June 2011
Volume 52, Issue 7
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Clinical Trials  |   June 2011
Randomized Clinical Trial Evaluating mETDRS versus Normal or High-Density Micropulse Photocoagulation for Diabetic Macular Edema
Author Affiliations & Notes
  • Daniel Lavinsky
    From the Federal University of São Paulo UNIFESP (Universidata Federal de São Paulo/EPM (Escola Paulista de Medicina), São Paulo, Brazil; and
  • Jose A. Cardillo
    From the Federal University of São Paulo UNIFESP (Universidata Federal de São Paulo/EPM (Escola Paulista de Medicina), São Paulo, Brazil; and
    the Hospital de Olhos Araraquara, Araraquara, Brazil.
  • Luiz A. S. Melo, Jr
    From the Federal University of São Paulo UNIFESP (Universidata Federal de São Paulo/EPM (Escola Paulista de Medicina), São Paulo, Brazil; and
  • Alessandro Dare
    the Hospital de Olhos Araraquara, Araraquara, Brazil.
  • Michel E. Farah
    From the Federal University of São Paulo UNIFESP (Universidata Federal de São Paulo/EPM (Escola Paulista de Medicina), São Paulo, Brazil; and
  • Rubens Belfort, Jr
    From the Federal University of São Paulo UNIFESP (Universidata Federal de São Paulo/EPM (Escola Paulista de Medicina), São Paulo, Brazil; and
  • Corresponding author: Daniel Lavinsky, Rua Botucatu, 820, Vila Clementino, São Paulo, SP 04023-062, Brazil; daniellavinsky@gmail.com
Investigative Ophthalmology & Visual Science June 2011, Vol.52, 4314-4323. doi:10.1167/iovs.10-6828
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      Daniel Lavinsky, Jose A. Cardillo, Luiz A. S. Melo, Alessandro Dare, Michel E. Farah, Rubens Belfort; Randomized Clinical Trial Evaluating mETDRS versus Normal or High-Density Micropulse Photocoagulation for Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2011;52(7):4314-4323. doi: 10.1167/iovs.10-6828.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To compare modified Early Treatment Diabetic Retinopathy Study (mETDRS) focal/grid laser photocoagulation with normal-density (ND-SDM) or high-density (HD-SDM) subthreshold diode-laser micropulse photocoagulation for the treatment diabetic macular edema (DME).

Methods.: A prospective, randomized, controlled, double-masked clinical trial with patients with previously untreated DME and best corrected visual acuity (BCVA) worse than 20/40 and better than 20/400. Patients were randomized to receive either mETDRS focal/grid photocoagulation (42 patients), ND-SDM (39 patients), or HD-SDM (42 patients). Before treatment and 1, 3, 6, and 12 months after treatment, all patients underwent ophthalmic examinations, BCVA, color fundus photography, fluorescein angiography, and optical coherence tomography (OCT).

Results.: At 12 months, the HD-SDM group had the best improvement in BCVA (0.25 logMAR), followed by the mETDRS group (0.08 logMAR), whereas no improvements were seen in the ND-SDM group (0.03 logMAR). All groups showed statistically significant progressive reduction of central macular thickness (CMT) throughout the study (P < 0.001). The HD-SDM group exhibited the greatest CMT reduction (154 μm), which was not significantly different from that of the mETDRS group (126 μm; P = 0.75).

Conclusions.: At 1 year, the clinical performance of HD-SDM was superior to that of the mETDRS photocoagulation technique, according to the anatomic and functional measures of improvement used in this investigation. A rationale for this treatment modality as a preferable approach is suggested, and the precise role of subthreshold micropulse laser treatment may become more defined as experience grows, guided by optimized treatment guidelines and more comprehensive trials. (Clinicaltrials.gov number, NCT00552435.)

