Panretinal photocoagulation versus intravitreal injection retreatment pain in high-risk proliferative diabetic retinopathy.
Lucena Célia Regina Farias de Araújo,Ramos Filho José Afonso,Messias André Márcio Vieira,Silva José Aparecido da,Almeida Felipe Piacentini Paes de,Scott Ingrid Ursula,Ribeiro Jefferson Augusto Santana,Jorge Rodrigo
Arquivos brasileiros de oftalmologia
PURPOSE:To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy. METHODS:Prospective study including patients with high-risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group) or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group). In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2), and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-µm additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection). Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums). RESULTS:Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (±SEM) was 4.7 ± 2.1 and was significantly lower (p<0.0001) than mean panretinal photocoagulation pain (60.8 ± 7.8). Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5. CONCLUSION:In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment was performed with an intravitreal injection in comparison with retinal photocoagulation. Further larger studies are necessary to confirm our preliminary findings.
Evaluating the Impact of Intravitreal Aflibercept on Diabetic Retinopathy Progression in the VIVID-DME and VISTA-DME Studies.
Mitchell Paul,McAllister Ian,Larsen Michael,Staurenghi Giovanni,Korobelnik Jean-Francois,Boyer David S,Do Diana V,Brown David M,Katz Todd A,Berliner Alyson,Vitti Robert,Zeitz Oliver,Metzig Carola,Lu Chengxing,Holz Frank G
PURPOSE:To evaluate the impact of intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Tarrytown, NY) versus laser on progression of diabetic retinopathy (DR) severity in Intravitreal Aflibercept Injection in Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME). DESIGN:Secondary and exploratory analyses of 2 phase 3, randomized, controlled studies. PARTICIPANTS:All patients with a baseline Diabetic Retinopathy Severity Scale (DRSS) score based on fundus photograph (full analysis), patients who progressed to proliferative DR (PDR) (safety analysis) in VIVID-DME (n = 403) and VISTA-DME (n = 459), or both. METHODS:We randomized patients with diabetic macular edema (DME) to intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after 5 initial monthly doses (2q8), or macular laser photocoagulation at baseline and sham injections at every visit. MAIN OUTCOME MEASURES:Proportions of patients with 2-step or more and 3-step or more improvements from baseline in DRSS score, who progressed to PDR, and who underwent panretinal photocoagulation (PRP). RESULTS:Among patients with an assessable baseline DRSS score, most showed moderately severe or severe nonproliferative DR. The proportions of patients treated with 2q4, 2q8, and laser with a 2-step or more improvement in DRSS score at week 100 were 29.3%, 32.6%, and 8.2%, respectively, in VIVID-DME and 37.0%, 37.1%, and 15.6%, respectively, in VISTA-DME; the proportions with a 3-step or more improvement in DRSS score were 7.3%, 2.3%, and 0%, respectively, and 22.7%, 19.9%, and 5.2%, respectively. Fewer patients in the 2q4 and 2q8 groups versus the laser group progressed to PDR at week 100 in VISTA-DME (1.5% and 2.2% vs. 5.3%) and VIVID-DME (3.2% and 2.0% vs. 12.3%). The proportions of patients who underwent PRP were 2.9%, 0.7%, and 4.5%, respectively, in VIVID-DME and 1.9%, 0.7%, and 5.2%, respectively, in VISTA-DME. The most frequent serious ocular adverse event at week 100 was cataract (pooled intravitreal aflibercept, 1.7% of patients; laser, 3.5% of patients). CONCLUSIONS:These analyses demonstrate the benefit of intravitreal aflibercept over laser with respect to DR progression, suggesting a benefit on DME, and on underlying DR.
Evaluation of the role of vascular endothelial growth factor in diabetic retinopathy.
Mahdy Reda A,Nada Waled M
PURPOSE:The study is aiming at investigating the correlation between vascular endothelial growth factor (VEGF) as an angiogenic factor and diabetic retinopathy in type 2 diabetic patients and the effect of panretinal coagulation and glycemic control on VEGF. METHODS:The study included 30 patients of type 2 diabetes, 10 of them did not suffer from any of the vascular complications of type 2 diabetes mellitus (group 1), 10 patients had nonproliferative diabetic retinopathy (group 2), 10 patients had proliferative diabetic retinopathy (PDR) (group 3) and (group 4), as well as 10 healthy subjects that served as control group. All participants were subjected to complete clinical examination including ophthalmic and medical examination, laboratory investigations comprising complete blood count, liver function test, serum creatinine, 24-hour urinary albumin excretion, lipid profile, fasting and 2-hour postprandial blood glucose, HbA(1C) and serum VEGF. RESULTS:The study reported a highly significant increase in the serum VEGF in the diabetic patients compared to the control group (p < 0.001), and there was also a highly significant increase in the serum VEGF in the patients with PDR versus nonproliferative diabetic retinopathy (40.55 ± 8.28 vs. 20.3 ± 2.45, p < 0.001). There was a reduction in the serum VEGF in a group of diabetic patients with poor glycemic control when their diabetic state corrected through 4 months of follow-up was highly significant (17.29 ± 1.61 before vs. 9.39 ± 0.82 after control p < 0.001) as well as the reduction in the serum VEGF which was observed in a group of patients with PDR when proper panretinal photocoagulation (PRP) was applied to their retinae with 4 months of follow-up (40.55 ± 8.28 before vs. 21.15 ± 1.76 after PRP, p < 0.001). CONCLUSION:Serum VEGF is significantly increased in diabetic patients, especially those with PDR, and this elevation of VEGF was reduced in uncontrolled diabetic patients with proper gycemic control, and in patients with PDR with proper PRP, indicating that VEGF is an angiogenic factor that reflects the degree of neovascularization in diabetic complications.
Efficacy of intravitreal bevacizumab combined with pan retinal photocoagulation versus panretinal photocoagulation alone in treatment of proliferative diabetic retinopathy.
Sameen Murtaza,Khan Muhammad Saim,Mukhtar Ahsan,Yaqub Muhammad Amer,Ishaq Mazhar
Pakistan journal of medical sciences
OBJECTIVE:To compare effectiveness of pan-retinal photocoagulation alone versus panretinal photocoagulation combined with intravitreal bevacizumab on visual acuity and central macular thickness in patients presenting with proliferative diabetic retinopathy. METHODS:This Randomized controlled trial was carried out at Armed Forces Institute of ophthalmology, Pakistan from Jan 2016 to Aug 2016. Seventy six eyes of 50 patients having proliferative diabetic retinopathy and diabetic macular edema were included in the study. All the patients were subjected to detailed clinical examination that included Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), slit lamp examination of anterior and posterior segments. Optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) were carried out and patients were divided in two groups (GP and GI). Three monthly sessions of Pan retinal photocoagulation (PRP) using Pattern Scan Laser (PASCAL) alone was performed in group GP while PRP along with three monthly intravitreal bevacizumab (IVB) was performed in group GI. BCVA and CMT was recorded 04 weeks after the third PRP session in both the groups. RESULTS:Seventy six eyes of 50 patients (38 in each group) were treated with three sessions of PRP alone and PRP with IVB in Group GP and GI respectively. Mean age of the patient in group GP was 57.47± 6.08 years while that in group GI was 55.69 ±6.58. The magnitude of induced change in BCVA was 0.09 ± 0.15 in GP while 0.22 + 0.04 in GI groups while mean induced change in CMT after treatment was 77.44 ± 92.30 um and 117.50 ± 93.82 um in group GP and GI. CONCLUSION:Laser PRP combined with IVB has superior visual and anatomical outcome than PRP alone in patients with combined presentation of PDR and DME.
A randomized study comparing the efficacy of bevacizumab and ranibizumab as pre-treatment for pars plana vitrectomy in proliferative diabetic retinopathy.
Pakzad-Vaezi Kaivon,Albiani David A,Kirker Andrew W,Merkur Andrew B,Kertes Peter J,Eng Kenneth T,Fallah Nader,Forooghian Farzin
Ophthalmic surgery, lasers & imaging retina
BACKGROUND AND OBJECTIVE:To compare intravitreal bevacizumab versus ranibizumab as adjuvant treatment prior to pars plana vitrectomy (PPV) in proliferative diabetic retinopathy (PDR) with respect to parameters of surgical complexity. PATIENTS AND METHODS:Prospective, randomized, double-masked pilot study of patients requiring PPV for nonclearing vitreous hemorrhage or tractional retinal detachment (TRD) secondary to PDR. Patients were randomized to receive either intravitreal bevacizumab or ranibizumab at standard doses 1 week preoperatively. Measured parameters included total surgical time, presence of TRD, intraoperative bleeding, iatrogenic retinal breaks, and use of endolaser and endodiathermy or silicone oil. RESULTS:A total of 29 patients were recruited. For surgical parameters, there were no statistically significant differences between the groups in the univariate analyses. Multivariable analysis showed no statistically significant difference for total surgical time. CONCLUSION:This pilot study suggests that intravitreal bevacizumab and ranibizumab are equivalent as surgical adjuvants when used as pre-treatment in patients with PDR undergoing PPV.
Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema.
Bressler Susan B,Glassman Adam R,Almukhtar Talat,Bressler Neil M,Ferris Frederick L,Googe Joseph M,Gupta Shailesh K,Jampol Lee M,Melia Michele,Wells John A,
American journal of ophthalmology
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.
Visual Field Changes Over 5 Years in Patients Treated With Panretinal Photocoagulation or Ranibizumab for Proliferative Diabetic Retinopathy.
Maguire Maureen G,Liu Danni,Glassman Adam R,Jampol Lee M,Johnson Chris A,Baker Carl W,Bressler Neil M,Gardner Thomas W,Pieramici Dante,Stockdale Cynthia R,Sun Jennifer K,
Importance:Preservation of peripheral visual field (VF) is considered an advantage for anti-vascular endothelial growth factor agents compared with panretinal photocoagulation (PRP) for treatment of proliferative diabetic retinopathy. Long-term data on VF are important when considering either treatment approach. Objective:To further evaluate changes in VF throughout 5 years among eyes enrolled in the Protocol S clinical trial, conducted by the DRCR Retina Network. Design, Setting, and Participants:Post hoc analyses of an ancillary study within a multicenter (55 US sites) randomized clinical trial. Individuals with eyes with proliferative diabetic retinopathy enrolled in Protocol S were included. Data were collected from February 2012 to February 2018. Analysis began in June 2018. Interventions:Panretinal photocoagulation or intravitreous injections of 0.5-mg ranibizumab. Diabetic macular edema, whenever present, was treated with ranibizumab in both groups. Panretinal photocoagulation could be administered to eyes in the ranibizumab group when failure or futility criteria were met. Main Outcomes and Measures:Mean change in total point score on VF testing with the Humphrey Field Analyzer 30-2 and 60-4 test patterns. Results:Of 394 eyes enrolled in Protocol S, 234 (59.4%) were targeted for this ancillary study. Of these, 167 (71.4%) had VF meeting acceptable quality criteria at baseline (median [interquartile range] age, 50 [43-58] years; 90 men [53.9%]). At 5 years, 79 (33.8%) had results available. The mean (SD) change in total point score in the PRP and ranibizumab groups was -305 (521) dB and -36 (486) dB at 1 year, respectively, increasing to -527 (635) dB and -330 (645) dB at 5 years, respectively (P = .04). After censoring VF results after PRP treatments in the ranibizumab group, the 5-year mean change in total point score was -201 (442) dB. In a longitudinal regression analysis of change in total point score including both treatment groups, laser treatment was associated with a mean point decrease of 208 (95% CI, 112-304) dB for the initial PRP session, 77 (95% CI, 21-132) dB for additional PRP sessions, and 325 (95% CI, 211-439) dB for endolaser. No association was found between change in point score and the number of ranibizumab injections during the previous year (-9 per injection [95% CI, -22 to 3]). Conclusions and Relevance:The limited data available from Protocol S suggest that there are factors besides PRP associated with VF loss in eyes treated for proliferative diabetic retinopathy. Further clinical research is warranted to clarify the finding. Trial Registration:ClinicalTrials.gov identifier: NCT01489189.
Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial.
Sivaprasad Sobha,Prevost A Toby,Bainbridge James,Edwards Rhiannon Tudor,Hopkins David,Kelly Joanna,Luthert Phil,Murphy Caroline,Ramu Jayashree,Sarafraz-Shekary Negin,Vasconcelos Joana,White-Alao Beverley,Hykin Philip
INTRODUCTION:Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. METHODS AND ANALYSIS:This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52 weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52 weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52 weeks. ETHICS AND DISSEMINATION:The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects' regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR. TRIAL REGISTRATION NUMBER:ISRCTN 32207582.
ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY AND RISK OF TRACTION RETINAL DETACHMENT IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY: Pooled Analysis of Five DRCR Retina Network Randomized Clinical Trials.
Bressler Neil M,Beaulieu Wesley T,Bressler Susan B,Glassman Adam R,Melia B Michele,Jampol Lee M,Jhaveri Chirag D,Salehi-Had Hani,Velez Gisela,Sun Jennifer K,
Retina (Philadelphia, Pa.)
PURPOSE:To investigate whether anti-vascular endothelial growth factor (anti-VEGF) for diabetic macular edema or proliferative diabetic retinopathy (PDR) increases the risk of traction retinal detachment (TRD) among eyes with PDR. METHODS:Pooled analysis of PDR eyes from Protocols I, J, N, S, or T with Early Treatment Diabetic Retinopathy Study level ≥61 (prompt vitrectomy was not planned) randomly assigned to the control group (laser photocoagulation, sham, or intravitreal saline; 396 eyes) or anti-VEGF (487 eyes). The primary outcome was investigator-identified TRD within 1 year of randomization. RESULTS:The 1-year cumulative probability of TRD was 6.8% (95% confidence interval: 4.6%-9.9%, 25 events) in control-group eyes and 4.8% (95% confidence interval: 3.2%-7.3%, 22 events) in anti-VEGF group eyes (hazard ratio = 0.95 [95% confidence interval: 0.54-1.66, P = 0.86]). The cumulative probability of vitrectomy for TRD was 4.4% (16 events) in control-group eyes and 2.2% (9 events) in anti-VEGF group eyes (P = 0.19). Percentage with TRD and vitrectomy for TRD were similar within strata of diabetic retinopathy severity. CONCLUSION:These findings do not support the hypothesis that anti-VEGF therapy for diabetic macular edema or PDR increases the risk of TRD among eyes with PDR similar to those enrolled in five DRCR Retina Network protocols for which prompt vitrectomy was not planned.
Intravitreal bevacizumab for proliferative diabetic retinopathy with new dense vitreous hemorrhage after full panretinal photocoagulation.
Sinawat S,Rattanapakorn T,Sanguansak T,Yospaiboon Y,Sinawat S
Eye (London, England)
PURPOSE:To evaluate the efficacy and safety of intravitreal bevacizumab (IVB) injections for the treatment of proliferative diabetic retinopathy (PDR) with new dense vitreous hemorrhage (VH) after previous full panretinal photocoagulation (PRP). METHODS:Prospective study of consecutive PDR with prior complete PRP patients, who presented with new dense VH, were treated with IVB injection. Complete ophthalmic examination and/or ocular ultrasonography were performed at baseline and 1, 6, and 12 weeks and 6, 9, and 12 months after the first injection. Reinjection was done in non-clearing and recurrent VH. RESULTS:Eighteen eyes of 18 patients, mean age 47.7 ± 12.69 years were included. In all, 14 (77.78%) patients had type 2 diabetes mellitus. Systemic hypertension and dyslipidemia were the most common systemic diseases. All cases were phakic eye with previous complete PRP. Patients received 1.6 ± 0.42 intravitreal injections over a 12-month period. VH cleared completely in 7 (38.89%), 9 (50%), and 13 (72.22%) eyes after 6 weeks, 6 months, and 12 months, respectively. Re-bleeding, however, occurred in 10 (56%) eyes during the follow-up period, and 5 (28%) eyes still had residual VH at the last visit. Statistically significant visual gain was observed in 9 (50%) eyes. Unfortunately, 2 (11%) eyes had severe visual loss because of the tractional retinal detachment (TRD). Mild ocular complication was detected in one patient. CONCLUSION:IVB injection had good efficacy and safety for treatment of new VH in patients with PDR and prior complete PRP. This procedure may be especially relevant for diabetic patients at high-risk for surgical intervention.
Long-term effects of ranibizumab on diabetic retinopathy severity and progression.
Ip Michael S,Domalpally Amitha,Hopkins J Jill,Wong Pamela,Ehrlich Jason S
Archives of ophthalmology (Chicago, Ill. : 1960)
OBJECTIVE:To evaluate effects of intravitreal ranibizumab on diabetic retinopathy (DR) severity over time in 2 phase 3 clinical trials (RIDE, NCT00473382; RISE, NCT00473330) of ranibizumab for diabetic macular edema. METHODS:Participants with diabetic macular edema (n=759) were randomized to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab intravitreal injections. Macular laser was available per protocol-specified criteria. Fundus photographs, taken at baseline and periodically, were graded by a central reading center; clinical examinations were performed monthly. The main outcome measures of this report are secondary/exploratory analyses including a 2-step or more and 3-step or more change on the Early Treatment Diabetic Retinopathy Study severity scale in the study eye and a composite DR progression outcome including photographic changes plus clinically important events such as occurrence of vitreous hemorrhage or need for panretinal laser. RESULTS:At 2 years, the percentage of participants with DR progression (worsening by ≥ 2 or ≥ 3 steps) was significantly reduced in ranibizumab-treated eyes compared with sham-treated eyes, and DR regression (improving by ≥ 2 or ≥ 3 steps) was significantly more likely. The cumulative probability of clinical progression of DR as measured by the composite outcome at 2 years was 33.8% of sham-treated eyes compared with 11.2% to 11.5% of ranibizumab-treated eyes. CONCLUSIONS:Intravitreal ranibizumab reduced the risk of DR progression in eyes with diabetic macular edema, and many ranibizumab-treated eyes experienced improvement in DR severity. Because these results are exploratory, the use of intravitreal ranibizumab specifically to reduce DR progression or cause DR regression requires further study.
Electroretinographic findings associated with panretinal photocoagulation (PRP) versus PRP plus intravitreal ranibizumab treatment for high-risk proliferative diabetic retinopathy.
Messias André,Ramos Filho José Afonso,Messias Katharina,Almeida Felipe P P,Costa Rogério A,Scott Ingrid U,Gekeler Florian,Jorge Rodrigo
Documenta ophthalmologica. Advances in ophthalmology
To evaluate changes in electroretinographic (ERG) findings after panretinal photocoagulation (PRP) compared to PRP plus intravitreal injection of ranibizumab (IVR) in eyes with high-risk proliferative diabetic retinopathy (PDR). Patients with high-risk PDR and no prior laser treatment were assigned randomly to receive PRP (PRP group; n = 9) or PRP plus IVR (PRPplus group; n = 11). PRP was administered in two sessions (weeks 0 and 2), and IVR was administered at the end of the first laser session (week 0) in the PRPplus group. Standardized ophthalmic evaluations including (ETDRS) best-corrected visual acuity (BCVA), and fluorescein angiography to measure area of fluorescein leakage (FLA), were performed at baseline and at weeks 16 (±2), 32 (±2) and 48 (±2). ERG was measured according to ISCEV standards at baseline and at week 48 (±2). At 48 weeks, 2,400-3,000 laser spots had been placed in eyes in the PRP group, while only 1,400-1,800 spots had been placed in the PRPplus group. Compared to baseline, there was a statistically significant (P < 0.05) FLA reduction observed at all study visits in both groups, with the reduction observed in the PRPplus group significantly larger than that in the PRP group at week 48. ROD b-wave amplitude was significantly reduced to 46 ± 5% (P < 0.05) of baseline in the PRP group and 64 ± 6% (P < 0.05) in the PRPplus group. This reduction was significantly larger in the PRP group than in the PRPplus group (P = 0.024; t Test). Similar results were observed for the dark-adapted Combined Response (CR) b-wave amplitude, with a reduction at 48 weeks compared to baseline of 45 ± 4% in the PRP group and 62 ± 5% in the PRPplus group; the reduction in CR b-wave amplitude was significantly larger in the PRP group than in the PRPplus group (P = 0.0094). CR a-wave, oscillatory potentials, cone single flash, and 30 Hz flicker responses showed statistically significant within-group reductions, but no differences in between-group analyses. These results suggest that treating high-risk PDR with PRP plus IVR is effective for PDR control, and permits the use of less extensive PRP which, in turn, induces less retinal functional loss, in particular for rod-driven post-receptoral responses, than treatment with PRP alone.
Panretinal photocoagulation (PRP) versus PRP plus intravitreal ranibizumab for high-risk proliferative diabetic retinopathy.
