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Panretinal Photocoagulation for Diabetic Retinopathy in the RIDE and RISE Trials: Not "1 and Done".
Gonzalez, VH, Wang, PW, Ruiz, CQ
Ophthalmology. 2021;(10):1448-1457
Abstract
PURPOSE To evaluate panretinal photocoagulation (PRP) treatment and re-treatment patterns in patients with diabetic retinopathy (DR) and diabetic macular edema (DME). DESIGN Post hoc analysis of the phase 3 RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) clinical trials of ranibizumab for the treatment of DME. PARTICIPANTS Seven hundred fifty-nine patients were randomized for treatment. METHODS Panretinal photocoagulation treatment patterns and clinical experiences were assessed by baseline PRP treatment status. MAIN OUTCOME MEASURES Number and timing of on-study PRP treatment sessions undergone through month 24. Time to new proliferative event (composite end point) was also assessed. RESULTS At baseline, approximately 25% of patients in RIDE and RISE had undergone PRP treatment before enrollment (22.2%, 24.4%, and 25.4% of patients in the sham, ranibizumab 0.3 mg, and ranibizumab 0.5 mg arms, respectively). In patients without prior PRP at baseline (n = 577), 9.5% of sham-treated patients underwent 1 or more PRP treatments through month 24, compared with 1.1% and 1.6% of patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg, respectively (P < 0.001 for both ranibizumab arms vs. sham). In patients with prior PRP at baseline (n = 182), 19.3% of sham-treated patients underwent 1 or more PRP treatments through month 24. No ranibizumab-treated patients with prior PRP at baseline required additional on-study PRP through month 24 (P < 0.001 for both ranibizumab arms vs. sham). Ranibizumab treatment also significantly reduced clinical DR progression among patients who underwent prior PRP. By month 24 in patients with prior PRP at baseline, the probability of experiencing a new proliferative event was 10.3% and 9.9% in patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg treatment, respectively, compared with 39.4% in sham-treated patients (P < 0.0001). Overall, sham-treated patients, including those patients who were PRP naïve at baseline who went on to require PRP, experienced more clinical events than ranibizumab-treated patients. CONCLUSIONS In RIDE and RISE, PRP treatment was not a "1 and done" procedure, with on-study PRP re-treatment occurring in patients both with and without prior PRP treatment at baseline. Ranibizumab treatment reduced on-study PRP treatment and DR progression regardless of prior PRP treatment status at baseline.
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Changes in entropy on polarized-sensitive optical coherence tomography images after therapeutic subthreshold micropulse laser for diabetic macular edema: A pilot study.
Ueda, K, Shiraya, T, Araki, F, Hashimoto, Y, Yamamoto, M, Yamanari, M, Ueta, T, Minami, T, Aoki, N, Sugiyama, S, et al
PloS one. 2021;(9):e0257000
Abstract
PURPOSE To investigate the dynamics of the healing process after therapeutic subthreshold micropulse laser (SMPL) for diabetic macular edema (DME) using polarization-sensitive optical coherence tomography (PS-OCT). METHODS Patients with treatment-native or previously-treated DME were prospectively imaged using PS-OCT at baseline, 1, 2, 3, and 6 months. The following outcomes were evaluated: changes in the entropy value per unit area (pixel2) in the retinal pigment epithelium (RPE) on the B-scan image; changes in the entropy value in each stratified layer (retina, RPE, choroid) based on the ETDRS grid circle overlaid with en face entropy mapping, not only the whole ETDRS grid area but also a sector irradiated by the SMPL; and the relationship between edema reduction and entropy changes. RESULTS A total of 11 eyes of 11 consecutive DME patients were enrolled. No visible signs of SMPL treatment were detected on PS-OCT images. The entropy value per unit area (pixel2) in the RPE tended to decrease at 3 and 6 months from baseline (35.8 ± 17.0 vs 26.1 ± 9.8, P = 0.14; vs 28.2 ± 18.3, P = 0.14). Based on the en face entropy mapping, the overall entropy value did not change in each layer in the whole ETDRS grid; however, decrease of entropy in the RPE was observed at 2, 3, and 6 months post-treatment within the SMPL-irradiated sectors (P < 0.01, each). There was a positive correlation between the change rate of retinal thickness and that of entropy in the RPE within the SMPL-irradiated sector at 6 months (r2 = 0.19, P = 0.039). CONCLUSION Entropy measured using PS-OCT may be a new parameter that facilitates objective monitoring of SMPL-induced functional changes in the RPE that could not previously be assessed directly. This may contribute to a more promising therapeutic evaluation of DME. CLINICAL TRIAL This clinical study was registered in UMIN-CTR (ID: UMIN000042420).