Diabetic macular edema (DME) affects approximately 29% of diabetic patients with a disease duration of 20 or more years and is one of the most frequent causes of visual loss in this population. 1 The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated a significant benefit of laser photocoagulation for the treatment of clinically significant macular edema, reducing the incidence of visual loss by approximately 50% at 3 years' follow-up. 2  
The original ETDRS photocoagulation technique was adopted throughout the world and gradually modified through the years, to become the present modified (m)ETDRS focal/grid photocoagulation protocol, which, according to a survey of the Diabetic Retinopathy Clinical Research Network (DRCR.net), reflects the treatment approach currently used by most retinal specialists. 3 Despite the improvements and the satisfactory results, adverse events such as central scotoma, loss of central vision, and decreased color vision can still occur, mostly caused by the progressive enlargement of the laser scars consequent to the visible burn endpoint of conventional threshold laser photocoagulation. 4 6 Laser burns at various levels of intensity are believed necessary for a successful treatment, 2,3 but have never been proven to be a prerequisite in the mechanism of action of laser photocoagulation. Conversely, recent understanding of the modification of gene expression mediated by the healing response of the RPE to thermal injury 7 suggests that the useful therapeutic cellular cascade is activated, not by laser-killed RPE cells, but by the still-viable RPE cells surrounding the burned areas that are reached by the heat diffusion at sublethal thermal elevation. 8  
New strategies have been developed for laser treatments that minimize the chorioretinal damage while maintaining at least similar treatment efficacy. New technologies, including micropulse 810-nm diode-laser photocoagulation, allow a finer control of the photothermal effects induced at the level of the RPE, to perform equally effective laser treatments with only sublethal thermal elevations, avoiding the excessive heat that causes visible burns, tissue necrosis, and related collateral effects. Numerous clinical studies have been conducted with subthreshold laser treatments with an 810-nm diode laser using a variety of micropulse parameters, and the lack of a well-defined treatment strategy is reflected in their variable results. 9,10 Another strategy is selective retinal therapy (SRT), which causes thermomechanical damage selective to the RPE, causing thermal modeling and theoretically causes re-establishment of a normal RPE monolayer. There are few clinical studies with this technique and although initial clinical data showed improvement in vision and retinal thickness, further experience will determine the safety and efficacy of this selective treatment. 11  
Unlike the extensively studied mETDRS, all current laser therapies targeting photocoagulation lesions titrated to a barely visible and nonvisible endpoint are still in great need of an accurate treatment protocol. Among the usual variables that determine the intensity of photocoagulation (spot size, power, and exposure duration), the density of laser placements has emerged as a new, important variable in subthreshold treatments. In fact, with subthreshold low-intensity techniques that produce only low and confined thermal elevations, there is very little lateral spread of heat from the RPE spots directly targeted by the laser. The smaller area of thermally stimulated RPE cells may negatively affect the therapeutic response, and an increased number of laser placements may be desirable to overcome the potential risk of undertreatment. In parallel with developments in new laser technologies, exploiting optimized parameters and treatment guidelines will be the key to progress in macular photocoagulation for ultimate tissue injury minimization and vision restoration. 
As a result, our group proposed a technique for optimizing photocoagulation protocols, using a barely visible and nonvisible endpoint and herein called high-density laser delivery, which could improve the mETDRS approach. By design, almost confluent, mild, or invisible burns are delivered throughout the macula, avoiding the foveal region (typically up to 900 laser lesions). Some burns can be placed on clinically normal-appearing retina if the entire retina was not abnormally thickened, including areas within the macula that are relatively distant from the area of thickening. The lack of comparative studies and our encouraging preliminary clinical results (Cardillo and Lavinsky, unpublished data, 2007) with this optimized approach, prompted us to explore this hypothesis in a controlled trial comparing three laser photocoagulation strategies for the treatment of diabetic macular edema (DME), including the standard mETDRS and the same subthreshold micropulsed 810-nm diode laser technique delivered in a normal-density (similar to the mETDRS technique) and high-density manner. 
Methods
This randomized, prospective, double-masked, controlled clinical trial was conducted at Hospital de Olhos de Araraquara and Federal University of São Paulo. The protocol was reviewed and approved by the Ethics and Research Committee of Federal University of São Paulo and was conducted in compliance with the Declaration of Helsinki. Each subject gave written informed consent to participate in the study. 
Study Population
Patients were older than 18 years of age, with clinically significant DME, HbA1c less than 10%, and no history of renal failure or uncontrolled hypertension. Best corrected visual acuity (BCVA) was better than 20/400 and worse than 20/40 measured by the ETDRS protocol, retinal thickening due to DME had to be within 500 μm of the macular center and with central macular thickness (CMT) of 250 μm or more measured by optical coherence tomography (Stratus OCT 3; Carl Zeiss Meditec, Inc., Dublin, CA), and patients could not have undergone prior laser or drug treatment for DME. Patients were not eligible if they had either thickening of the epiretinal membrane or vitreomacular traction syndrome, had been treated with panretinal photocoagulation within 4 months before enrollment, or had undergone major ocular surgery (including cataract surgery) within 6 months. Other exclusion criteria were rubeosis iridis or severe glaucoma, poor dilation, other retinal vascular diseases, any condition that could interfere with visual acuity or OCT measurement, other than macular edema, and an increased foveal avascular zone on fluorescein angiography. 
Treatment Randomization and Masking
Qualified patients were assigned to receive (1) mETDRS focal/grid photocoagulation with a 532-nm frequency-doubled Nd:YAG laser (Iridex, Mountain View, CA), (2) normal-density subthreshold diode-laser micropulse (ND-SDM) photocoagulation, or (3) high-density subthreshold diode-laser micropulse (HD-SDM) photocoagulation, both with an 810-nm diode-laser (Opto FastPulse, Opto Electronics, SA, São Paulo, Brazil). The assignment was performed based on simple randomization using a table of computer-generated random numbers. Numbered opaque envelopes were used for allocation concealment. BCVA was measured in logarithm of the minimum angle of resolution (logMAR) by certified, masked visual acuity examiners using ETDRS charts and standardized procedures without reference to the patient's chart and before a history was taken. A masked investigator performed the OCT and ophthalmic examinations. Double masking was achieved by not informing patients of which laser modality they would undergo. Data were entered on standard data collection forms, and an independent study monitor performed source data verification. 
Treatment Procedures
Patients underwent a complete medical and ophthalmic history, ocular examination, BCVA, fundus color photography, fluorescein angiography, and OCT before enrollment in the study. A complete blood panel and HbA1c test were performed, and systemic arterial hypertension was investigated. If the patient was eligible to participate in the study, laser photocoagulation was scheduled. 
In accordance with the randomization table and fluorescein angiography, eyes were treated under pupillary dilatation and topical anesthesia, using a standard contact lens (Mainster; Ocular Instruments, Bellevue, WA). Modified ETDRS photocoagulation was performed with a 532-nm green laser with 75-μm aerial spot diameter (78 μm on the retina through a 0.96× Mainster lens), 0.05-second exposure duration, and power adjusted for a barely visible tissue reaction endpoint (Fig. 1). The procedure consisted of focal treatment of leaking microaneurysms and grid treatment of all areas of diffuse leakage or nonperfusion (Table 1). Laser burns were placed two spot diameters apart and included the area nasal to the fovea, with no treatment placed within 500 μm of the optic disc. 
Figure 1.
 
(A) Fundus color photography of the barely visible mETDRS burn endpoint immediately after treatment. (B) Fundus color photography of an HD-SDM nonvisible endpoint immediately after treatment.
Figure 1.
 
(A) Fundus color photography of the barely visible mETDRS burn endpoint immediately after treatment. (B) Fundus color photography of an HD-SDM nonvisible endpoint immediately after treatment.
Table 1.
 
Treatment Characteristics
Table 1.
 