Filho José A R,Messias André,Almeida Felipe P P,Ribeiro Jefferson A S,Costa Rogério A,Scott Ingrid U,Jorge Rodrigo
PURPOSE:To evaluate the effects of panretinal photocoagulation (PRP) compared with PRP plus intravitreal injection of 0.5 mg of ranibizumab (IVR) in patients with high-risk proliferative diabetic retinopathy (PDR). METHODS:Prospective study included patients with high-risk PDR and no prior laser treatment randomly assigned to receive PRP (PRP group) or PRP plus IVR (PRPplus group). PRP was administered in two sessions (weeks 0 and 2), and IVR was administered at the end of the first laser session in the PRPplus group. Standardized ophthalmic evaluations including best-corrected visual acuity (BCVA) measured according to the methods used in the Early Treatment Diabetic Retinopathy Study (BCVA), fluorescein angiography to measure area of fluorescein leakage (FLA) and optical coherence tomography (OCT) for the assessment of central subfield macular thickness (CSMT), were performed at baseline and at weeks 16 (± 2), 32 (± 2) and 48 (± 2). RESULTS:Twenty-nine of 40 patients (n = 29 eyes) completed the 48-week study follow-up period. At baseline, mean ± SE FLA (mm(2)) was 9.0 ± 1.3 and 11.7 ± 1.3 (p = 0.1502); BCVA (logMAR) was 0.31 ± 0.05 and 0.27 ± 0.06 (p = 0.6645); and CSMT (μm) was 216.3 ± 10.7 and 249.4 ± 36.1 (p = 0.3925), in the PRP and PRPplus groups, respectively. There was a significant (p < 0.05) FLA reduction at all study visits in both groups, with the reduction observed in the PRPplus group significantly larger than that in the PRP group at week 48 (PRP = 2.9 ± 1.3 mm(2) ; PRPplus = 5.8 ± 1.3 mm(2) ; p = 0.0291). Best-corrected visual acuity worsening was observed at 16, 32 and 48 weeks after treatment in the PRP group (p < 0.05), while no significant BCVA changes were observed in the PRPplus group. A significant CSMT increase was observed in the PRP group at all study visits, while a significant decrease in CSMT was observed in the PRPplus group at week 16, and no significant difference in CSMT from baseline was observed at weeks 32 and 48. CONCLUSIONS:Intravitreal ranibizumab after PRP was associated with a larger reduction in FLA at week 48 compared with PRP alone in eyes with high-risk PDR, and the adjunctive use of IVR appears to protect against the modest visual acuity loss and macular swelling observed in eyes treated with PRP alone.
Panretinal Photocoagulation Plus Intravitreal Bevacizumab Versus Panretinal Photocoagulation Alone for Proliferative Diabetic Retinopathy.
Ali Warda,Abbasi Kanwal Zareen,Raza Ali
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP
OBJECTIVE:To compare panretinal photocoagulation (PRP) plus intravitreal bevacizumab (IVB) against PRP alone in the treatment of proliferative diabetic retinopathy (PDR) in terms of mean change in best corrected visual acuity (BCVA), neovessels on disc (NVD) and neovessels elsewhere (NVE). STUDY DESIGN:Experimental study. PLACE AND DURATION OF STUDY:Department of Ophthalmology, Benazir Bhutto Hospital, Rawalpindi, from December 2014 to July 2015. METHODOLOGY:Sixty eyes were randomized into two groups with 30 eyes in each. In group A, IVB was given 15 days prior to PRP but in group B only PRP was given. In both groups, BCVA and neovessels status at disc and elsewhere was assessed before and at day 30. NVDs were judged as per percentage of NVD occupying surface of the disc (DD%). NVE were also judged as per reference to diameter of disc surface. RESULTS:The mean age of the study patients was 52.27 ±6.7 years. Mean BCVA (logMAR) in the PRP plus IVB group improved considerably from mean 0.64 ±0.17 to mean 0.49 ±0.21 at 30th day. However, in PRP group, there was no significant change in BCVA 0.64 ±0.16 at baseline to 0.63 ±0.18 at day 30. There were extremely significant changes between the two groups at 4th week (p<0.001). Mean NVE at baseline in PRP plus group was 3.30 ±0.95% at baseline that changes to 1.50 ±1.06% at day 30. While in only PRP group, mean NVE was 3.33 ±0.7% at baseline and 3.17 ±0.7% at one month of follow-up. In PRP plus group, NVD changes from mean 31.27 ±9.8% at baseline to 11.40 ±5.5% at one month of follow-up. In only PRP group, NVD changes from mean 31.13 ±10.23% at baseline to 29.53 ±11.04% at 1 month of follow-up. There were extremely significant changes between two groups at day 30 (p<0.001). CONCLUSION:Intravitreal bevacizumab in short duration is effective as adjunctive treatment to PRP with early and greater rate of regression of retinal neovessel than PRP alone in PDR patients.
INTRAVITREAL BEVACIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Results From the Pan-American Collaborative Retina Study Group (PACORES) at 24 Months of Follow-up.
Arevalo J Fernando,Lasave Andres F,Wu Lihteh,Maia Mauricio,Diaz-Llopis Manuel,Alezzandrini Arturo A,Brito Miguel,
Retina (Philadelphia, Pa.)
PURPOSE:To evaluate the effects of intravitreal bevacizumab (IVB) on retinal neovascularization in patients with proliferative diabetic retinopathy (PDR). METHODS:Retrospective multicenter interventional case series. A chart review was performed of 81 consecutive patients (97 eyes) with retinal neovascularization due to PDR, who received at least 1 IVB injection. RESULTS:The mean age of the patients was 55.6 ± 11.6 years. The mean number of IVB injections was 4 ± 2.5 injections (range, 1-8 injections) per eye. The mean interval between IVB applications was 3 ± 7 months. The mean duration of follow-up was 29.6 ± 2 months (range, 24-30 months). Best-corrected visual acuity and optical coherence tomography improved statistically significantly (P < 0.0001, both comparisons). Three eyes without previous panretinal photocoagulation ("naive" eyes) and with vitreous hemorrhage did not require vitreoretinal surgery. Five (5.2%) eyes with PDR progressed to tractional retinal detachment requiring vitrectomy. No systemic adverse events were noted. CONCLUSION:Intravitreal bevacizumab resulted in marked regression of retinal neovascularization in patients with PDR and previous panretinal photocoagulation. Intravitreal bevacizumab in naive eyes resulted in control or regression of 42.1% of eyes without adjunctive laser or vitrectomy during 24 months of follow-up. There were no safety concerns during the 2 years of follow-up of IVB for PDR.
LSFG findings of proliferative diabetic retinopathy after intravitreal injection of bevacizumab.
Enaida Hiroshi,Okamoto Kenji,Fujii Hitoshi,Ishibashi Tatsuro
Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye
The authors investigate the changes of chorioretinal blood flow using laser speckle flowgraphy (LSFG) in efficacy of treatment. Intravitreal bevacizumab was injected in a patient with proliferative diabetic retinopathy. LSFG measures the relative velocity index of erythrocytes (mean blur rate) in a previously confirmed area, with neovascularization elsewhere (NVE), neovascularization of the disc (NVD), and without neovascularization. The authors compared mean blur rate before and after bevacizumab injection in each area. In LSFG images, regression of blood flow was observed at the area of neovascularization sequentially as the change of color pattern. Finally, decrease of the mean blur rate of an average 32.7% was observed in the NVE area. Similarly, a reduction of 31.9% of mean blur rate was observed in the NVD area. However, in the area of without neovascularization, reduction of mean blur rate was not observed. This suggested the useful possibility of measuring chorioretinal blood flow changes by drug intervention using LSFG analysis.
A randomized controlled trial of panretinal photocoagulation with and without intravitreal ranibizumab in treatment-naive eyes with non-high-risk proliferative diabetic retinopathy.
Ferraz Daniel A,Vasquez Lisa M,Preti Rony C,Motta Augusto,Sophie Raafay,Bittencourt Millena G,Sepah Yasir J,Monteiro Mário L R,Nguyen Quan Dong,Takahashi Walter Yukihiko
Retina (Philadelphia, Pa.)
PURPOSE:To compare the efficacy of panretinal photocoagulation (PRP) and intravitreal ranibizumab injection with PRP alone in patients with treatment-naive bilateral non-high-risk proliferative diabetic retinopathy. METHODS:Sixty eyes of 30 patients were randomized either to the study group (SG) receiving PRP plus 2 ranibizumab injections or to the control group (CG) receiving PRP alone. Mean change in best-corrected visual acuity and in optical coherence tomography were compared at baseline and 1, 3, and 6 months. RESULTS:Best-corrected visual acuity was significantly better at 6 months in the SG; however, there was decrease in best-corrected visual acuity in the CG. Central macula thickness decreased significantly at 6 months in SG when compared with baseline (-47.6 μm, P < 0.001) and did not reveal significant difference in the CG. In eyes with diabetic macular edema, best-corrected visual acuity increased by 3.6 letters (P = 0.06) in the SG and decreased by 4.4 letters in the CG (P = 0.003). Central macula thickness decreased by 69.3 μm (P = 0.001) in the SG and decreased by 45.5 μm (P = 0.11) in the CG. CONCLUSION:Intravitreal ranibizumab in combination with PRP can be an effective treatment in eyes with non-high-risk proliferative diabetic retinopathy and diabetic macular edema.
Microaneurysm turnover in diabetic retinopathy assessed by automated RetmarkerDR image analysis--potential role as biomarker of response to ranibizumab treatment.
Leicht Simon F,Kernt Marcus,Neubauer Aljoscha,Wolf Armin,Oliveira Carlos Manta,Ulbig Michael,Haritoglou Christos
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde
PURPOSE:To evaluate the influence of a ranibizumab treatment on microaneurysm (MA) turnover in diabetic retinopathy. METHODS:Sixty-nine eyes were included in this retrospective study. We compared a group of 33 eyes with ranibizumab treatment for diabetic macular edema to 36 eyes with nonproliferative diabetic retinopathy only. Nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) images were obtained at a mean 4.76 ± 1.69 days prior to the first ranibizumab injection (baseline) and again 35.94 ± 2.44 days after the third consecutive injection in a 4-week interval. In untreated controls, images were obtained at baseline and 97.81 ± 3.16 days thereafter. Images were analyzed using the RetmarkerDR software (Critical Health SA, Coimbra, Portugal), and the turnover of MAs was documented and analyzed. Thereafter, MA turnover was correlated with central retinal thickness (CRT) as assessed by OCT. RESULTS:At baseline, patients in the treatment group had 5.64 ± 0.75 MAs. One month after 3 ranibizumab injections, measured MAs decreased to 4.03 ± 0.66. In the untreated control group, the initial number of 3.36 ± 0.6 MAs remained almost unchanged over 3-4 months (2.89 ± 0.57 MAs). Dynamic analysis showed that after ranibizumab treatment 3.06 ± 0.5 new MAs appeared, while 5.09 ± 0.79 disappeared. In the control group, 2.11 ± 0.4 new MAs appeared and 2.61 ± 0.48 disappeared. MA turnover was significantly higher with ranibizumab compared to the control group (8.15 ± 1.14 vs. 4.72 ± 0.81, p < 0.001). Consistently, CRT decreased from 444 to 330 µm in the ranibizumab group, while there was no change in the control group (291 vs. 288 µm). CONCLUSION:The treatment of macular edema using ranibizumab does not only reduce macular thickness, but also has an impact on the turnover of MAs in diabetic retinopathy. RetmarkerDR analysis showed that more pre-existent MAs disappeared than new MAs developed, and the absolute number of MAs also decreased.
Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy.