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Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.
Ehlers, JP, Uchida, A, Hu, M, Figueiredo, N, Kaiser, PK, Heier, JS, Brown, DM, Boyer, DS, Do, DV, Gibson, A, et al
Ophthalmology. Retina. 2019;(12):1056-1066
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PURPOSE To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study. DESIGN A post hoc subanalysis of a phase III, prospective clinical trial. PARTICIPANTS Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8). METHODS All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point. MAIN OUTCOME MEASURES The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA). RESULTS Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits. CONCLUSIONS Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
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The RELATION study: efficacy and safety of ranibizumab combined with laser photocoagulation treatment versus laser monotherapy in NPDR and PDR patients with diabetic macular oedema.
Lang, GE, Liakopoulos, S, Vögeler, J, Weiß, C, Spital, G, Gamulescu, MA, Lohmann, C, Wiedemann, P
Acta ophthalmologica. 2018;(3):e377-e385
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PURPOSE To assess efficacy and safety of intravitreal ranibizumab 0.5 mg plus laser (COMBI) versus laser monotherapy (LASER) in patients with visual impairment due to diabetic macular oedema (DME) in either nonproliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) and to analyse the relevance of inner versus outer retinal thickness. METHODS In this double-masked, multicentre phase IIIb study, patients (N = 128) were randomized (2:1) to receive COMBI (n = 85) versus LASER (n = 43). Patients received four initial monthly injections of ranibizumab 0.5 mg (COMBI) or sham (LASER) followed by pro re nata (PRN) injections. In both groups, patients received laser at baseline and additional laser at 3 monthly intervals, as needed. The study was started in 2010 and was prematurely terminated due to approval of ranibizumab for DME. RESULTS The least squares (LS) mean change in mean best-corrected visual acuity (BCVA) from baseline to month 12 was higher in the COMBI (6.5) versus LASER (2.3) group (LS mean difference: 4.2 [95% CI 0.9; 7.4] letters, p = 0.01, primary end-point). There was also a tendency in the same direction for the subgroup of 26 patients with PDR (LS mean difference 14.7, p = 0.11). Mean central retinal thickness decreased by 107.3 μm in the COMBI group and by 80.3 μm in the LASER group from baseline to month 12 (p = 0.28). Ranibizumab was well tolerated. CONCLUSION This study showed that ranibizumab plus laser is a valuable treatment option for the management of DME. Patients with DME in PDR might also benefit from combined therapy compared to laser alone.
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Targeted Retinal Photocoagulation for Diabetic Macular Edema with Peripheral Retinal Nonperfusion: Three-Year Randomized DAVE Trial.
Brown, DM, Ou, WC, Wong, TP, Kim, RY, Croft, DE, Wykoff, CC, ,
Ophthalmology. 2018;(5):683-690
Abstract
PURPOSE To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME). DESIGN Phase I/II prospective, randomized, controlled clinical trial. PARTICIPANTS Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus. METHODS Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1-disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated. MAIN OUTCOME MEASURES Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered. RESULTS At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters (P = 0.20) and mean CRT improved 302 and 152 μm (P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10-34) and 27.1 (range, 12-36), with 73% (362/496) and 80% (433/538) of PRN injections administered (P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively (P = 0.30). CONCLUSIONS In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone.
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Outcomes With As-Needed Aflibercept and Macular Laser Following the Phase III VISTA DME Trial: ENDURANCE 12-Month Extension Study.