Treatment Characteristics
Burn Characteristics mETDRS ND-SDM HD-SDM
Direct treatment Directly treat all leaking microaneurysms 500–3000 μm from the center of the macula (but not within 500μm of the disc). NA NA
Burn size for direct treatment μm 75 NA NA
Burn duration for direct treatment, s 0.05–0.1 NA NA
Grid treatment All areas with diffuse leakage or nonperfusion within area considered for grid treatment. Entire area considered for grid treatment. Entire area considered for treatment (including unthickened retina)
Area considered for grid treatment 500–3000 μm superiorly, nasally, and inferiorly from the center of the macula 500–3500 μm temporally from macular center. No burns are placed within 500 μm of the disc. 500–3000 μm superior ly, nasally, and inferiorly from the center of the macula 500–3500 μm temporally from macular center. No burns are placed within 500 μm of the disc. 500–3000 μm superiorly, nasally, and inferiorly from the center of the macula 500– 3500 μm temporally from the macular center. No burns are placed within 500μm of the disc.
Burn size for grid, μm 75 125 125
Burn duration 0.05–0.10 s 2200 μs 15% DC 300 ms 2200 μs 15% DC 300 ms
Burn separation for grid treatment Two visible burn widths apart. Approximately two invisible burn widths apart. Confluent invisible burns
The micropulse laser power to be used in both normal- and high-density subthreshold treatments was derived for each eye from a test burn. This procedure was performed with an 810-nm laser in the continuous-wave (CW) emission mode with a 125-μm diameter spot through the 0.96× lens (130 μm on the retina) outside the posterior pole, with the power titrated power upward until a white burn became visible. The subthreshold treatments were then performed with the same 130-μm retinal spot size, switching the laser from the CW to the micropulse emission mode at 15% duty cycle (Table 1) and increasing the power determined in the test burn by 20% (15% DC micropulse power = 1.2 × test burn CW power). The ND-SDM photocoagulation was delivered in the same grid as in the mETDRS protocol, with two spot diameters spaced over the same areas, but without visible burn endpoint and without direct focal coagulation of microaneurysms (Fig. 1). The HD-SDM treatment was delivered with confluent subthreshold invisible applications over the entire area of macular edema and unthickened retina, with no attempt to specifically target or avoid microaneurysms (Table 1). 
ETDRS BCVA, central macular thickness assessed by OCT, and fluorescein angiography were repeated at 3, 6, 9, and 12 months of follow-up. Macular laser photocoagulation could be repeated in 3 or 6 months if DME persisted, and such treatment was warranted in the opinion of the investigator, according to the presence of increased macular thickness on OCT, decreased visual acuity, or significant macular edema on angiography. 
Outcome Measures
Primary outcome measures were changes from baseline in ETDRS BCVA and in CMT assessed by OCT (Stratus OCT 3; Carl Zeiss Meditec, Inc.) 12 months after treatment. Observed secondary outcomes were potential complications of laser photocoagulation, such as macular scarring, central scotoma, or any other adverse collateral effect. 
Statistical Methods
A sample size of 35 subjects in each group was needed to achieve 80% power to detect a difference of 0.20 logMAR change in visual acuity from baseline between groups, considering a significance level of 0.01 and a common SD in each group of 0.25 logMAR visual acuity change. Regarding CMT, a sample size of 39 individuals in each group was needed to achieve 80% power to detect a difference of 75 μm in CMT change from baseline between groups, considering a significance level of 0.01 and a common SD in each group of 100 μm for CMT change. 
Data were presented as absolute and relative frequency for sex, race, type of diabetes mellitus, retinopathy severity, and BCVA letter change; mean (SD) for age, HbA1c change in CMT, and BCVA improvement; and median (minimum–maximum) for absolute CMT and BCVA. 
The Fisher exact test was used to compare sex, race, and the type of diabetes mellitus between groups. Analysis of variance was used to compare age and HbA1c between groups. The Kruskal-Wallis test was used to compare the duration of diabetes mellitus and retinopathy severity between groups. 
The Friedman test was used to evaluate the changes in CMT and BCVA within each treatment group throughout the study. The changes from baseline in CMT and BCVA were compared between groups by using the Kruskal-Wallis test (comparisons between the three groups) and Mann-Whitney test (pairwise comparisons). The proportion of subjects that obtained an improvement in visual acuity of 15 or more letters from baseline was compared between groups by the Fisher exact test. Because of multiple comparisons, the significance level was set at 0.01 rather than 0.05. 
Results
Of the 123 patients enrolled, 42 were randomized to receive mETDRS focal/grid photocoagulation, 39 to receive ND-SDM photocoagulation, and 42 to receive HD-SDM photocoagulation. No patient was discontinued because of improper entry or protocol violations, but six patients were lost to follow-up. Figure 2 shows a flow chart of the patients throughout the study. The demographic characteristics of the patient population are listed in Table 2
Figure 2.
 
Flowchart showing progression of patients during the study.
Figure 2.
 
Flowchart showing progression of patients during the study.
Table 2.
 
Sample Demographics
Table 2.
 
Sample Demographics
Variable Treatment Group P
High Density Normal Density Modified ETDRS
Eyes, n 42 39 42 NA
Sex, n (%) 0.97
    Male 18 (43) 18 (46) 19 (45)
    Female 24 (57) 21 (54) 23 (55)
Race, n (%) 0.98
    White 34 (81) 33 (85) 33 (79)
    Black 2 (5) 2 (5) 2 (5)
    Asian 2 (5) 2 (5) 2 (5)
    Mixed 4 (10) 2 (5) 5 (12)
Age, mean (SD), y 61.9 (8.5) 62.0 (7.4) 61.8 (7.0) 0.99
Diabetes mellitus
    Type, n (%) 0.99
        I 1 (2) 0 (0) 1 (2)
        II 41 (98) 39 (100) 41 (98)
    Duration, median (min–max) 12 (5–27) 11 (5–25) 12 (7–23) 0.77
    HbA1c, mean (SD), % 8.2 (0.6) 8.0 (0.6) 7.9 (0.6) 0.14
    Retinopathy severity, n (%) 0.85
        Mild NPDR 8 (19) 7 (18) 6 (14)
        Moderate NPDR 9 (21) 11 (28) 11 (26)
        Moderately severe NPDR 22 (52) 17 (44) 20 (48)
        Severe NPDR 1 (2) 2 (5) 3 (7)
        Mild PDR 2 (5) 2 (5) 2 (5)
        Moderate PDR 0 (0) 0 (0) 0 (0)
        High-risk PDR 0 (0) 0 (0) 0 (0)
The mean (SD) age of the patients was 61.9 (8.5) years in the HD-SDM group, 62 (7.4) years in the ND-SDM group, and 61.8 (7.0) years in the mETDRS group. Although proliferative diabetic retinopathy (PDR) was not an exclusion criterion, we included only six patients with mild PDR and six patients with severe nonproliferative diabetic retinopathy (NPDR). Most of the patients included in this trial had mild to moderately severe NPDR, and panretinal photocoagulation was not performed during the follow-up period. No significant differences between groups were observed regarding sex, race, and type and duration of diabetes mellitus, HbA1c, and severity of retinopathy. The precise duration of macular edema was difficult to determine, but it was probably longer than 24 weeks. 
Effect of Treatment on Central Macular Thickness
At baseline, the median CMT was not significantly different (P = 0.31) in the three treatment groups. Throughout the study, a progressive reduction of CMT occurred in all groups, as shown in Table 3, which summarizes the CMT changes during the course of the study. 
Table 3.
 
Central Macular Thickness
Table 3.
 
