibizumab groups. All comparisons are made with reference to the ranibizumab plus deferred laser group, as this management strategy is presently favored by DRCR.net because it may offer greater vision benefits when directly compared with ranibizumab plus prompt laser. Eyes managed with ranibizumab and prompt laser are included for completeness. The short-term vision and anatomic outcomes following the initiation of very deferred ranibizumab therapy also are explored.
Methods
The study procedures have been reported, and are summarized below. The study adhered to the tenets of the Declaration of Helsinki. The Health Insurance Portability and Accountability Act–compliant informed consent forms were approved by multiple institutional review boards. The study is listed on www.clinicaltrials.gov under identifier NCT00445003 (website registration date 03/06/2007). The protocol is available on the DRCR.net website ( www.drcr.net ; date accessed: February 5, 2015). Participants had at least 1 eye with approximate Snellen equivalent visual acuity of 20/32-20/320 and DME involving the central macula. Prior DME treatment was permitted if performed in compliance with a protocol-defined washout period. At baseline, 828 eyes were assigned to 1 of 4 treatment groups (sham + prompt focal/grid laser, ranibizumab + prompt laser, ranibizumab + deferred [≥24 weeks] laser, or triamcinolone + prompt laser).
Visits occurred every 4 weeks through the first year, and then every 4–16 weeks through 5 years, depending on visual acuity, OCT, and the participant’s last treatment date. Re-treatment at each visit was based on protocol-specific criteria. Based on the 1-year visual acuity and OCT outcomes showing superior results in eyes assigned to the ranibizumab groups, the protocol was revised to allow participants assigned to laser or triamcinolone + laser the opportunity to initiate intravitreous ranibizumab between approximately 1.5 and 3 years (variation owing to enrollment date). These groups are referred to herein as laser/very deferred ranibizumab and triamcinolone + laser/very deferred ranibizumab. Eyes with a letter score <78 (Snellen equivalent 20/32 or worse) and a central subfield thickness ≥250 μm (using Stratus or Stratus OCT-equivalent values) were considered for treatment with ranibizumab; however, initiating ranibizumab was at the investigator’s discretion. Once ranibizumab was initiated, investigators were required to follow the ranibizumab treatment algorithm.
Statistical Analysis
For all outcome analyses, the ranibizumab + deferred laser group was compared with the other 3 treatment groups. A longitudinal discrete time mixed-model analysis incorporating discrete generalized estimating equations to account for correlated data from participants with 2 study eyes was used to compare visual acuity and OCT central subfield thickness change from baseline through the 5-year visit among treatment groups. All analyses were adjusted for the baseline value of the outcome and number of study eyes. Visual acuity changes were truncated to ±30 letters to minimize the effects of outliers. Generalized linear regression models were used to analyze binary variables. The Bonferroni method was used to adjust confidence intervals for the 3 pairwise treatment comparisons; P values less than .0167 were considered statistically significant. SAS 9.4 (SAS, Cary, North Carolina, USA) was used for all analyses.
Safety data include all randomized participants, irrespective of extension study participation and eligibility. All other analyses excluded 26 study eyes of 18 participants from 1 clinical site in which a majority of eyes at baseline were judged not to meet the OCT eligibility criterion of central subfield thickness ≥250 μm when graded manually at a central reading center. Systemic adverse events and death among participants with 2 study eyes (1 eye in the laser group and the other eye in either of the original ranibizumab groups or the triamcinolone + laser group) were assigned to the appropriate drug exposure group. Data for all events that occurred among participants contributing a single study eye were analyzed according to the original treatment assignment, recognizing that very deferred ranibizumab was administered to many participants in the laser and the triamcinolone + laser groups by the 5-year visit.