Davidović Sofija P,Nikolić Stanislava V,Curić Nikola J,Latinović Slobodanka L J,Drašković Dragan O,Cabarkapa Velibor S,Stošić Zoran Z
European journal of ophthalmology
PURPOSE:Avastin (bevacizumab) intravitreal injections are widely used for treatment of diabetic retinopathy. The aim of our study was to analyze effect of 1.25 mg of intravitreal Avastin on serum concentration of vascular endothelial growth factor (VEGF) in diabetic patients. METHODS:Participants were 10 diabetic patients on insulin therapy, without any other eye or systemic disease, and no kidney disfunction. Both eyes of diabetic patients were injected simultaneously with 1.25 mg of intravitreal Avastin, as a first step in treatment of nonproliferative diabetic retinopathy with clinically significant macular edema (4 patients), and of proliferative diabetic retinopathy (6 patients). Fluorescein angiography was performed prior to and laser therapy followed 1 month after Avastin treatment. VEGF concentration in patients serum was measured by ELISA technique: on the day of the Avastin administration, and 1, 7, and 28 days after intravitreal injection. RESULTS:In all analyzed participants, 24 hours after Avastin treatment, serum levels of VEGF were lower then basal (preinjection value). Maximal reduction of serum VEGF was noted on the 7th postoperative day. Twenty-eight days after, VEGF level in serum was raised, without completely reaching basal preoperative concentrations in most patients. CONCLUSIONS:Intravitreal injections of anti-VEGF drugs have an effect on decreasing systemic VEGF values. Rhythm of changes in serum VEGF concentrations and lowest detected concentration on the seventh postinjection day are according to pharmacokinetics of Avastin in serum and vitreous, reported by similar studies. The small number of patients involved in this pilot study implicates the need for further studies.
Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation.
Bressler Neil M,Edwards Allison R,Beck Roy W,Flaxel Christina J,Glassman Adam R,Ip Michael S,Kollman Craig,Kuppermann Baruch D,Stone Thomas W,
Archives of ophthalmology (Chicago, Ill. : 1960)
OBJECTIVE:To compare the effect of intravitreal triamcinolone acetonide with focal/grid photocoagulation on the progression of diabetic retinopathy. METHODS:We performed an exploratory analysis of participants with diabetic macular edema randomly assigned to receive laser therapy or intravitreal triamcinolone acetonide (1 or 4 mg). Fundus photographs were obtained at baseline and 1, 2, and 3 years. The main outcome measure was progression to proliferative diabetic retinopathy or worsening of 2 or more severity levels on reading-center masked assessment of 7-field fundus photographs, plus additional eyes that received panretinal photocoagulation or had a vitreous hemorrhage. RESULTS:From July 15, 2004, through May 5, 2006, 840 eyes from 693 participants were enrolled in the study and randomly assigned to receive laser therapy (n = 330), 1 mg of triamcinolone acetonide (n = 256), or 4 mg of triamcinolone acetonide (n = 254). The cumulative probability of progression of retinopathy at 2 years was 31% (laser group), 29% (1-mg group), and 21% (4-mg group) (P = .64 in the 1-mg group and .005 in the 4-mg group compared with the laser group). These differences appeared to be sustained at 3 years. CONCLUSIONS:Intravitreal triamcinolone acetonide (4 mg) appeared to reduce the risk of progression of diabetic retinopathy. Given the exploratory nature of this analysis and because intravitreal triamcinolone adverse effects include cataract formation and glaucoma, use of this treatment merely to reduce the rates of progression of proliferative diabetic retinopathy or worsening of the level of diabetic retinopathy does not seem warranted at this time.
Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema.
, ,Aiello Lloyd Paul,Beck Roy W,Bressler Neil M,Browning David J,Chalam K V,Davis Matthew,Ferris Frederick L,Glassman Adam R,Maturi Raj K,Stockdale Cynthia R,Topping Trexler M
OBJECTIVE:To describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial. DESIGN:Discussion of treatment protocol for DME. PARTICIPANTS:Subjects with vision loss resulting from DME involving the center of the macula. METHODS:The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser treatment in eyes with vision loss resulting from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. To share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. MAIN OUTCOME MEASURES:Clinical guidelines based on a DRCR.net protocol. RESULTS:The treatment protocol required real-time feedback from a web-based data entry system for intravitreal injections, focal/grid laser treatment, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. CONCLUSIONS:Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.
Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial.
Mirshahi A,Roohipoor R,Lashay A,Mohammadi S-F,Abdoallahi A,Faghihi H
European journal of ophthalmology
PURPOSE:To evaluate the additional therapeutic effect of single intravitreal bevacizumab injection on standard laser treatment in the management of proliferative diabetic retinopathy. METHODS:A prospective, fellow-eye sham controlled clinical trial was conducted on 80 eyes of 40 high-risk characteristic proliferative diabetic retinopathy type II diabetics. All cases received standard laser treatment according to Early Treatment Diabetic Retinopathy Study protocol. Avastin-assigned eyes received 1.25 mg intravitreal bevacizumab (Genentech Inc., San Francisco, CA) on the first session of their laser treatments. Fluorescein angiography was performed at baseline and at weeks 6 and 16, and proliferative diabetic retinopathy regression was evaluated in a masked fashion. RESULTS:The median age was 52 years (range: 39-68) and 30% of the participants were male. All patients were followed for 16 weeks. A total of 87.5% of Avastin-injected eyes and 25% of sham group showed complete regression at week 6 of follow-up (p<0.005). However, at week 16, PDR recurred in a sizable number of the Avastin-treated eyes, and the complete regression rate in the two groups became identical (25%; p=1.000); partial regression rates were 70% vs 65%. In the subgroup of Avastin-treated eyes, multivariate analysis identified hemoglobin A1c as the strongest predictor of proliferative diabetic retinopathy recurrence (p=0.033). CONCLUSIONS:Intravitreal bevacizumab remarkably augmented the short-term response to scatter panretinal laser photocoagulation in high-risk characteristic proliferative diabetic retinopathy but the effect was short-lived, as many of the eyes showed rapid recurrence. Alternative dosing (multiple and/or periodic intravitreal Avastin injections) is recommended for further evaluation.
Intravitreal bevacizumab (Avastin) and panretinal photocoagulation in the treatment of high-risk proliferative diabetic retinopathy.
Yang Chang-Sue,Hung Kuo-Che,Huang Yi-Ming,Hsu Wen-Ming
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
PURPOSE:To report the short-term efficacy and safety of intravitreal bevacizumab (Avastin) injection with panretinal laser photocoagulation (PRP) in patients with high-risk proliferative diabetic retinopathy (PDR) according to the Early Treatment Diabetic Retinopathy Study criteria. METHODS:A prospective, interventional case series study was conducted in 17 patients (20 eyes) with high-risk PDR, who were treated with intravitreal bevacizumab (2.5 mg) followed by PRP when the peripheral vitreous became clear or 2 weeks after injection. Patients underwent complete ophthalmic evaluation, including Snellen visual acuity and fluorescein angiography at baseline, 1, 3, and 6 months after bevacizumab injection. Main outcome measures included the serial changes in visual acuity, vitreous clear-up time, and neovascularization on the disc (NVD) regression time. RESULTS:All patients had obvious reduction in angiographic leakage and involution of retinal neovascularization (NV) at the 1- and 3-month follow-up. The mean follow-up time was 7.5 months. The vitreous hemorrhage (VH) showed a partial resolution as early as 1 week, and complete regression at 3 months. The mean vitreous clear-up time after intravitreal Avastin was 8.5±2.2 weeks. The mean time interval from intravitreal Avastin to NVD regression was 10.8±3.4 weeks. Mean logarithm of the minimum angle resolution visual acuity improved from 1.03 at baseline to 0.36 at 1-month, 0.38 at 3-month, and 0.48 at the 6-month follow-up (P<0.01). Three eyes (18%) required vitrectomy surgery during follow-up. The indication for vitrectomy was dense, persistent VH in 2 eyes, and focal tractional retinal detachment (TRD) in 1 eye. Recurrent retinal NV with minor preretinal hemorrhage was observed in 6 eyes (30%) 3 months after the first injection, and resolved after repeated bevacizumab injections. Patients received an average of 1.4 injections (range: 1-2). Seven eyes (35%) underwent 2 injections. One eye (5%) had ocular complication of PDR progression to TRD. No systemic adverse events were observed following injections. CONCLUSIONS:Short-term results suggest combined intravitreal bevacizumab and PRP achieved rapid clearance of VH, regression of retinal NV, and visual improvement in the treatment of high-risk PDR. Long-term study is warranted to assess the long-term efficacy and safety.
Contrast sensitivity evaluation in high risk proliferative diabetic retinopathy treated with panretinal photocoagulation associated or not with intravitreal bevacizumab injections: a randomised clinical trial.
Preti Rony Carlos,Ramirez Lisa Mariel Vasquez,Monteiro Mario Luiz Ribeiro,Carra Mario Kehdi,Pelayes David E,Takahashi Walter Yukihiko
The British journal of ophthalmology
PURPOSE:To compare the effect on contrast sensitivity (CS) measurements of panretinal photocoagulation (PRP) associated with intravitreal bevacizumab (IVB) injections versus PRP alone in high risk proliferative diabetic retinopathy (HR-PDR). DESIGN:Prospective, randomised, masked, controlled trial. PARTICIPANTS:42 patients with HR-PDR with visual acuity ≥20/200. METHODS:Eyes were randomised to one of two groups: one underwent PRP and IVB injections (study group) and the other PRP alone (control group). PRP was performed three times during the study and IVB injection was administered twice. MAIN OUTCOME MEASURES:Mean change in CS threshold scores between and within groups, from baseline to 6 months. RESULTS:Seven patients presented with vitreous haemorrhage and were removed from the study. Mean results for CS threshold (at 1.5, 3, 6, 12 and 18 cycles per degree (cpd) frequencies) for patients with and without diabetic macular oedema showed no significant differences (p>0.05 for all comparisons) between the two groups. In 35 eyes in the control group, compared with baseline values, there was significant worsening (p<0.05) of CS at 1.5, 12 and 18 cpd after 1 month, at 12 cpd after 3 months, and at 6 and 12 cpd after 6 months. In the study group, there was significant improvement in CS at 3 cpd, 3 months after treatment. CONCLUSIONS:In eyes with HR-PDR, PRP treatment is associated with deterioration of CS while adjuvant use of bevacizumab prevents such deterioration. CS evaluation seems to support the adjuvant use of bevacizumab when using PRP for the treatment of HR-PDR. ClinicalTrials.gov Identifier NCT 01389505.
Fenofibrate - a potential systemic treatment for diabetic retinopathy?