Central Macular Thickness
Visit High Density Normal Density Modified ETDRS
Baseline 371 (297–879) 379 (279–619) 370 (269–710)
3 Months 301 (203–698) 332 (223–610) 306 (209–512)
6 Months 291 (201–577) 316 (215–627) 290 (208–501)
9 Months 252 (187–449) 317 (207–666) 279 (201–493)
12 Months 226 (187–513) 311 (207–599) 249 (199–475)
The reduction of CMT was significantly more pronounced in the HD-SDM and mETDRS groups than in the ND-SDM group (P < 0.001), and there was no statistically significant difference between the HD-SDM group and the mETDRS group (P = 0.75). The mean reduction of HD-SDM was 154 μm and that of mETDRS was 126 μm after 1 year (Table 4), when both were significantly different from the ND-SDM group, which had a 32-μm reduction throughout the study (P < 0.001). 
Table 4.
 
Central Macular Thickness Decrease over Study Follow-up
Table 4.
 
Central Macular Thickness Decrease over Study Follow-up
Change from Baseline Central Macular Thickness (μm) P
High Density Normal Density Modified ETDRS Between 3 Groups High Density vs. Normal Density High Density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months −93 (102) −20 (71) −67 (78) 0.002 0.001 0.22 0.01
6 Months −117 (119) −20 (97) −94 (86) <0.001 <0.001 0.60 0.001
9 Months −144 (140) −34 (106) −112 (107) 0.001 <0.001 0.59 0.01
12 Months −154 (157) −32 (107) −126 (126) <0.001 <0.001 0.75 0.001
Effect of Treatment on Visual Acuity
At baseline, the median BCVA in logMAR was not significantly different in the three treatment groups. In the mETDRS group, BCVA was 0.80 (0.30–1.30) at baseline and improved to 0.75 (0.30–1.30) at 3 months and to 0.65 (0.30–1.30) at 12 months. In the ND-SDM group, BCVA was 0.70 (0.40–1.30) at baseline, but did not improve during follow-up, with values of 0.80 (0.40–1.30) at 3 months and 0.80 (0.30–1.30) at 12 months. In the HD-SDM group, BCVA was 0.90 (0.30–1.30) at baseline and improved to 0.70 (0.22–1.30) after 3 months and to 0.52 (0.22–1.30) at 12 months (Table 5). When we compared the BCVA results of the three groups, the HD-SDM group had the best improvement of 0.25 (0.31) logMAR at 12 months (P = 0.009), compared with no improvement in the ND-SDM group (P < 0.001) and 0.08 (0.23) in the mETDRS group (P = 0.009; Table 6). 
Table 5.
 
BCVA
Table 5.
 
BCVA
Visit High Density Normal Density Modified ETDRS
Baseline 0.90 (0.30–1.30) 0.70 (0.40–1.30) 0.80 (0.30–1.30)
3 Months 0.70 (0.22–1.30) 0.80 (0.40–1.30) 0.75 (0.30–1.30)
6 Months 0.60 (0.22–1.30) 0.80 (0.40–1.30) 0.70 (0.22–1.30)
9 Months 0.60 (0.22–1.30) 0.80 (0.30–1.30) 0.70 (0.30–1.30)
12 Months 0.52 (0.22–1.30) 0.80 (0.30–1.30) 0.65 (0.30–1.30)
Table 6.
 
BCVA Improvement over Study Follow-up
Table 6.
 
BCVA Improvement over Study Follow-up
Change from Baseline Visual Acuity (logMAR) P
High Density Norman Density Modified ETDRS Between Three Groups High Density vs. Normal density High density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months −0.12 (0.18) 0.02 (0.14) −0.04 (0.14) 0.001 <0.001 0.05 0.009
6 Months −0.15 (0.21) 0.03 (0.18) −0.07 (0.15) <0.001 <0.001 0.07 0.002
9 Months −0.19 (0.27) 0.00 (0.27) −0.07 (0.19) 0.001 <0.001 0.02 0.11
12 Months −0.25 (0.31) 0.03 (0.22) −0.08 (0.23) <0.001 <0.001 0.009 0.01
We performed a subanalysis of visual acuity change from baseline and divided patients based on total letters gained or lost. We observed that, at 3 months, 24% of the HD-SDM patients had an increase of ≥15 letters, compared with 3% of the ND-SDM and 12% of mETDRS group. By the end of the study, 48% of the HD-SDM patients increased more than 15 letters, compared with 5% of the ND-SDM and 23% of the mETDRS patients. Only two (5%) of the HD-SDM patients showed a decrease of more than 15 letters at 12 months; however, six (16%) patients in the ND-SDM group and four (10%) in the mETDRS group had a ≥15-letter decrease (Table 7). When comparing HD-SDM with mETDRS, regarding more than 15 letters gained or lost, we detected a statistically significant difference after 12 months (P = 0.03); however, this difference was present throughout the study when we compared HD-SDM and ND-SDM (Table 8). 
Table 7.
 
BCVA Change
Table 7.
 
BCVA Change
Change from Baseline High Density Normal Density Modified ETDRS
3 Months
    ≥15 Letters better 10 (24) 1 (3) 5 (12)
    10–14 Letters better 2 (5) 0 (0) 1 (2)
    5–9 Letters better 1 (2) 0 (0) 2 (5)
    0±4 Letters 27 (66) 31 (82) 32 (76)
    5–9 Letters worse 1 (2) 2 (5) 1 (2)
    10–14 Letters worse 0 (0) 3 (8) 1 (2)
    ≥15 Letters worse 0 (0) 1 (3) 0 (0)
6 Months
    ≥15 Letters better 11 (28) 1 (3) 8 (19)
    10–14 Letters better 3 (8) 2 (5) 1 (2)
    5–9 Letters better 2 (5) 0 (0) 3 (7)
    0±4 Letters 21 (53) 28 (74) 27 (64)
    5–9 Letters worse 1 (3) 1 (3) 1 (2)
    10–14 Letters worse 1 (3) 3 (8) 1 (2)
    ≥15 Letters worse 1 (3) 3 (8) 1 (2)
9 Months
    ≥15 Letters better 14 (35) 3 (8) 8 (20)
    10–14 Letters better 5 (13) 1 (3) 4 (10)
    5–9 Letters better 5 (13) 3 (8) 1 (2)
    0±4 Letters 12 (30) 22 (59) 22 (54)
    5–9 Letters worse 2 (5) 2 (5) 3 (7)
    10–14 Letters worse 0 (0) 1 (3) 1 (2)
    ≥15 Letters worse 2 (5) 5 (14) 2 (5)
12 Months
    ≥15 Letters better 19 (48) 2 (5) 9 (23)
    10–14 Letters better 2 (5) 2 (5) 2 (5)
    5–9 Letters better 5 (13) 0 (0) 3 (8)
    0±4 Letters 10 (25) 26 (70) 20 (50)
    5–9 Letters worse 2 (5) 0 (0) 1 (3)
    10–14 Letters worse 0 (0) 1 (3) 1 (3)
    ≥15 Letters worse 2 (5) 6 (16) 4 (10)
Table 8.
 