Wykoff, CC, Le, RT, Khurana, RN, Brown, DM, Ou, WC, Wang, R, Clark, WL, Boyer, DS, ,
American journal of ophthalmology. 2017;:56-63
Abstract
PURPOSE To determine whether the efficacy and safety achieved with 2.0 mg intravitreal aflibercept injections (IAIs) for diabetic macular edema (DME) during the phase III VISTA DME trial were maintained with individualized, as-needed treatment. DESIGN Phase IV, multicenter, open-label extension study. METHODS Sixty patients completing VISTA DME elected to enter the ENDURANCE extension study. All patients received IAIs in the presence of clinically relevant DME. Patients were observed at 4-, 8-, or 12-week intervals depending on the need for treatment. Main outcome measures were mean IAIs given through month 12 (M12), the proportion of patients receiving no IAIs, and the role of macular laser in decreasing treatment burden among patients requiring ongoing IAIs. RESULTS A mean of 4.5 IAIs were administered through M12. Eighteen (30%) patients required no IAIs, and among those who met IAI retreatment criteria, a mean of 6.0 IAIs were administered through M12. Best-corrected visual acuity gains achieved during VISTA DME were maintained and stable with individualized dosing during ENDURANCE, fluctuating by <1.5 mean letters from the baseline at all time points. Likewise, mean central retinal thickness remained relatively stable during ENDURANCE. Thirty-seven (62%) patients met macular laser criteria at a mean of 19.5 weeks with no significant difference in the frequency of IAIs before or after macular laser. CONCLUSION Vision gains achieved during the 3-year VISTA DME trial were maintained through M12 of the ENDURANCE extension study with a reduced treatment frequency, with 30% of patients receiving no IAIs. No significant reduction in IAI frequency was observed after macular laser application.
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Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy.
Muqit, MM, Marcellino, GR, Henson, DB, Young, LB, Patton, N, Charles, SJ, Turner, GS, Stanga, PE
Acta ophthalmologica. 2013;(3):251-8
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PURPOSE To investigate the clinical effects and safety of targeted pattern scan laser (Pascal) retinal photocoagulation (TRP) in proliferative diabetic retinopathy (PDR). METHODS Prospective and non-randomized study of 28 eyes with treatment-naive proliferative diabetic retinopathy (PDR). Single-session 20-ms-Pascal TRP strategy applied 1500 burns to zones of retinal capillary non-perfusion and intermediate retinal ischaemia guided by wide-field fluorescein angiography (Optos). Main outcome measures at 12 and 24 weeks included; PDR grade (assessed by two masked retina specialists); central retinal thickness (CRT); mean deviation (MD) using 24-2 Swedish interactive threshold algorithm (SITA)-standard visual fields (VF); and ETDRS visual acuity (VA). RESULTS Following primary TRP, there was PDR regression in 76% of patients at 12 weeks (κ = 0.70; p < 0.001). No laser re-treatment was required at 4 weeks, and 10 eyes underwent repeat TRP at 12 weeks. Wide-field Optos angiography at 24 weeks showed complete disease regression in 37% and partial regression in 33%. Additional panretinal laser photocoagulation (PRP) was planned for active PDR in 30%. There were significant reductions in CRT over time (10.4 μm at 12-weeks, p = 0.007; 12.1 μm at 24-weeks, p = 0.0003). The MD on VFs improved after 12 weeks (+1.25 dB; p = 0.015) and 24 weeks (+1.26 dB, p = 0.01). The VA increased by +3 letters at 24 weeks (95% CI, 1.74-5.01; p < 0.0001). CONCLUSIONS This pilot study reports that Optos-guided Pascal 20-ms TRP using 1500 burns for treatment-naive PDR is a promising procedure with favourable safety profile.
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Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy.