Wong Tien Yin,Simó Rafael,Mitchell Paul
American journal of ophthalmology
PURPOSE:To review clinical and experimental data for fenofibrate as a possible systemic treatment for diabetic retinopathy. DESIGN:Perspective. METHODS:Review of clinical studies focused on 2 major randomized controlled trials: the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes)-Eye studies. Progression was defined in FIELD as laser treatment for proliferative retinopathy or macular edema or increase by ≥ 2 steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and in ACCORD-Eye as ≥ 3 steps (ETDRS scale) or proliferative disease requiring laser or vitrectomy treatment. Experimental studies investigating the mode of action of fenofibrate were reviewed. RESULTS:The 2 trials included 11 388 patients with type 2 diabetes mellitus, of whom 5701 were treated with fenofibrate (± statin) for up to 5 years. Fenofibrate reduced first laser treatment by 31% (P = .0002), and progression of diabetic retinopathy with absolute reductions of 5.0% over 5 years (P = .022, FIELD) and 3.7% over 4 years (P = .006, ACCORD-Eye). There was greater benefit in patients with than without preexisting retinopathy. The putative mechanisms implicated in the mode of action of fenofibrate involve lipid and nonlipid pathways, including beneficial effects on apoptosis, oxidative stress, inflammation, blood-retinal barrier breakdown, and neuroprotection. CONCLUSIONS:There are now robust and consistent clinical data to recommend fenofibrate as an adjunctive treatment for early diabetic retinopathy in patients with type 2 diabetes mellitus, taking into account the risks vs benefits of therapy. Further elucidating its mode of action will help to refine how best to use fenofibrate in the management of diabetic retinopathy.
[Diabetic retinopathy--Current aspects of therapy].
Tost Frank,Kempin Robert,Grossjohann Rico,Herfurth Sabine
Medizinische Monatsschrift fur Pharmazeuten
Pathological changes of the small blood vessels are the main risk for diabetic retinopathy. A distinction is made between proliferative and non-proliferative processes. The diabetic macular edema can manifest itself at any stage of the diabetic retinopathy and poses a serious threat to vision and quality of life. Evidence based therapy primarily focuses on laser coagulation. Laser coagulation suspends progression of the disease and is used particularly for extrafoveolar edema. Especially a pathological swelling, such as the cystoid edema, in this central part of the retina, can cause a rapid deterioration of vision. The treatment of cystoid macular edema with intravitreal application of drugs is a widespread therapeutical approach. Invasive therapeutical drug application into the vitreous cavity has to be sterile in order to prevent infection. The usage of VEGF (Vascular endothelial growth factor) antagonists is an effective treatment for the diabetic macular edema. Several drugs are now available for intravitreal injection. Nevertheless a small number of medical drugs regularly administered to patients still have to be approved by the authorities (off-label use). One can distinguish mainly between VEGF antagonist (growth factor antagonist) like ranibizumab, aflibercept and bevacizumab and steroid therapy which includes dexamethasone, fluocinolone and triamcinolone.
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 Gabriele E,Liakopoulos Sandra,Vögeler Jessica,Weiß Claudia,Spital Georg,Gamulescu Maria-Andreea,Lohmann Chris,Wiedemann Peter
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.
The use of fenofibrate in the management of patients with diabetic retinopathy: an evidence-based review.
Sharma Neil,Ooi Ju-Lee,Ong Jong,Newman Douglas
Australian family physician
BACKGROUND:Diabetic retinopathy is a significant cause of vision impairment, especially affecting those of working age. There are two large, randomised controlled trials examining the effect of fenofibrate on diabetic retinopathy. OBJECTIVE:We summarise their findings, and report on the available safety data. DISCUSSION:The FIELD study reported that patients treated with fenofibrate had a statistically significant relative risk reduction in the need for laser treatment for maculopathy and proliferative retinopathy. The ACCORD-Eye study reported a statistically significant reduction in diabetic retinopathy progression in patients treated with fenofibrate and statin combination therapy compared to statin therapy alone. There is firm evidence that fenofibrate slows the progression of diabetic retinopathy and the need for more invasive treatment modalities in patients with type 2 diabetes, especially those with pre-existing retinopathy. In October 2013, Australia became the first country in the world to approve the use of this medication for this specific indication.
Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy.
Van Bergen Tine,Hu Tjing-Tjing,Etienne Isabelle,Reyns Geert E,Moons Lieve,Feyen Jean H M
Experimental eye research
The current standard of care in clinical practice for diabetic retinopathy (DR), anti-vascular endothelial growth factor (VEGF) therapy, has shown a significant improvement in visual acuity. However, treatment response can be variable and might be associated with potential side effects. This study was designed to investigate inhibition of placental growth factor (PlGF) as a possible alternative therapy for DR. The effect of the anti-PlGF antibody (PL5D11D4) was preclinically evaluated in various animal models by investigating different DR hallmarks, including inflammation, neurodegeneration, vascular leakage and fibrosis. The in vivo efficacy was tested in diabetic streptozotocin (STZ) and Akimba models and in the laser induced choroidal neovascularization (CNV) mouse model. Intravitreal (IVT) administration of the anti-PlGF antibody was compared to anti-VEGFR-2 antibody (DC101), anti-VEGF antibody (B20), VEGF-Trap (aflibercept) and triamcinolone acetonide (TAAC). Vascular leakage was investigated in the mouse STZ model by fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) perfusion and in the Akimba model by fluorescein angiography (FA). Repeated IVT administration of the anti-PlGF antibody reduced vascular leakage, which was comparable to a single administration of VEGFR-2 inhibition in the mouse STZ model. PL5D11D4 treatment did not alter retinal ganglion cell (RGC) density, as demonstrated by Brn3a staining, whereas DC101 significantly reduced RGC number with 20%. Immunohistological stainings were performed to investigate inflammation (CD45, F4/80) and fibrosis (collagen type 1a). In the CNV model, IVT injection(s) of PL5D11D4 dose-dependently reduced inflammation and fibrosis, as compared to PBS treatment. Equimolar single administration of the anti-PlGF antibody and aflibercept (21 nM) and TAAC decreased leukocyte and macrophage infiltration with 50%, whereas DC101 and B20 (21 nM) had no effect on the inflammatory response. Similar results were observed in the mouse STZ model on the number of microglia and macrophages in the retina. Repeated administration of PL5D11D4 (21 nM) and TAAC similarly reduced fibrosis, while no effect was observed after equimolar DC101, B20 nor aflibercept administration (21 nM). In summary, the anti-PlGF antibody showed comparable efficacy as well-characterized VEGF-inhibitor on the process of vascular leakage, but differentiates itself by also reducing inflammation and fibrosis, without triggering a neurodegenerative response.
A Review of Ranibizumab for the Treatment of Diabetic Retinopathy.
Stewart Michael W
Ophthalmology and therapy
INTRODUCTION:Laser photocoagulation has been the standard treatment for diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) for several decades. The discovery of vascular endothelial growth factor (VEGF) and the subsequent determination of its critical role in the development DME and PDR has led to the development of VEGF inhibitory drugs. Ranibizumab was the first anti-VEGF drug approved for the treatment of both DME and diabetic retinopathy in eyes with DME. METHODS:Medline searches with the keywords "ranibizumab," "diabetic macular edema," and "proliferative diabetic retinopathy" were performed to identify pertinent pre-clinical studies and clinical trials. Top-line data, with emphasis on pivotal trials, was identified and incorporated into this manuscript. Findings from small uncontrolled trials were generally not used unless they filled important gaps in our understanding of anti-VEGF therapy. RESULTS:Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF-A with high affinity. Three parallel lines of clinical research have produced level I evidence supporting the superiority of ranibizumab over laser photocoagulation for the treatment of DME. Regular injections also lead to improvement in diabetic retinopathy severity scores in a large minority of eyes. Ranibizumab is effective for PDR and produces less visual field loss than laser photocoagulation. It has an excellent safety profile, with low incidence of ocular and systemic adverse events. CONCLUSIONS:Ranibizumab has become a frequently used first-line therapy for the treatment of DME. Emerging data suggest that it may become an important treatment for DR and PDR.
PHOTOCOAGULATION VERSUS RANIBIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Should Baseline Characteristics Affect Choice of Treatment?
Bressler Susan B,Beaulieu Wesley T,Glassman Adam R,Gross Jeffrey G,Melia Michele,Chen Eric,Pavlica Michael R,Jampol Lee M,
Retina (Philadelphia, Pa.)
PURPOSE:Among eyes with proliferative diabetic retinopathy, identify whether baseline characteristics impact the benefit of ranibizumab over panretinal photocoagulation (PRP) in DRCR.net Protocol S. METHODS:Participants had proliferative diabetic retinopathy, visual acuity of 20/320 or better, and no previous PRP. Eyes were randomized to PRP or intravitreous 0.5-mg ranibizumab. RESULTS:Ranibizumab was superior to PRP for change in visual acuity and development of vision-impairing central-involved diabetic macular edema over 2 years (P < 0.001). Among 25 characteristics, there were none in which participants assigned to PRP had superior outcomes relative to ranibizumab-assigned participants. The relative benefit of ranibizumab over PRP for change in visual acuity seemed greater in participants with higher mean arterial pressure (P = 0.03), without previous focal/grid laser (P = 0.03), with neovascularization of the disk and elsewhere on clinical examination (P = 0.04), and with more advanced proliferative diabetic retinopathy on photographs (P = 0.02). For development of vision-impairing central-involved diabetic macular edema, the relative benefit of ranibizumab over PRP seemed greater among nonwhite participants (P = 0.01) and those with higher mean arterial pressure (P = 0.01). CONCLUSION:There were no characteristics identified in which outcomes were superior with PRP compared with ranibizumab. These exploratory analyses provide additional support that ranibizumab may be a reasonable alternative to PRP for proliferative diabetic retinopathy over a 2-year period.
Evaluation Of The Timing Of Intravitreal Bevacizumab Injection As Adjuvant Therapy To Panretinal Photocoagulation In Patients With Diabetic Macular Edema Secondary To Diabetic Retinopathy.
Kartasasmita Arief,Harley Ohisa
Clinical ophthalmology (Auckland, N.Z.)
Objective:To evaluate the difference in intravitreal bevacizumab (IVB) injection timing as adjuvant therapy to panretinal photocoagulation in patients with diabetic retinopathy combined with diabetic macular edema. Methods:This was a retrospective nonrandomized study. Forty eyes with severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) were divided into two groups; the IVB injection prior to, or after, panretinal photocoagulation. Changes in central macular thickness between the two groups were measured. Results:There was no significant difference in change in central macular thickness between two groups after treatment (=0.66), neither in eyes with severe NPDR groups (=0.48) nor eyes with PDR (=0.82). Conclusion:IVB injection after panretinal photocoagulation gives insignificant difference in changes in central macular thickness with injection prior to laser treatment in patients with diabetic retinopathy combined with diabetic macular edema.
Efficacy and safety of ranibizumab with or without panretinal laser photocoagulation versus laser photocoagulation alone in proliferative diabetic retinopathy - the PRIDE study.