Results
Of the original 673 participants, 520 (77%) provided consent to extend follow-up from 3 to 5 years (646 of 828 study eyes; 78%). Excluding deaths, the 5-year study visit was completed by 77% of the entire cohort and 94% of study eyes of participants agreeing to the extension study. Completion rates appeared balanced by treatment group ( Supplemental Table 1 , available at AJO.com ). Systemic and ocular baseline characteristics for extension study participants were similar among the 4 treatment groups (data not shown), and a comparison of those who completed the 5-year visit to those who did not is reported in Table 1 .
| Did Not Complete 5-Year Extension Study Visit | |||
|---|---|---|---|
| Completed 5-Year Extension Study Visit | Consented to Be in Extension Study b | Did Not Consent to Be in Extension Study c | |
| N = 558 Eyes (450 Participants) | N = 88 Eyes (70 Participants) | N = 182 Eyes (153 Participants) | |
| Baseline Characteristics | |||
| Sex: women, n (%) | 247 (44%) | 34 (39%) | 75 (41%) |
| Age (y), median (25 th , 75 th percentile) | 63 (57, 69) | 63 (56, 70) | 65 (56, 72) |
| Race, n (%) | |||
| White | 409 (73%) | 68 (77%) | 123 (68%) |
| Black | 86 (15%) | 13 (15%) | 39 (21%) |
| Hispanic | 49 (9%) | 6 (7%) | 15 (8%) |
| Asian | 8 (1%) | 1 (1%) | 2 (1%) |
| Native Hawaiian/other Pacific Islander | 1 (<1%) | 0 | 0 |
| Multiracial | 1 (<1%) | 0 | 2 (1%) |
| Unknown/not reported | 4 (<1%) | 0 | 1 (<1%) |
| Diabetes type, n (%) | |||
| Type 1 | 39 (7%) | 9 (10%) | 17 (9%) |
| Type 2 | 509 (91%) | 78 (89%) | 156 (86%) |
| Uncertain | 10 (2%) | 1 (1%) | 9 (5%) |
| Duration of diabetes (y), median (25 th , 75 th percentile) | 17 (10, 23) | 15 (12, 25) | 17 (10, 24) |
| Insulin used, n (%) | 323 (58%) | 54 (61%) | 122 (67%) |
| HbA1c d (%), median (25 th , 75 th percentile) | 7.3 (6.5, 8.2) | 7.0 (6.2, 8.3) | 7.7 (6.8, 8.8) |
| Prior cardiovascular event, e n (%) | 156 (28%) | 42 (48%) | 78 (43%) |
| Hypertension, e n (%) | 449 (80%) | 79 (90%) | 151 (83%) |
| Number of study eyes, n (%) | |||
| 1 study eye | 342 (61%) | 52 (59%) | 124 (68%) |
| 2 study eyes | 216 (39%) | 36 (41%) | 58 (32%) |
| Prior PRP, n (%) | 136 (24%) | 21 (24%) | 31 (17%) |
| Prior treatment for DME, n (%) | 371 (66%) | 52 (59%) | 119 (65%) |
| Prior photocoagulation for DME, n (%) | 340 (61%) | 45 (51%) | 107 (59%) |
| Prior IVT for DME, n (%) | 81 (15%) | 21 (24%) | 25 (14%) |
| Prior vitrectomy for DME, n (%) | 23 (4%) | 5 (6%) | 11 (6%) |
| Prior peribulbar triamcinolone for DME, n (%) | 24 (4%) | 2 (2%) | 5 (3%) |
| Prior anti-VEGF for DME, n (%) | 58 (10%) | 13 (15%) | 18 (10%) |
| IOP (mm Hg), median (25 th , 75 th percentile) | 16 (14, 18) | 16 (14, 18) | 16 (14, 18) |
| Lens status phakic (clinical examination), n (%) | 393 (70%) | 45 (51%) | 117 (64%) |
| E-ETDRS visual acuity (letter score), median (25 th , 75 th percentile) | 66 (57, 73) | 67 (56, 73) | 62 (53, 71) |
| Central subfield thickness on OCT f (μm), median (25 th , 75 th percentile) | 395 (321, 498) | 376 (311, 491) | 373 (298, 471) |
| Retinal volume on OCT f (mm 3 ), median (25 th , 75 th percentile) | 8.5 (7.7, 9.9) | 8.5 (7.7, 9.2) | 8.5 (7.6, 9.7) |
| Retinopathy severity level on fundus photograph (ETDRS severity scale), f n (%) | |||
| No DR/minimal NPDR (10, 12, 14, 15, 20) | 9 (2%) | 2 (2%) | 0 |
| Mild/moderate NPDR (35, 43) | 123 (23%) | 21 (24%) | 32 (18%) |
| Moderately severe/severe NPDR (47, 53) | 240 (45%) | 30 (35%) | 81 (47%) |
| Mild-/moderate-/high-risk PDR (60, 61, 65, 71) | 160 (30%) | 33 (38%) | 61 (35%) |
| Characteristics at last completed visit | |||
| Timing of last completed visit, wk, median (25th, 75th percentile) | 257 (254, 262) | 188 (155, 215) | 88 (51, 154) |
| E-ETDRS visual acuity (letter score), median (25 th , 75 th percentile) | 75 (63, 82) | 74 (63, 81) | 67 (53, 76) |
| Central subfield thickness on OCT (μm), median (25 th , 75 th percentile) g | 254 (209, 308) | 238 (195, 287) | 239 (195, 298) |
a Visits occurring between window 244 and 276 weeks from randomization were included as 5-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 5-year target date were used.