BCVA Change Better or Worse Than 15 Letters during the Study Follow-up
Table 8.
 
BCVA Change Better or Worse Than 15 Letters during the Study Follow-up
Change from Baseline Visual Acuity Change P
High Density n (%) Normal Density n (%) Modified ETDRS n (%) Between Three Groups High Density vs. Normal Density High Density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months 0.01 0.007 0.16 0.20
    ≥15 Letters better 10 (24) 1 (3) 5 (12)
    <15 Letters better 31 (76) 37 (97) 37 (88)
6 Months 0.007 0.003 0.44 0.03
    ≥15 Letters Better 11 (28) 1 (3) 8 (19)
    <15 Letters Better 29 (72) 37 (97) 34 (81)
9 Months 0.01 0.006 0.14 0.20
    ≥15 Letters Better 14 (35) 3 (8) 8 (20)
    <15 Letters Better 26 (65) 34 (92) 33 (80)
12 Months <0.001 <0.001 0.03 0.05
    ≥15 Letters Better 19 (48) 2 (5) 9 (23)
    <15 Letters Better 21 (52) 35 (95) 31 (77)
Retreatment
No retreatment was necessary for 44% of the mETDRS patients, 49% of HD-SDM, and 2% of ND-SDM. One retreatment was performed in 32% of the mETDRS patients, 38% of HD-SDM, and 21% of ND-SDM, and two retreatments were necessary for 24% of mETDRS patients, 13% of HD-SDM, and 77% of ND-SDM. 
Adverse Events
There were no severe adverse events related to treatment in any of the three groups. Laser scars throughout the macula were present in patients who underwent mETDRS photocoagulation, although there were no complaints of decreased visual acuity or color sensitivity. No visible laser burns were normally found in patients treated with subthreshold diode-laser micropulse photocoagulation, although we were able to identify some very light laser-induced lesions. During the follow-up of this study, we did not find significant enlargement of laser scars resulting from either conventional CW laser threshold photocoagulation or subthreshold diode laser micropulse treatments (Fig. 3). 
Figure 3.
 
Baseline fundus color photography, red-free photography, and fluorescein angiography (FA) (A) of an mETDRS group patient; (B) of the same patient 3 months after mETDRS treatment, showing barely visible burns in the color photograph, although the laser scars can be easily identified in FA; (C) of an HD-SDM group patient before treatment; and (D) of the same patient after HD-SDM treatment, showing that even in FA, micropulsed treatment remains nonvisible.
Figure 3.
 