Lang Gabriele E,Stahl Andreas,Voegeler Jessica,Quiering Claudia,Lorenz Katrin,Spital Georg,Liakopoulos Sandra
PURPOSE:Panretinal photocoagulation (PRP) is the current standard of care in proliferative diabetic retinopathy (PDR). However, treatment with anti-vascular endothelial growth factor agents might offer better patient outcomes with fewer side-effects. The PRIDE study aimed to assess the efficacy and safety of ranibizumab with or without PRP compared with PRP alone in patients with PDR. METHODS:A total of 106 PDR patients without diabetic macular oedema were randomized to receive ranibizumab 0.5 mg monotherapy (n = 35), PRP (n = 35) or combined ranibizumab 0.5 mg/PRP (n = 36). The primary objective of this 12-month, multicentre, phase II study was to investigate the change in area of retinal neovascularization (NV). Complete regression of leakage and best-corrected visual acuity (BCVA) were key secondary end-points. RESULTS:At Month 12, there was a statistically significant difference of -2.83 mm² in the least square mean change in NV area between the ranibizumab monotherapy and PRP group, favouring ranibizumab (95% CI [-5.45; -0.21], p = 0.0344). At Month 3, 67%/0%/67% of the patients in the ranibizumab/PRP/combination groups, respectively, showed complete regression of leakage from NVs, while at Month 12, 28%/8%/18% showed complete regression of leakage from NVs. BCVA change was greater in the ranibizumab group compared with the PRP monotherapy group at Month 12 (+1.6 letters; 95% CI [-2.3; 5.5] versus -3.9 letters; 95% CI [-7.8; -0.1], p = 0.0495). CONCLUSIONS:Ranibizumab monotherapy is an alternative treatment option to laser treatment in patients with PDR. Ranibizumab showed stronger effects on NV leakage and area reduction while offering better visual acuity results than PRP alone.
Vascular endothelial growth factor inhibition and proliferative diabetic retinopathy, a changing treatment paradigm?
Wu Lihteh,Acón Dhariana,Wu Andrés,Wu Max
Taiwan journal of ophthalmology
Prior to the development of panretinal photocoagulation (PRP) in the 1970s, proliferative diabetic retinopathy (PDR) was the most common cause of blindness in diabetic patients. The diabetic retinopathy study demonstrated that PRP could decrease severe visual loss from PDR by 50%. Since then and for the past four decades, PRP has been the treatment of choice for eyes with PDR. In the past decade, vascular endothelial growth factor (VEGF) inhibition has become the treatment of choice for diabetic macular edema (DME). When treated intensively with anti-VEGF drugs, about one-third of eyes with DME experience an improvement in their diabetic retinopathy severity scale. Randomized clinical trials comparing ranibizumab to PRP and aflibercept to PRP have shown that VEGF inhibitors cause regression of intraocular neovascularization but need to be given on a fairly regular basis. Despite these promising results, concerns about treatment adherence have surfaced. Patients with PDR that are treated solely with anti-VEGF drugs and somehow interrupt their treatment are at a high risk of developing irreversible blindness. Combination treatment of PRP plus an anti-VEGF drug may be the treatment of choice for PDR.
Effect of intravitreal triamcinolone acetonide injection at the end of vitrectomy for vitreous haemorrhage related to proliferative diabetic retinopathy.
Takamura Yoshihiro,Shimura Masahiko,Katome Takashi,Someya Hideaki,Sugimoto Masahiko,Hirano Takao,Sakamoto Taiji,Gozawa Makoto,Matsumura Takehiro,Inatani Masaru,
The British journal of ophthalmology
BACKGROUND/AIMS:To investigate whether intravitreal injection of triamcinolone acetonide (IVTA) combined with vitrectomy prevents postoperative inflammation in patients with vitreous haemorrhage (VH) due to proliferative diabetic retinopathy (PDR). METHODS:This prospective, multicentre, randomised study conducted at seven sites in Japan enrolled patients diagnosed as having VH following PDR. Patients underwent vitrectomy with (IVTA+VIT group) or without (VIT group) IVTA at the end of the surgery. Anterior flare intensity (AFI), central retinal thickness (CRT), best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were measured before and at 3 days, 1 week, 1, 3 and 6 months after surgery and compared. RESULTS:Number of patients who completed 6 months of follow-up was 40 and 41 in VIT group and IVTA+VIT group, respectively. AFI was significantly higher in the VIT group than in the IVTA+VIT group at 3 days (P=0.033), 1 week (P=0.019) and 1 month (P=0.037). There were no significant differences in CRT, BCVA and IOP between the groups through the observational periods. In the cases with macular oedema >350 µm of CRT at 3 days, CRT was significantly lower in the IVTA+VIT group than in the VIT group at 1 month (P=0.041). CONCLUSIONS:IVTA combined with vitrectomy and cataract surgery contributed to inhibit the postoperative inflammation in patients with VH due to PDR. The effect of IVTA in the reduction of diabetic macular oedema may be limited to the early stage after surgery. TRIAL REGISTRATION NUMBER:UMIN000020376, Post-results.
Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Patient-Centered Outcomes From a Randomized Clinical Trial.
Beaulieu Wesley T,Bressler Neil M,Melia Michele,Owsley Cynthia,Mein Calvin E,Gross Jeffrey G,Jampol Lee M,Glassman Adam R,
American journal of ophthalmology
PURPOSE:To compare patient-centered outcomes in patients with proliferative diabetic retinopathy (PDR) treated with ranibizumab vs panretinal photocoagulation (PRP). DESIGN:Randomized clinical trial. METHODS:Setting: Multicenter (55 U.S. sites). PATIENT POPULATION:Total of 216 adults with 1 study eye out of 305 adults (excluding participants with 2 study eyes, because each eye received a different treatment) with PDR, visual acuity 20/320 or better, no history of PRP. INTERVENTION:Ranibizumab (0.5 mg/0.05 mL) vs PRP. MAIN OUTCOME MEASURES:Change from baseline to 2 years in composite and prespecified subscale scores from the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), University of Alabama Low Luminance Questionnaire (UAB-LLQ), and Work Productivity and Activity Impairment Questionnaire (WPAIQ). RESULTS:For the NEI VFQ-25 and UAB-LLQ composite scores, ranibizumab-PRP treatment group differences (95% CI) were +4.0 (-0.2, +8.3, P = .06) and +1.8 (-3.5, +7.1, P = 0.51) at 1 year, and +2.9 (-1.5, +7.2, P = .20) and +2.3 (-2.9, +7.5, P = .37) at 2 years, respectively. Work productivity loss measured with the WPAIQ was 15.6% less with ranibizumab (-26.3%, -4.8%, P = .005) at 1 year and 2.9% (-12.2%, +6.4%, P = .54) at 2 years. Eighty-three ranibizumab participants (97%) were 20/40 or better in at least 1 eye (visual acuity requirement to qualify for an unrestricted driver's license in many states) at 2 years compared with 82 PRP participants (87%, adjusted risk ratio = 1.1, 95% CI: 1.0, 1.2, P = .005). CONCLUSIONS:Though differences in some work productivity and driving-related outcomes favored ranibizumab over PRP, no differences between treatment regimens for PDR were identified for most of the other patient-centered outcomes considered.
Evaluation of Intravitreal Ranibizumab on the Surgical Outcome for Diabetic Retinopathy With Tractional Retinal Detachment.
Dong Feng,Yu Chenying,Ding Haiyuan,Shen Liping,Lou Dinghua
This study aims to investigate intravitreal injection of Ranibizumab on the surgical outcome for diabetic patients who had tractional retinal detachment but did not receive any preoperative retinal photocoagulation.Ninety-seven patients (97 eyes) who had diabetic retinopathy with tractional retinal detachment were enrolled to receive 23-G pars plana vitrectomy (PPV). They were assigned to an experimental group (Group I, n = 47 eyes) and a control group (Group II, n = 50 eyes). The patients in Group I were given 1 injection of intravitreal Ranibizumab (Lucentis 0.5 mg/0.05 mL) 1 week before surgery, whereas those in Group II went down to surgery directly. Follow-ups were performed for 6 months to 3 years (16 ± 6 months), and indicators observed included postoperative best-corrected visual acuity, complications, and retinal thickness in the macula measured by optical coherence tomography.In Group I, BCVA improved from logMAR 1.92 ± 0.49 to logMAR 0.81 ± 0.39 following surgery, whereas in Group II, BCVA improved from logMAR 1.91 ± 0.49 to logMAR 0.85 ± 0.41. There was significant postoperative gain in vision, but there was no significant difference between the 2 groups at postoperative follow-up visits. The mean duration of vitrectomy in Group I and Group II was (40 ± 7) minutes and (53 ± 9) minutes, respectively, with significant difference. Iatrogenic breaks were noted in 5 eyes (11%) in the experimental group and 17 eyes (34%) in the control group; the difference was significant. The retinal thickness in the macula measured by OCT was (256 ± 44) μm and (299 ± 84) μm in Group I and Group II respectively with significant difference. Besides, there were significantly more eyes in Group II that required silicone oil tamponade and postoperative retinal photocoagulation.23-G PPV combined with intravitreal tamponade and panretinal photocoagulation still remains an effective regimen for the treatment of diabetic retinopathy complicated with tractional retinal detachment. Preoperative intravitreal injection of Ranibizumab could shorten surgical duration, reduce intraoperative complications, and sometimes spare the need for silicone oil tamponade and postoperative retinal photocoagulation, alleviating patients' suffering from surgery.
Choroidal thickness in diabetic retinopathy: the influence of antiangiogenic therapy.
Laíns Inês,Figueira João,Santos Ana Rita,Baltar Alda,Costa Miguel,Nunes Sandrina,Farinha Cláudia,Pinto Rita,Henriques José,Silva Rufino
Retina (Philadelphia, Pa.)
PURPOSE:To analyze the effect of anti-vascular endothelial growth factor agents (anti-VEGF) in submacular choroidal thickness (CT) of diabetic retinopathy (DR) patients. METHODS:Cross-sectional study, which included 25 DR patients (50 eyes) divided in 2 groups, according to DR stage and previous treatments: nonproliferative DR and diffuse diabetic macular edema in both eyes, submitted to macular laser in both eyes and anti-VEGF injection only in 1 eye (nonproliferative diabetic retinopathy + diabetic macular edema group, n = 11); and proliferative DR in both eyes, treated with panretinal photocoagulation in both eyes and anti-VEGF injection only in 1 eye (proliferative diabetic retinopathy group, n = 14). In the study visit, all patients underwent optical coherence tomography with enhanced depth imaging protocol. Choroidal segmentation was performed manually. The medium CT in central macular area (CCT) and the CT in centrofoveal B-scan were obtained automatically. RESULTS:The 25 eyes treated with anti-VEGF showed a reduction on CCT (P = 0.002) and subfoveal CT (P = 0.004), compared with the fellow eyes treated with laser only. Independent evaluation of PDR group revealed similar results (CCT, P = 0.02; subfoveal CT, P = 0.03). In nonproliferative diabetic retinopathy + diabetic macular edema group, CCT was also significantly thinner in eyes treated with anti-VEGF (P = 0.04). A correlation between the number of injections and a thinner CT was found in this group (P = 0.03) and in the evaluation of all eyes together (P = 0.03). CONCLUSION:Diabetic eyes treated with anti-VEGF agents have reduced CT.