b Includes the following between enrollment in the extension and the 5-year visit: deaths (50), withdrawals from the study (21), loss to follow-up (15), unknown (2).
c Includes those who discontinued from the study prior to the opportunity to re-consent.
d Missing HbA1c data for 16, 1, and 16 eyes, respectively.
e Medical history of condition.
f Missing (or ungradable) OCT and fundus photograph data as follows for the completer and noncompleters (with and without extension study), respectively: central subfield (0, 0, 1), retinal volume (118, 22, 48), and retinopathy severity (26, 2, 8).
g Missing (or ungradable) OCT data as follows for the completer and noncompleters (with and without extension study), respectively: 18, 10, 17.
Study Treatment During Follow-up
At 5 years, the median number of ranibizumab injections for the ranibizumab + deferred laser group was 17. During years 4 and 5, the median number of injections was 1 and 0, with 55% and 48% of eyes, respectively, in the ranibizumab + deferred laser group, receiving at least 1 additional ranibizumab injection. The median number of injections administered to these eyes was 4 and 3 injections during years 4 and 5, respectively. Table 2 shows similar ranibizumab administration in the ranibizumab + prompt laser eyes.
| Laser/Very Deferred Ranibizumab | Ranibizumab + Prompt Laser | Ranibizumab + Deferred Laser | Triamcinolone + Laser/Very Deferred Ranibizumab | |
|---|---|---|---|---|
| Injections | ||||
| 156-week visit a | N = 233 | N = 144 | N = 147 | N = 150 |
| Treated with ranibizumab from baseline to 156-week visit, n (%) | 93 (40%) | 144 (100%) | 147 (100%) | 55 (37%) |
| Ranibizumab injections from baseline to 156-week visit in those eyes, median (IQR) | 5 (3, 7) | 12 (8, 17) | 15 (9, 22) | 6 (3, 8) |
| Treated with triamcinolone from baseline to 156-week visit, n (%) | — | — | — | 150 (100%) |
| Triamcinolone injections from baseline to 156-week visit in those eyes, median (IQR) | 4 (3, 6) | |||
| Treated with ranibizumab from 104- to 156-week visit, n (%) | 89 (38%) | 82 (57%) | 99 (67%) | 51 (34%) |
| Ranibizumab injections from 104- to 156-week visit in those eyes, median (IQR) | 4 (2, 6) | 3 (2, 5) | 4 (2, 6) | 5 (3, 7) |
| Treated with triamcinolone from 104- to 156-week visit, n (%) | — | — | — | 44 (29%) |
| Triamcinolone injections from 104- to 156-week visit in those eyes, median (IQR) | 1 (1, 3) | |||
| 208-week visit b | N = 205 | N = 127 | N = 122 | N = 131 |
| Treated with ranibizumab from baseline to 208-week visit, n (%) | 112 (55%) | 127 (100%) | 122 (100%) | 76 (58%) |
| Ranibizumab injections from baseline to 208-week visit in those eyes, median (IQR) | 7 (5, 12) | 12 (9, 20) | 17 (10, 25) | 8 (5, 12) |
| Treated with triamcinolone from baseline to 208-week visit, n (%) | — | — | — | 131 (100%) |