Baseline fundus color photography, red-free photography, and fluorescein angiography (FA) (A) of an mETDRS group patient; (B) of the same patient 3 months after mETDRS treatment, showing barely visible burns in the color photograph, although the laser scars can be easily identified in FA; (C) of an HD-SDM group patient before treatment; and (D) of the same patient after HD-SDM treatment, showing that even in FA, micropulsed treatment remains nonvisible.
Discussion
The present study proposes a more comprehensive laser therapeutic strategy for DME. On the basis of this treatment protocol for early-onset DME, the subthreshold micropulse 810-nm diode laser technique delivered in a high-density manner was superior to the standard mETDRS and the same subthreshold micropulse 810-nm diode laser technique delivered in a normal-density manner over at least 1 year of follow-up, with significantly more eyes gaining substantial vision and significantly fewer eyes losing substantial vision. Unexpected adverse effects of treatment were minimal and theoretically, the less destructive nature of the micropulse approach could explain the better visual acuity outcome despite the comparable decrease in retinal thickening observed with both treatments. On the other hand, the same subthreshold technique delivered in the conventional manner (normal-density group) failed to yield the same outcome. Although minimizing the laser intensity may enhance selectivity, an inappropriate customized treatment algorithm may prevent the treatment from providing an adequate therapeutic benefit. Focal/grid laser has been the mainstay of treatment for DME until the recent findings of the DRCR network, which suggested that intravitreal ranibizumab with prompt or deferred laser is more effective. 12,13 However, in addition to newer treatments modalities, exploiting innovative laser technologies in parallel to a focused and engineered intervention will be the breakthrough pathway to progress in DME treatment for ultimate, sustained vision restoration. 
Despite the importance of focal/grid photocoagulation in treating DME, new technologies and technique modifications are usually exploited without rationalizing laser interaction with tissues. Although the minimization of the laser intensity will reduce the drawbacks of conventional laser photocoagulation, if the treatment density is not compensated for accordingly, the treatment will be inaccurate and probably ineffective. Clearly, the current lack of a well-defined treatment algorithm for balancing laser energy and treatment area is reflected in the variation in recently reported results, hindering a meaningful comparison with our study findings. 9,10,14,15 In addition, one must be careful not to assume that all subthreshold laser treatments will yield the same results. Subthreshold treatments cover a spectrum of laser lesion intensities, from no lesion produced even at the microscopic level, to a microscopic destruction of RPE and outer segment structures despite the clinical invisibility of the delivered lesions. 16,17 Similarly, suprathreshold laser photocoagulation covers a wide array of visible laser lesions, from a faint, mild gray lesion to extremely intense, whiter lesions. 18  
To date, there are no known dose–response clinical studies addressing pulse energy, duration, treatment density, and ideal lesion endpoint. As a consequence, proper laser application targeting invisible or subvisible lesions remains to be determined. Distant from the ultimate and most desirable micropulse protocol, but guided by extensive preclinical trial testing, we performed SDM treatment in this study with a micropulse power 20% higher (1.2 times) than the CW power of each eye's test burn, a pulse duration of 300 ms, and a duty cycle of 15%, thereby using roughly only one fifth of the energy that would produce a threshold burn. Both micropulse groups were treated with exactly the same subthreshold power criteria, differing only by a mathematically calculated four to five times greater density application. A dose–response clinical assessment, in conjunction with a lesion density analysis tested in a prospective clinical trial, gives this investigation a unique importance in the current scenario of newer laser technologies and DME treatment optimization. 
By allowing a finer control of laser-induced thermal effect, micropulse technology may offer a promising alternative for an enhanced beneficial effect compared with mETDRS focal/grid photocoagulation. Confirming our premise, our study showed, at 12 months, a greater positive treatment response in visual acuity in the HD-SDM group than in the other two groups. Treatment group differences regarding change in retinal thickening diverged from the effect on visual acuity, with a lesser reduction in the ND-SDM group, and no difference between the HD-SDM and mETDRS groups at 1 year. Since no adverse affects were observed, we believe that the milder and more selective nature of the micropulse approach compared to previous threshold strategies is the reason for the better visual acuity outcome, despite the comparable decrease in retinal thickening observed in the two treatments. 
OCT-measured macular thickness has been shown to be an objective and reproducible outcome. 19 However, although one would expect that a reduction in macular edema would be followed by improvement in visual acuity, recent studies have demonstrated the unreliable concordance between the two parameters OCT-measured thickness and BCVA in patients with DME, for reasons that are still not fully understood. 20 Other means of quantifying macular function and retinal sensitivity would help to address this interesting finding. In fact, a recent microperimetry comparison favored micropulse versus ETDRS photocoagulation in patients with center macula- involved DME. 21  
Interestingly, the greater functional gain observed in the HD-SDM group was only statistically significant at the 12-month outcome assessment. We hypothesize that a progressive healing and usually less scarring retinal restoration associated with lighter laser lesions, should explain this relatively more significant late gain of vision. 18 Nevertheless, the lack of an equivalent response in the ND-SDM group could be solely attributable to a minor and insufficient RPE-stimulated area, although there are published studies that show that ND-SDM is not inferior to mETDRS. 14 This inferior response is also reflected in the significant increase in the retreatment rate of the ND-SDM patients, which indicates that, with these laser settings, this modality is inferior and should not be used in clinical practice. As a result, the dose regimen tested in this investigation fits a realistic clinical scenario and may provide an alternative that will achieve substantial visual gain in the modern era of DME treatment. Furthermore, given the inherent advantages of laser photocoagulation, particularly regarding patient convenience and treatment cost effectiveness, the strategy studied may achieve a breakthrough in the development of more successful treatment modalities, suggesting a possible new way to improve DME treatment in parallel with drug development. 
The results of the present study highlight the importance of focal/grid photocoagulation in managing DME. Although the ETDRS demonstrated that focal/grid photocoagulation improves visual outcome in DME, it has been widely believed that the benefit was in reducing the frequency of visual loss and not in improving visual acuity. However, this general conclusion ignores the fact that most eyes in the ETDRS group had normal or near-normal visual acuity and thus did not have the potential for substantial visual acuity improvement. In a subset of 114 ETDRS eyes meeting the aforementioned criterion of being treated with focal/grid photocoagulation, the results were similar to the findings in the present study. A prior DRCR.net study evaluating macular photocoagulation regimens also demonstrated that visual acuity improvement is not uncommon after focal/grid photocoagulation for DME. Twenty-nine percent of patients treated with the mETDRS technique gained 15 or more letters at 12 months, and only 6% of patients treated lost 15 or more letters. In this same study, the mild macular grid (MMG) technique was less effective in reducing OCT-measured retinal thickening than was the more extensively evaluated mETDRS laser photocoagulation approach. 3 However, diverging from our suggested algorithm of enhancing treatment density while minimizing laser lesions, the researchers intentionally designed an even wider burn separation for the MMG group (two visible burn widths apart for the mETDRS technique and two to three visible burn widths apart for the MMG technique). As reaffirmed in the present study, all technique modifications should be rationalized and more extensively exploited for laser energy/treatment density/ideal lesion endpoint optimization before clinical assessment, to add data to the validity of the findings. On the contrary, on the basis of the data from this protocol, the HD-SDM technique was superior to focal/grid laser for the treatment of DME involving the center of the macula through at least 1 year of follow-up, with more eyes gaining substantial vision and significantly fewer eyes losing substantial vision. 
Several authors have reported their criteria for titrating micropulse laser power in their SDM treatments, which can be 0.5 times, 22 2 times, 14,23 3 times, 16,24 or up to 5 times 9 the power of the test burn. In several clinical trials, the micropulse diode laser has been used for treatment of diabetic macular edema, demonstrating stabilization of vision, with a significant decrease in macular edema in most cases. 14,15,24 28 The lack of a standardized technique, with the multiple treatment strategies for the micropulse approach used in these studies, discourages a direct comparison with our findings. Altogether, these lines of evidence aggregate the available information and complement the knowledge regarding treatment safety and efficacy. 
SDM treatment is based on the release of micropulses of low energy per pulse, in an attempt to confine the energy to the RPE cells, avoiding thermal spread. Biological effects are induced with invisible sublethal burns produced with the micropulse laser, because denaturation of intracellular proteins may occur at exposures as low as one tenth to one hundredth of visible threshold burn, and the RPE hyperplasia associated with mitotic activity has been reported using energy as low as 10 mJ. 29 31 In this study, the absence of clinically and angiographically visible signs corresponding to the laser spots indicates that the treatment administered was subthreshold. That a significant outcome can be obtained with less damaging laser treatments is an encouraging and a highly desirable clinical achievement. In theory, clinical response could be related to the laser-induced activation of cytokine expression and upregulation of matrix metalloproteinase (MMP)-3 in the retina, 32 promoting subsequent cellular changes that correct the pathologic imbalance and stop the spread and migration of the RPE cells at the edges of the lasered site. 7,8,33  
Moreover, the theory that the actual therapeutic effect of the CW laser threshold photocoagulation may be indirectly derived from a nonlethal thermal insult to viable RPE cells surrounding the laser burn, rather than from the necrotic burn itself, 8 suggests that with subthreshold low-energy micropulse exposures, the absence of thermal spread should be compensated for with a higher density of applications to effectively treat the same retinal area. This is the theoretical rationale for the density optimization strategy as a more comprehensive plan for the treatment of DME under subthreshold protocols. However, its premature stage of development along with uncertain parameters and intrinsic delivery characteristics raises some concerns about this technique. In clinical practice, we found subthreshold micropulse diode laser photocoagulation difficult to perform, and a learning curve definitely applies to even an experienced retinal surgeon. 
According to this rationale, the greater number of spots delivered using HD-SDM, suggests that some areas were re-treated inadvertently during the same treatment session, indicating a clear demand for a treatment plan, as has been indicated by Luttrull et al. 34 Indocyanine green angiography has been shown to precisely localize subthreshold infrared (810 nm) photocoagulation sites immediately after treatment. Although this procedure will not make treatment sessions shorter, the method could be advantageous in identifying the location of the laser lesions in assessing initial therapy, avoiding re-treating previously treated sites, and providing additional laser therapy if indicated. 35 Autofluorescence was used previously to compare visible burns to nonvisible micropulse treatment, and investigators did not identify any long term hypo- or hyperautofluorescence in the micropulse group, although in the visible burns they could identify increased autofluorescence up to 9 months. 21 In view of the importance of this technique as reaffirmed in this study, additional studies are also needed to develop a better understanding of when photocoagulation is complete and of the optimal interval for repeating treatment. To this end, we envision that an automated method with patterns of scanning subthreshold laser delivery, such as the PASCAL system, offers enough promise to overcome most of the concerns pointed out. 
Overall, the present study has some design limitations. No definitive conclusions concerning safety and long-term efficacy can be reached based on the results of this relatively small, limited clinical trial. In addition, a more extensive study protocol assessing the benefit of this new strategy in patients with a wider range of visual acuity and a wider range of retinal thickness, even in eyes with prior macular photocoagulation, is mandatory. In this trial, we enrolled only patients with early-onset DME, with no evident signs of retinal degeneration, macular ischemia, and foveal hard exudate deposits or those judged by the investigators to have the potential to benefit from laser treatment. Nevertheless, that the same treating physician administered the photocoagulation decreases the generalization of the study results. Although, we cannot draw definitive conclusions based on our initial findings, our study forms the groundwork for future investigations. 
In conclusion, the findings of our study neither advocate nor support the use of subthreshold micropulse laser treatment of DME and suggest a superior short-term clinical performance for the HD-SDM technique over mETDRS focal/grid photocoagulation, based on the anatomic and functional measures of improvement used in this investigation. Overall, the superior therapeutic response of HD-SDM may constitute the proof of principle that more destructive laser lesions are unnecessary in macular photocoagulation for DME and that the lack of response may also be attributable to the lack of a personalized treatment protocol. The benefits of this selective retina-sparing treatment raise the possibility of improving the gold standard. Although a rationale for this treatment modality as a preferable approach is suggested, the precise role of subthreshold micropulse laser treatment may become more defined, as experience grows, guided by optimized treatment guidelines and more comprehensive trials. Advances in laser technology and modes of delivery will make treatment for DME a dynamic area and will highlight the need for continuing investigation and periodic review of guidelines to maintain pace with new developments in optimizing patient care. 
Footnotes
 Presented at the Retina Society Annual Meeting, Scottsdale, Arizona, September 2008.
Footnotes
 Disclosure: D. Lavinsky, None; J.A. Cardillo, None; L.A.S. Melo, Jr, None; A. Dare, None; M.E. Farah, None; R. Belfort, Jr, None
The authors thank Giorgio Dorin for his review of this article and insights on micropulse photocoagulation. Al Leyva helped with editing the English in the manuscript. 
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Figure 1.
 