Koss, MJ, Beger, I, Koch, FH
Eye (London, England). 2012;(2):307-14
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PURPOSE To evaluate the treatment of central serous chorioretinopathy (CSC) with either subthreshold diode laser MicroPulse (SDM) or intravitreal bevacizumab (BCZ). METHODS This comparative, controlled, prospective study conducted over a period of 10 months examined 52 eyes of 52 patients with (a) treatment with SDM at the active leakage site guided by fluorescein angiography (FA) (n=16 eyes), (b) intravitreal injection of 1.25 mg BCZ (n=10 eyes), or (c) observation (n=26 eyes). Outcome measures included changes in retinal pigment epithelium (RPE) leakage at FA, central macular thickness (CMT), best-corrected visual acuity (BCVA), and 10° macular perimetry. RESULTS At the end of the study, there was 12.5% persistent leakage in the SDM, compared with 60% in the BCZ and 92% in the control group. Mean CMT decreased by 94 μm in the SDM, 38 μm in the BCZ, and did not change in the control group. Mean BCVA improved more than 6 early treatment of diabetic retinopathy study letters in the SDM, decreased by one letter in the BCZ, and by two letters in the control group. In the SDM group, mean perimetric deficit improved by 1.5 decibels and corrected lost variance by 2.6. In the BCZ, it improved by 0.6, and in the control group by 0.5. Retreatment was required in 7/16 eyes of the SDM group (43.75%), and in 5/10 eyes of the BCZ group (50%). CONCLUSION SDM photocoagulation was superior to intravitreal injections of 1.25 mg BCZ in the treatment of CSC, which resulted in enhanced visual acuity and macular perimetry.
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The course of response to focal/grid photocoagulation for diabetic macular edema.
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Retina (Philadelphia, Pa.). 2009;(10):1436-43
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PURPOSE The purpose of this study was to determine whether eyes with center-involved diabetic macular edema, treated with focal/grid photocoagulation, in which there is a reduction in central subfield thickness (CST) measured with optical coherence tomography after 16 weeks, will continue to improve if retreatment is deferred. METHODS This is a prospective, multicenter, observational, single-group focal/grid photocoagulation study of 122 eyes with center-involved diabetic macular edema (optical coherence tomography CST > or =250 microm). At the 16-week visit and continuing every 8 weeks, eyes were assessed for retreatment and additional laser treatment was deferred if the visual acuity letter score improved > or =5 letters or optical coherence tomography CST decreased > or =10% compared with the visit 16 weeks prior. RESULTS Of the 115 eyes that completed the 16-week visit, 54 (47%) had a decrease in CST by > or =10% compared with baseline. Of these, 26 (48%) had a CST > or =250 microm at 16 weeks and were evaluable at 32 weeks. Eleven (42%; 95% confidence interval, 23-63%) of the 26 eyes had a further decrease in CST > or =10% from 16 weeks to 32 weeks without further treatment. CONCLUSION Sixteen weeks after focal/grid laser for diabetic macular edema in eyes with a definite reduction, but not resolution, of central edema, 23% to 63% likely will continue to improve without additional treatment.
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"Light" versus "classic" laser treatment for clinically significant diabetic macular oedema.
Bandello, F, Polito, A, Del Borrello, M, Zemella, N, Isola, M
The British journal of ophthalmology. 2005;(7):864-70
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AIM: To compare the effectiveness of "light" versus "classic" laser photocoagulation in diabetic patients with clinically significant macular oedema (CSMO). METHODS A prospective randomised pilot clinical trial in which 29 eyes of 24 diabetic patients with mild to moderate non-proliferative diabetic retinopathy (NPDR) and CSMO were randomised to either "classic" or "light" Nd:YAG 532 nm (frequency doubled) green laser. "Light" laser treatment differed from conventional ("classic") photocoagulation in that the energy employed was the lowest capable to produce barely visible burns at the level of the retinal pigment epithelium. Primary outcome measure was the change in foveal retinal thickness as measured by optical coherence tomography (OCT); secondary outcomes were the reduction/elimination of macular oedema on contact lens biomicroscopy and fluorescein angiography, change in visual acuity, contrast sensitivity, and mean deviation in the central 10 degrees visual field. Examiners were masked to patients' treatment. RESULTS 14 eyes were assigned to "classic" and 15 were assigned to "light" laser treatment. At 12 months, seven (50%) of 14 eyes treated with "classic" and six (43%) of 14 eyes treated with "light" laser had a decrease of foveal retinal thickness on OCT (p = 0.79). A comparison of reduction/elimination of oedema, visual improvement, visual loss, change in contrast sensitivity, and mean deviation in the central 10 degrees showed no statistical difference between the groups at 12 months (p>0.05 for all groups). CONCLUSIONS This study suggests that "light" photocoagulation for CSMO may be as effective as "classic" laser treatment, thus supporting the rationale for a larger equivalence trial.