| Triamcinolone injections from baseline to 208-week visit in those eyes, median (IQR) | 4 (3, 6) | |||
| Treated with ranibizumab from 156- to 208-week visit, n (%) | 85 (41%) | 58 (46%) | 67 (55%) | 68 (52%) |
| Ranibizumab injections from 156- to 208-week visit in those eyes, median (IQR) | 5 (3, 8) | 3 (1, 5) | 4 (2, 6) | 5 (3, 8) |
| Treated with triamcinolone from 156- to 208-week visit, n (%) | — | — | — | 13 (10%) |
| Triamcinolone injections from 156 to 208 week visit in those eyes – median (IQR) | 1 (1, 2) | |||
| 260-week visit c | N = 198 | N = 124 | N = 111 | N = 125 |
| Treated with ranibizumab from baseline to 260-week visit, n (%) | 114 (58%) | 124 (100%) | 111 (100%) | 77 (62%) |
| Ranibizumab injections from baseline to 260-week visit in those eyes, median (IQR) | 8 (5, 15) | 13 (9, 24) | 17 (11, 27) | 9 (6, 16) |
| Treated with triamcinolone from baseline to 260-week visit, n (%) | — | — | — | 125 (100%) |
| Triamcinolone injections from baseline to 260-week visit in those eyes, median (IQR) | 4 (3, 6) | |||
| Treated with ranibizumab from 208- to 260-week visit, n (%) | 70 (35%) | 47 (38%) | 53 (48%) | 57 (46%) |
| Ranibizumab injections from 208- to 260-week visit in those eyes, median (IQR) | 3 (2, 6) | 4 (2, 5) | 3 (2, 5) | 4 (2, 7) |
| Treated with triamcinolone from 208- to 260-week visit, n (%) | — | — | — | 5 (4%) |
| Triamcinolone injections from 208- to 260-week visit in those eyes, median (IQR) | 2 (1, 3) | |||
| Laser | ||||
| 156-week visit a | N = 233 | N = 144 | N = 147 | N = 150 |
| Number of focal/grid laser treatments from baseline to 156-week visit | ||||
| Median (25 th , 75 th percentiles) | 4 (2, 5) | 3 (2, 4) | 0 (0, 2) | 3 (2, 5) |
| Did not receive laser, n (%) | 1 (<1%) | 0 | 79 (54%) | 0 |
| 208-week visit b | N = 205 | N = 127 | N = 122 | N = 131 |
| Number of focal/grid laser treatments from baseline to 208-week visit | ||||
| Median (25 th , 75 th percentiles) | 4 (2, 6) | 3 (2, 5) | 0 (0, 2) | 3 (2, 6) |
| Did not receive laser, n (%) | 0 | 0 | 68 (56%) | 0 |
| Eyes without focal/grid laser treatments from 156- to 208-week visit, n (%) | 181 (88%) | 111 (87%) | 111 (91%) | 111 (85%) |
| 260-week visit c | N = 198 | N = 124 | N = 111 | N = 125 |
| Number of focal/grid laser treatments from baseline to 260-week visit | ||||
| Median (25 th , 75 th percentiles) | 4 (2, 6) | 3 (2, 5) | 0 (0, 2) | 3 (2, 6) |
| Did not receive laser, n (%) | 0 | 0 | 62 (56%) | 0 |
| Eyes without focal/grid laser treatments from 208- to 260-week visit, n (%) | 177 (89%) | 112 (90%) | 108 (97%) | 109 (87%) |
a Limited to study participants that completed the 156-week visit; includes participants who did and did not provide consent for the extension study.
b Limited to study participants that completed the 208-week visit.
c Limited to study participants that completed the 260-week visit.