(A) Fundus color photography of the barely visible mETDRS burn endpoint immediately after treatment. (B) Fundus color photography of an HD-SDM nonvisible endpoint immediately after treatment.
Figure 1.
 
(A) Fundus color photography of the barely visible mETDRS burn endpoint immediately after treatment. (B) Fundus color photography of an HD-SDM nonvisible endpoint immediately after treatment.
Figure 2.
 
Flowchart showing progression of patients during the study.
Figure 2.
 
Flowchart showing progression of patients during the study.
Figure 3.
 
Baseline fundus color photography, red-free photography, and fluorescein angiography (FA) (A) of an mETDRS group patient; (B) of the same patient 3 months after mETDRS treatment, showing barely visible burns in the color photograph, although the laser scars can be easily identified in FA; (C) of an HD-SDM group patient before treatment; and (D) of the same patient after HD-SDM treatment, showing that even in FA, micropulsed treatment remains nonvisible.
Figure 3.
 
Baseline fundus color photography, red-free photography, and fluorescein angiography (FA) (A) of an mETDRS group patient; (B) of the same patient 3 months after mETDRS treatment, showing barely visible burns in the color photograph, although the laser scars can be easily identified in FA; (C) of an HD-SDM group patient before treatment; and (D) of the same patient after HD-SDM treatment, showing that even in FA, micropulsed treatment remains nonvisible.
Table 1.
 
Treatment Characteristics
Table 1.
 
Treatment Characteristics
Burn Characteristics mETDRS ND-SDM HD-SDM
Direct treatment Directly treat all leaking microaneurysms 500–3000 μm from the center of the macula (but not within 500μm of the disc). NA NA
Burn size for direct treatment μm 75 NA NA
Burn duration for direct treatment, s 0.05–0.1 NA NA
Grid treatment All areas with diffuse leakage or nonperfusion within area considered for grid treatment. Entire area considered for grid treatment. Entire area considered for treatment (including unthickened retina)
Area considered for grid treatment 500–3000 μm superiorly, nasally, and inferiorly from the center of the macula 500–3500 μm temporally from macular center. No burns are placed within 500 μm of the disc. 500–3000 μm superior ly, nasally, and inferiorly from the center of the macula 500–3500 μm temporally from macular center. No burns are placed within 500 μm of the disc. 500–3000 μm superiorly, nasally, and inferiorly from the center of the macula 500– 3500 μm temporally from the macular center. No burns are placed within 500μm of the disc.
Burn size for grid, μm 75 125 125
Burn duration 0.05–0.10 s 2200 μs 15% DC 300 ms 2200 μs 15% DC 300 ms
Burn separation for grid treatment Two visible burn widths apart. Approximately two invisible burn widths apart. Confluent invisible burns
Table 2.
 
Sample Demographics
Table 2.
 
Sample Demographics
Variable Treatment Group P
High Density Normal Density Modified ETDRS
Eyes, n 42 39 42 NA
Sex, n (%) 0.97
    Male 18 (43) 18 (46) 19 (45)
    Female 24 (57) 21 (54) 23 (55)
Race, n (%) 0.98
    White 34 (81) 33 (85) 33 (79)
    Black 2 (5) 2 (5) 2 (5)
    Asian 2 (5) 2 (5) 2 (5)
    Mixed 4 (10) 2 (5) 5 (12)
Age, mean (SD), y 61.9 (8.5) 62.0 (7.4) 61.8 (7.0) 0.99
Diabetes mellitus
    Type, n (%) 0.99
        I 1 (2) 0 (0) 1 (2)
        II 41 (98) 39 (100) 41 (98)
    Duration, median (min–max) 12 (5–27) 11 (5–25) 12 (7–23) 0.77
    HbA1c, mean (SD), % 8.2 (0.6) 8.0 (0.6) 7.9 (0.6) 0.14
    Retinopathy severity, n (%) 0.85
        Mild NPDR 8 (19) 7 (18) 6 (14)
        Moderate NPDR 9 (21) 11 (28) 11 (26)
        Moderately severe NPDR 22 (52) 17 (44) 20 (48)
        Severe NPDR 1 (2) 2 (5) 3 (7)
        Mild PDR 2 (5) 2 (5) 2 (5)
        Moderate PDR 0 (0) 0 (0) 0 (0)
        High-risk PDR 0 (0) 0 (0) 0 (0)
Table 3.
 