Placental growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases.
Nguyen Quan Dong,De Falco Sandro,Behar-Cohen Francine,Lam Wai-Ching,Li Xuri,Reichhart Nadine,Ricci Federico,Pluim Jennifer,Li William W
The role of vascular endothelial growth factor (VEGF), including in retinal vascular diseases, has been well studied, and pharmacological blockade of VEGF is the gold standard of treatment for neovascular age-related macular degeneration, retinal vein occlusion and diabetic macular oedema. Placental growth factor (PGF, previously known as PlGF), a homologue of VEGF, is a multifunctional peptide associated with angiogenesis-dependent pathologies in the eye and non-ocular conditions. Animal studies using genetic modification and pharmacological treatment have demonstrated a mechanistic role for PGF in pathological angiogenesis. Inhibition decreases neovascularization and microvascular abnormalities across different models, including oxygen-induced retinopathy, laser-induced choroidal neovascularization and in diabetic mice exhibiting retinopathies. High levels of PGF have been found in the vitreous of patients with diabetic retinopathy. Despite these strong animal data, the exact role of PGF in pathological angiogenesis in retinal vascular diseases remains to be defined, and the benefits of PGF-specific inhibition in humans with retinal neovascular diseases and macular oedema remain controversial. Comparative effectiveness research studies in patients with diabetic retinal disease have shown that treatment that inhibits both VEGF and PGF may provide superior outcomes in certain patients compared with treatment that inhibits only VEGF. This review summarizes current knowledge of PGF, including its relationship to VEGF and its role in pathological angiogenesis in retinal diseases, and identifies some key unanswered questions about PGF that can serve as a pathway for future basic, translational and clinical research.
Diabetic retinopathy: intravitreal vascular endothelial growth factor inhibitors for diabetic macular oedema.
Mohamed Quresh Amir,Fletcher Emily C,Buckle Miranda
BMJ clinical evidence
INTRODUCTION:Diabetic retinopathy is the most common microvascular complication of diabetes. It is also the most common cause of blindness in working-age adults in industrialised nations. Older people and those with worse diabetes control, hypertension, and hyperlipidaemia are most at risk. Diabetic macular oedema, which can occur at any stage of diabetic retinopathy, is related to increased vascular permeability and breakdown of the blood retinal barrier, in part related to increased vascular endothelial growth factor (VEGF) levels. About 1% to 3% of people with diabetes suffer vision loss because of diabetic macular oedema. METHODS AND OUTCOMES:We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of intravitreal VEGF inhibitors versus each other for diabetic macular oedema? What are the effects of intravitreal VEGF inhibitors plus laser therapy versus intravitreal VEGF inhibitors alone for diabetic macular oedema? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS:At this update, searching of electronic databases retrieved 240 studies. After deduplication and removal of conference abstracts, 149 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 90 studies and the further review of 59 full publications. Of the 59 full articles evaluated, eight systematic reviews and four RCTs were added at this update. We performed a GRADE evaluation for four PICO combinations. CONCLUSIONS:In this systematic overview, we categorised the efficacy for six comparisons based on information about the effectiveness and safety of intravitreal VEGF inhibitors aflibercept, bevacizumab, and ranibizumab, and each of these intravitreal VEGF inhibitors plus laser therapy.
A Case of Diabetic Macular Edema with Improvement in Severity of Diabetic Retinopathy following Frequent Anti-Vascular Endothelial Growth Factor Treatment.
Yoshida Shigeo,Yamana Satoshi,Inoue Rumi,Kubo Yuki,Kobayashi Yoshiyuki,Nakama Takahito,Sonoda Koh-Hei,Ishibashi Tatsuro
Nippon Ganka Gakkai zasshi
Background: Intravitreal anti-vascular endothelial growth factor (VEGF) drug injections are the gold standard for the treatment of diabetic macular edema (DME). We report a case of DME in which frequent anti-VEGF treatment resulted in improvement of diabetic retinopathy.Case: A 73-year old woman with DME who had previously undergone bilateral posterior subtenon injections of triamcinolone acetonide and vitrectomy OD presented at Kyushu University Hospital. Best corrected visual acuity was 0.1 OD and 0.15 OS. The central macular thickness was 1570 μm OD and 578 μm OS. We performed focal macular laser photocoagulation OU but the DME was not resolved. Subsequent intravitreal anti-VEGF drug injections(approximately 20 times/2 years)resulted in an improvement of the best corrected visual acuity (0.3 OD, 0.6 OS) and CMT (1570 μm OD, 578 μm OS). There was an improvement of 2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score OU.Conclusion: Frequent anti-VEGF treatment can improve the severity of diabetic retinopathy.
[The rational use of anti-vascular endothelial growth factor drugs to assist the treatment of diabetic retinopathy].
Zhao M W,Sun Y Y,Xu X
[Zhonghua yan ke za zhi] Chinese journal of ophthalmology
Diabetic retinopathy (DR) is one of the most important etiologies of diabetic blindness. The vascular endothelial growth factor (VEGF) is thought to mediate pathophysiological changes of DR. Anti-VEGF therapy for DRdevelops rapidly. However, there are some misunderstandings about its clinical application, and the strategy is not clear. Sometimes its therapeutic effects are even exaggerated. In this article, by discussing whether anti-VEGF therapy can reverse the course of DR disease, promote the absorption of vitreous hemorrhage, and replace fundus laser therapy, the application strategy of anti-VEGF therapy for DR is proposed. At present, anti-VEGF therapy cannot completely replace retinal photocoagulation therapy, and its clinical application value should not be exaggerated. More innovative drugs and therapies are expected to provide new ways forthe treatment of DR while preserving visual function. .
Recent clinically relevant highlights from the Diabetic Retinopathy Clinical Research Network.
Krick Tracy W,Bressler Neil M
Current opinion in ophthalmology
PURPOSE OF REVIEW:To present some recent clinically relevant results from Diabetic Retinopathy Clinical Research (DRCR) Network trials that may guide management of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR). RECENT FINDINGS:Among eyes with DME and visual acuity 20/50 or worse, aflibercept, on average, had greater improvement in visual acuity over 2 years compared with bevacizumab or ranibizumab. Aflibercept is associated with higher rates of improvements in diabetic retinopathy severity among eyes with PDR and vision-impairing DME at baseline compared with bevacizumab or ranibizumab. Among eyes with persistent central-involved DME after at least six antivascular endothelial growth factor (anti-VEGF) injections, no difference in mean visual acuity improvement was observed between eyes that received continued ranibizumab and sham injections versus ranibizumab and intravitreous sustained dexamethasone drug-delivery system, especially for phakic eyes. For eyes with PDR, ranibizumab was associated with lower rates of developing PDR-worsening events compared with panretinal photocoagulation, especially among eyes that did not receive ranibizumab for central-involved DME at baseline. Ranibizumab is cost-effective for PDR for eyes with, not without, vision-impairing central-involved DME, highlighting challenges when safety and efficacy results are at odds with cost-effectiveness results. SUMMARY:Aflibercept for DME, in certain circumstances, is more likely to have superior visual acuity and anatomical outcomes compared with bevacizumab or ranibizumab. No vision benefits are apparent, especially for phakic eyes, by adding intravitreous corticosteroids for persistent DME following anti-VEGF injections.
Anti-VEGF Therapy for Persistent Neovascularization after Complete Panretinal Photocoagulation in Proliferative Diabetic Retinopathy.
Mehanna Carl-Joe,Abdul Fattah Maamoun,Haddad Sandra,Tamim Hani,Ghazi Nicola,Salti Haytham
PURPOSE:To report the rate of new vessel (NV) regression after monthly injections of bevacizumab in laser-treated proliferative diabetic retinopathy (PDR) eyes with persistent neovascularization. DESIGN:Prospective cohort study. PARTICIPANTS:Eyes with PDR with incomplete response to prior complete panretinal photocoagulation (PRP). METHODS:Ninety eyes of 80 patients with persistent PDR (pPDR) despite adequate PRP were prospectively followed on a monthly basis with anti-vascular endothelial growth factor (VEGF) injections when needed and stereo fundus images looking at the regression of NVs. MAIN OUTCOME MEASURES:Regression of NVs. RESULTS:A total of 70 of 90 eyes (77.8%) had regression of the NV. Mean number of injections to reach quiescence was 9±3 for pPDR in the high-risk characteristics (HRC) group (80 eyes) and 3±1 for PDR in the group without HRC (10 eyes) (P < 0.001). All patients with PDR without HRC responded to the adjuvant therapy, whereas 75.0% of the eyes with PDR with HRC responded. Eyes with initial retinal neovascularization all responded to the adjuvant treatment. Eyes without a vitreous hemorrhage at study entry were more likely to respond (odds ratio, 5.43; 95% confidence interval, 1.37-21.44; P < 0.01). Therapy was judged unsuccessful because of the continuous growth of the NV despite treatment (3 eyes), the development of traction (5 eyes), and the development of a dense vitreous hemorrhage (6 eyes). CONCLUSIONS:Anti-VEGF rescue therapy has a potential role in select cases of laser-treated PDR with persistent NVs and no evidence of traction to achieve regression of neovessels.
Gene therapy for diabetic retinopathy: Are we ready to make the leap from bench to bedside?
Wang Jiang-Hui,Ling Damien,Tu Leilei,van Wijngaarden Peter,Dusting Gregory J,Liu Guei-Sheung
Pharmacology & therapeutics
Diabetic retinopathy (DR), a chronic and progressive complication of diabetes mellitus, is a sight-threatening disease characterized in the early stages by neuronal and vascular dysfunction in the retina, and later by neovascularization that further damages vision. A major contributor to the pathology is excess production of vascular endothelial growth factor (VEGF), a growth factor that induces formation of new blood vessels and increases permeability of existing vessels. Despite the recent availability of effective treatments for the disease, including laser photocoagulation and therapeutic VEGF antibodies, DR remains a significant cause of vision loss worldwide. Existing anti-VEGF agents, though generally effective, are limited by their short therapeutic half-lives, necessitating frequent intravitreal injections and the risk of attendant adverse events. Management of DR with gene therapies has been proposed for several years, and pre-clinical studies have yielded enticing findings. Gene therapy holds several advantages over conventional treatments for DR, such as a longer duration of therapeutic effect, simpler administration, the ability to intervene at an earlier stage of the disease, and potentially fewer side-effects. In this review, we summarize the current understanding of the pathophysiology of DR and provide an overview of research into DR gene therapies. We also examine current barriers to the clinical application of gene therapy for DR and evaluate future prospects for this approach.