Very deferred ranibizumab was initiated in 130 eyes (57%) and 89 eyes (62%) originally assigned to laser and triamcinolone + laser, respectively, of participants who consented to the extension phase. Nearly half of the eyes managed with very deferred ranibizumab received the initial dose between the 2- and 3-year visit ( Supplemental Table 2 , available at AJO.com ). At 5 years, among eyes receiving ranibizumab, the median number of ranibizumab injections was 8 and 9 in the laser and triamcinolone + laser groups, respectively ( Table 2 ). Table 2 shows the infrequent administration of intravitreous triamcinolone to the triamcinolone + laser group beyond the 3-year visit. No substantive differences in baseline characteristics were apparent between eyes that received ranibizumab and those that did not in the very deferred ranibizumab groups ( Supplemental Table 3 , available at AJO.com ).
Focal/grid laser photocoagulation was primarily performed in the first 3 years in all 4 treatment groups; 15%, or fewer eyes, in each group received laser between the 3- and 5-year visit. In the ranibizumab + deferred laser group, in which laser was not required, 56% never received laser during this 5-year study; for all other treatment groups, the 5-year median total number of laser sessions ranged from 3 to 4 ( Table 2 ).
Visual Acuity
Figure 1 shows the mean visual acuity change from baseline over time by original treatment group assignment. The differences between the vision gains observed in the ranibizumab + deferred laser vs the very deferred ranibizumab groups progressively narrowed between years 2 and 5. The mean changes in visual acuity letter scores from baseline to the 5-year visit were +10 for ranibizumab + deferred laser, +8 for ranibizumab + prompt laser, +5 for laser, and +7 for triamcinolone + laser ( Table 3 ). After adjustment for baseline visual acuity and number of eyes, the difference in mean change (95% confidence interval [CI]) in visual acuity letter score at the 5-year visit between the ranibizumab + deferred laser group and the laser/very deferred ranibizumab or triamcinolone + laser/very deferred ranibizumab was 4.4 (1.2–7.6, P = .001) and 2.8 (−0.9 to 6.5, P = .067), respectively. At 5 years, the laser/very deferred ranibizumab eyes had a lower percentage of eyes with ≥10 letter improvement from baseline in visual acuity relative to the ranibizumab + deferred laser group (relative risk [RR] 0.71, 95% CI 0.55–0.91) ( Table 3 and Supplemental Figure , available at AJO.com ). An area under the curve analysis was also conducted since the eyes managed with very deferred ranibizumab achieved their larger vision gains later in the follow-up period relative to eyes managed with ranibizumab from study entry; this methodology evaluates vision gains that are averaged over time and showed superior outcomes with ranibizumab + deferred laser ( Table 3 ).
| Laser/Very Deferred Ranibizumab | Ranibizumab + Prompt Laser | Ranibizumab + Deferred Laser | Triamcinolone + Laser/Very Deferred Ranibizumab | |
|---|---|---|---|---|
| 4-year visit a | N = 205 | N = 127 | N = 122 | N = 131 |
| Visual acuity – letter score | ||||