Central Macular Thickness
Table 3.
 
Central Macular Thickness
Visit High Density Normal Density Modified ETDRS
Baseline 371 (297–879) 379 (279–619) 370 (269–710)
3 Months 301 (203–698) 332 (223–610) 306 (209–512)
6 Months 291 (201–577) 316 (215–627) 290 (208–501)
9 Months 252 (187–449) 317 (207–666) 279 (201–493)
12 Months 226 (187–513) 311 (207–599) 249 (199–475)
Table 4.
 
Central Macular Thickness Decrease over Study Follow-up
Table 4.
 
Central Macular Thickness Decrease over Study Follow-up
Change from Baseline Central Macular Thickness (μm) P
High Density Normal Density Modified ETDRS Between 3 Groups High Density vs. Normal Density High Density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months −93 (102) −20 (71) −67 (78) 0.002 0.001 0.22 0.01
6 Months −117 (119) −20 (97) −94 (86) <0.001 <0.001 0.60 0.001
9 Months −144 (140) −34 (106) −112 (107) 0.001 <0.001 0.59 0.01
12 Months −154 (157) −32 (107) −126 (126) <0.001 <0.001 0.75 0.001
Table 5.
 
BCVA
Table 5.
 
BCVA
Visit High Density Normal Density Modified ETDRS
Baseline 0.90 (0.30–1.30) 0.70 (0.40–1.30) 0.80 (0.30–1.30)
3 Months 0.70 (0.22–1.30) 0.80 (0.40–1.30) 0.75 (0.30–1.30)
6 Months 0.60 (0.22–1.30) 0.80 (0.40–1.30) 0.70 (0.22–1.30)
9 Months 0.60 (0.22–1.30) 0.80 (0.30–1.30) 0.70 (0.30–1.30)
12 Months 0.52 (0.22–1.30) 0.80 (0.30–1.30) 0.65 (0.30–1.30)
Table 6.
 
BCVA Improvement over Study Follow-up
Table 6.
 
BCVA Improvement over Study Follow-up
Change from Baseline Visual Acuity (logMAR) P
High Density Norman Density Modified ETDRS Between Three Groups High Density vs. Normal density High density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months −0.12 (0.18) 0.02 (0.14) −0.04 (0.14) 0.001 <0.001 0.05 0.009
6 Months −0.15 (0.21) 0.03 (0.18) −0.07 (0.15) <0.001 <0.001 0.07 0.002
9 Months −0.19 (0.27) 0.00 (0.27) −0.07 (0.19) 0.001 <0.001 0.02 0.11
12 Months −0.25 (0.31) 0.03 (0.22) −0.08 (0.23) <0.001 <0.001 0.009 0.01
Table 7.
 
BCVA Change
Table 7.
 
BCVA Change
Change from Baseline High Density Normal Density Modified ETDRS
3 Months
    ≥15 Letters better 10 (24) 1 (3) 5 (12)
    10–14 Letters better 2 (5) 0 (0) 1 (2)
    5–9 Letters better 1 (2) 0 (0) 2 (5)
    0±4 Letters 27 (66) 31 (82) 32 (76)
    5–9 Letters worse 1 (2) 2 (5) 1 (2)
    10–14 Letters worse 0 (0) 3 (8) 1 (2)
    ≥15 Letters worse 0 (0) 1 (3) 0 (0)
6 Months
    ≥15 Letters better 11 (28) 1 (3) 8 (19)
    10–14 Letters better 3 (8) 2 (5) 1 (2)
    5–9 Letters better 2 (5) 0 (0) 3 (7)
    0±4 Letters 21 (53) 28 (74) 27 (64)
    5–9 Letters worse 1 (3) 1 (3) 1 (2)
    10–14 Letters worse 1 (3) 3 (8) 1 (2)
    ≥15 Letters worse 1 (3) 3 (8) 1 (2)
9 Months
    ≥15 Letters better 14 (35) 3 (8) 8 (20)
    10–14 Letters better 5 (13) 1 (3) 4 (10)
    5–9 Letters better 5 (13) 3 (8) 1 (2)
    0±4 Letters 12 (30) 22 (59) 22 (54)
    5–9 Letters worse 2 (5) 2 (5) 3 (7)
    10–14 Letters worse 0 (0) 1 (3) 1 (2)
    ≥15 Letters worse 2 (5) 5 (14) 2 (5)
12 Months
    ≥15 Letters better 19 (48) 2 (5) 9 (23)
    10–14 Letters better 2 (5) 2 (5) 2 (5)
    5–9 Letters better 5 (13) 0 (0) 3 (8)
    0±4 Letters 10 (25) 26 (70) 20 (50)
    5–9 Letters worse 2 (5) 0 (0) 1 (3)
    10–14 Letters worse 0 (0) 1 (3) 1 (3)
    ≥15 Letters worse 2 (5) 6 (16) 4 (10)
Table 8.
 
BCVA Change Better or Worse Than 15 Letters during the Study Follow-up
Table 8.
 
BCVA Change Better or Worse Than 15 Letters during the Study Follow-up
Change from Baseline Visual Acuity Change P
High Density n (%) Normal Density n (%) Modified ETDRS n (%) Between Three Groups High Density vs. Normal Density High Density vs. Modified ETDRS Normal Density vs. Modified ETDRS
3 Months 0.01 0.007 0.16 0.20
    ≥15 Letters better 10 (24) 1 (3) 5 (12)
    <15 Letters better 31 (76) 37 (97) 37 (88)
6 Months 0.007 0.003 0.44 0.03
    ≥15 Letters Better 11 (28) 1 (3) 8 (19)
    <15 Letters Better 29 (72) 37 (97) 34 (81)
9 Months 0.01 0.006 0.14 0.20
    ≥15 Letters Better 14 (35) 3 (8) 8 (20)
    <15 Letters Better 26 (65) 34 (92) 33 (80)
12 Months <0.001 <0.001 0.03 0.05
    ≥15 Letters Better 19 (48) 2 (5) 9 (23)
    <15 Letters Better 21 (52) 35 (95) 31 (77)
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