| Median (25 th , 75 th ) | 74 (64, 80) | 76 (63, 82) | 76 (71, 83) | 74 (63, 82) |
| Mean ± standard deviation | 70 ± 15 | 71 ± 18 | 74 ± 13 | 71 ± 13 |
| ≥20/40, n (%) | 142 (69%) | 89 (70%) | 98 (80%) | 89 (68%) |
| ≤20/200, n (%) | 7 (3%) | 8 (6%) | 3 (2%) | 3 (2%) |
| Change from baseline | ||||
| Median (25 th , 75 th ) | +8 (0, +15) | +9 (+1, +17) | +11 (+5, +19) | +10 (+1, +15) |
| Mean ± standard deviation | +7 ± 13 | +8 ± 13 | +10 ± 13 | +8 ± 12 |
| Difference in mean change from ranibizumab + deferred laser b | 3.6 | 2.8 | 2.9 | |
| (95% CI) b , c | (0.8 to 6.4) | (−0.7 to 6.3) | (−0.5 to 6.2) | |
| [ P value] b | [.002] | [.055] | [.040] | |
| Distribution of visual acuity change, n (%) | ||||
| ≥15 letter improvement | 55 (27%) | 41 (32%) | 45 (37%) | 38 (29%) |
| 14–10 letter improvement | 36 (18%) | 20 (16%) | 23 (19%) | 31 (24%) |
| 9–5 letter improvement | 42 (20%) | 23 (18%) | 24 (20%) | 19 (15%) |
| Same ± 4 letters | 41 (20%) | 27 (21%) | 19 (16%) | 27 (21%) |
| 5–9 letters worse | 9 (4%) | 4 (3%) | 4 (3%) | 5 (4%) |
| 10–14 letters worse | 6 (3%) | 5 (4%) | 2 (2%) | 4 (3%) |
| ≥15 letters worse | 16 (8%) | 7 (6%) | 5 (4%) | 7 (5%) |
| Difference in proportion with ≥10 letter improvement, vs ranibizumab +deferred laser (95% CI) c | 12% (−1% to 25%) | 7% (−8% to 22%) | 4% (−11% to 19%) | |
| Relative risk (95% CI) c | 0.80 (0.63–1.02) | 0.86 (0.64–1.14) | 1.00 | 0.94 (0.73–1.20) |
| 5-year visit d | N = 198 | N = 124 | N = 111 | N = 125 |
| Visual acuity – letter score | ||||
| Median (25 th , 75 th ) | 73 (61, 80) | 76 (65, 82) | 77 (68, 82) | 74 (62, 82) |
| Mean ± standard deviation | 68 ± 18 | 71 ± 18 | 74 ± 14 | 70 ± 17 |
| ≥20/40, n (%) | 119 (60%) | 85 (69%) | 83 (75%) | 84 (67%) |
| ≤20/200, n (%) | 10 (5%) | 7 (6%) | 2 (2%) | 7 (6%) |
| Change from baseline | ||||
| Median (25 th , 75 th ) | +7 (−1, +14) | +9 (+3, +16) | +12 (+4, +19) | +9 (−1, +16) |
| Mean ± standard deviation | +5 ± 14 | +8 ± 13 | +10 ± 13 | +7 ± 14 |
| Difference in mean change from ranibizumab + deferred laser b | 4.4 | 2.0 | 2.8 | |
| (95% CI) b , c | (1.2 to 7.6) | (−1.6 to 5.7) | (−0.9 to 6.5) | |
| [ P value] b | .001 | .186 | .067 | |
| Average visual acuity change over 5 years, using AUC method, median (25 th , 75 th ) | +6 (−1, +11) | +9 (+4, +14) | +10 (+5, +15) | +6 (0, +11) |
| Difference in mean AUC vs ranbizumab + deferred laser | +4.9 | +1.7 | +4.1 | |
| [ P value] | <.001 | .13 | <.001 | |
| Distribution of visual acuity change | ||||
| ≥15 letter improvement | 48 (24%) | 34 (27%) | 42 (38%) | 41 (33%) |
| 14–10 letter improvement | 32 (16%) | 24 (19%) | 22 (20%) | 21 (17%) |
| 9–5 letter improvement | 40 (20%) | 24 (19%) | 18 (16%) | 17 (14%) |
| Same ± 4 letters | 40 (20%) | 28 (23%) | 13 (12%) | 26 (21%) |
| 5–9 letters worse | 14 (7%) | 3 (2%) | 7 (6%) | 4 (3%) |
| 10–14 letters worse | 4 (2%) | 4 (3%) | 3 (3%) | 5 (4%) |
| ≥ 15 letters worse | 20 (10%) | 7 (6%) | 6 (5%) | 11 (9%) |
| Difference in proportion with ≥10 letter improvement, vs ranbizumab + deferred laser (95% CI) c | 17% (3%–30%) | 11% (−5% to 26%) | 8% (−7% to 24%) | |
| Relative risk (95% CI) c | 0.71 (0.55–0.91) | 0.79 (0.60–1.05) | 1.00 | 0.85 (0.65–1.11) |
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