New treatments for diabetic retinopathy.
Das A,Stroud S,Mehta A,Rangasamy S
Diabetes, obesity & metabolism
Diabetic retinopathy is the major cause of vision loss in middle-aged adults. Alteration of the blood-retinal barrier (BRB) is the hallmark of diabetic retinopathy and, subsequently, hypoxia may result in retinal neovascularization. Tight control of systemic factors such as blood glucose, blood pressure and blood lipids is essential in the management of this disease. Vascular endothelial growth factor (VEGF) is one of the most important factors responsible for alteration of the BRB. The introduction of anti-VEGF agents has revolutionized the therapeutic strategies used in people with diabetic retinopathy, and the use of laser therapy has been modified. In the present article, we examine the clinical features and pathophysiology of diabetic retinopathy and review the current status of new treatment recommendations for this disease, and also explore some possible future therapies.
Significance of the antiangiogenic mechanisms of thalidomide in the therapy of diabetic retinopathy.
Behl Tapan,Kaur Ishneet,Goel Heena,Kotwani Anita
Diabetic retinopathy is an ocular complication associated with the chronic endocrine disorder of diabetes mellitus. Angiogenesis is adjudged as a prime modulatory event in this complication. The formation of new blood vessels on the pre-existing vasculature gives rise to an abundance of anatomical and physiological alterations which ultimately results in vision loss. The drastic consequences of this complication prompt the obligation of developing effective therapies for its cure. The existing therapy mainly includes destructive techniques such as laser photocoagulation. Owing to the various drawbacks associated with this technique, there is a need to develop alternative therapies which could halt the progression of diabetic retinopathy without causing considerable damage to the retinal cells. One such possible alternative treatment being researched upon is the antiangiogenic therapy. Since angiogenesis is a critical event during the progression of this disorder, targeting this event may perhaps prove effective in its treatment. Amongst several antiangiogenic agents, thalidomide holds a reputable position due to its effectiveness in terminating angiogenesis during various pathological conditions. This review focuses on the diverse molecular mechanisms proposed to explain the antiangiogenic properties of thalidomide and their applicability in diabetic retinopathy.
Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).
Figueira João,Fletcher Emily,Massin Pascale,Silva Rufino,Bandello Francesco,Midena Edoardo,Varano Monica,Sivaprasad Sobha,Eleftheriadis Haralabos,Menon Geeta,Amaro Miguel,Ayello Scheer Sarah,Creuzot-Garcher Catherine,Nascimento João,Alves Dalila,Nunes Sandrina,Lobo Conceição,Cunha-Vaz José,
PURPOSE:Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN:Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS:Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS:Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES:The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS:Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS:Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.
Recent advancements in diabetic retinopathy treatment from the Diabetic Retinopathy Clinical Research Network.
Baker Carl W,Jiang Yi,Stone Thomas
Current opinion in ophthalmology
PURPOSE OF REVIEW:Diabetic retinopathy and diabetic macular edema (DME) are common eye diseases leading to vision loss. The Diabetic Retinopathy Clinical Research Network (DRCRnet), a collaboration of private and academic practices supported by the National Eye Institute and the National Institute of Diabetes, Digestive and Kidney Diseases has studied diabetic eye disease for 13 years. This review will discuss the network's findings over the last year, when some of its most important contributions were reported. RECENT FINDINGS:The DRCRnet reported intravitreal bevacizumab, ranibizumab and aflibercept all improve visual acuity in DME. With baseline vision of 20/30 to 20/40, all agents had similar efficacy. With baseline vision of 20/50 or worse, aflibercept resulted in superior visual improvement. Protocol S, which compared panretinal photocoagulation with intravitreal injections of ranibizumab for proliferative diabetic retinopathy (PDR), found vision outcomes and surgery rates were not inferior in the injection group. Secondary outcomes indicate improved functional results with ranibizumab supporting injections as a possible alternative treatment for PDR. SUMMARY:The DRCRnet has helped clarify the role of various treatments for both DME and PDR, and will continue to evaluate treatments for these vision-threatening conditions.
Cost Evaluation of Early Vitrectomy versus Panretinal Photocoagulation and Intravitreal Ranibizumab for Proliferative Diabetic Retinopathy.
Lin James,Chang Jonathan S,Yannuzzi Nicolas A,Smiddy William E
PURPOSE:To evaluate costs and cost-utility of early vitrectomy (pars plana vitrectomy [PPV]) compared with panretinal photocoagulation (PRP) and intravitreal ranibizumab (IVR) for proliferative diabetic retinopathy (PDR) without diabetic macular edema. DESIGN:A decision analysis model of cost-utility. PARTICIPANTS:There were no participants. METHODS:A decision analysis was based on results from the Diabetic Retinopathy Clinical Research Network Protocol S comparing treatment of PRP with IVR (0.3 mg) in PDR without incident macular edema to model the total 2-year costs and outcomes for each treatment scenario. These values were compared with the 2-year hypothetical costs of early PPV for PDR. Centers for Medicare and Medicaid Services data were used to calculate associated modeled costs in a hospital/facility-based and nonfacility setting. Cost-utility was calculated on the basis of the preserved visual utility and estimated life years remaining. In addition, costs for lifetime treatment were modeled for all scenarios and used to calculate lifetime quality-adjusted life years (QALY) costs for each scenario. Sensitivity analyses were performed to evaluate the impact of the model's assumptions. MAIN OUTCOME MEASURES:Cost of treatment, utility, and cost per QALY. RESULTS:The modeled cost per QALY of treatment for PDR for 2 years of utility in the facility (nonfacility) setting was $163 988 ($102 559) in the PRP group, $436 992 ($326 424) in the IVR group, and $181 144 ($107 965) in the PPV group. Sensitivity analysis showed that both IVR and PPV groups would have equivalent costs per QALY over the first 2 years if 78% (facility) and 80% (nonfacility) of patients in the PPV group required additional treatment with IVR (at the dose of 10.1 injections as in Protocol S). Beyond 2 years, the cost per QALY in the facility (nonfacility) setting was calculated as $61 695 ($21 752) in the PRP group, $338 348 ($239 741) in the IVR group, and $63 942 ($22 261) in the PPV group. CONCLUSIONS:Early PPV as a strategy for treatment of PDR without macular edema demonstrates cost-utility similar to management with PRP and more favorable cost-utility compared with IVR in the short term. This advantage over IVR continues when lifetime costs are factored.
Outcomes of Eyes Lost to Follow-up with Proliferative Diabetic Retinopathy That Received Panretinal Photocoagulation versus Intravitreal Anti-Vascular Endothelial Growth Factor.
Obeid Anthony,Su Daniel,Patel Samir N,Uhr Joshua H,Borkar Durga,Gao Xinxiao,Fineman Mitchell S,Regillo Carl D,Maguire Joseph I,Garg Sunir J,Hsu Jason
PURPOSE:To compare anatomic and functional outcomes in eyes with proliferative diabetic retinopathy (PDR) that were lost to follow-up (LTFU) for more than 6 months after treatment with either intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) agents or panretinal photocoagulation (PRP). DESIGN:Retrospective cohort study. PARTICIPANTS:Fifty-nine patients who were LTFU immediately after treatment for more than 6 months between September 2013 and September 2016. METHODS:Patients with eyes receiving either intravitreal anti-VEGF treatment or PRP with the next follow-up visit occurring more than 6 months after treatment were identified. Visual acuity (VA) and anatomic outcomes at the visit before being LTFU, the return visit, the 6-month visit after return, the 12-month visit after return, and the final visit were gathered and compared between the 2 treatment groups. MAIN OUTCOMES MEASURES:Visual acuity and anatomic outcomes. RESULTS:Seventy-six eyes of 59 patients were included in the study, of which 30 received IVI with anti-VEGF and 46 received PRP. In the anti-VEGF group, mean VA worsened significantly when comparing the visit before being LTFU (0.43±0.38 logarithm of the minimum angle of resolution [logMAR]) with the return visit (0.97±0.80 logMAR; P = 0.001) as well as with the final visit (0.92±0.94 logMAR; P = 0.01). In the PRP group, mean VA worsened significantly when comparing the visit before being LTFU (0.42±0.34 logMAR) with the return visit (0.62±0.64 logMAR; P = 0.03). However, no significant difference was observed at the final visit (0.46±0.47 logMAR; P = 0.38). There was a significantly greater number of eyes with tractional retinal detachment in the IVI group compared with the PRP group at the final visit (10 vs. 1, respectively; P = 0.005). There was a significantly greater incidence of neovascularization of the iris in the IVI arm compared with the PRP arm at the final visit (4 vs. 0, respectively; P = 0.02). CONCLUSIONS:Eyes with PDR that received only intravitreal anti-VEGF demonstrated worse anatomic and functional outcomes after being LTFU compared with eyes that received PRP. Given the potential sequelae of being LTFU, the choice of treatment for PDR must be considered carefully.
Fukushima Harumi,Kato Satoshi
Nihon rinsho. Japanese journal of clinical medicine
Diabetic retinopathy is a major cause of vision loss in Japan. Recent progress in the treatments of diabetic retinopathy includes the use of pattern scan laser photocoagulation, subthreshold micropulse laser photocoagulation, and micro incision vitreous surgery with chandelier illumination and wide-angle viewing system. The use of triamcinolone, indocyanine green or brilliant blue G, which are used to visualize the vitreous and the internal limiting membrane, respectively, has greatly facilitated vitreous surgery. As for intraocular drug therapy, antivascular endothelial growth factor agents are now available for diabetic retinopathy, useful not only for treating diabetic macular edema, but also for controlling bleeding during vitreous surgery and for temporarily suppressing the symptoms of proliferative diabetic retinopathy.
Ranibizumab for High-Risk Proliferative Diabetic Retinopathy: An Exploratory Randomized Controlled Trial.
Figueira João,Silva Rufino,Henriques José,Caldeira Rosa Paulo,Laíns Inês,Melo Pedro,Gonçalves Nunes Sandrina,Cunha-Vaz José
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde
PURPOSE:To compare the efficacy and safety of intravitreal ranibizumab (IVR) in monotherapy or associated with panretinal photocoagulation (PRP) versus conventional PRP, for high-risk proliferative diabetic retinopathy (PDR) without vitreoretinal traction. PROCEDURES:Multicenter randomized trial, with 3 treatment arms: PRP versus IVR alone and PRP + IVR combined treatment. Follow-up was performed at months 3, 6 and 12. RESULTS:Thirty-five subjects were randomized and 32 used for analysis. Complete regression of neovessels elsewhere occurred in 100% (PRP + IVR), 75% (IVR) and 69.2% (PRP) and for neovessels of the disk in 44.4% (PRP + IVR), 37.5% (IVR) and 30.8% (PRP). During the 1-year duration of treatment, there was no need for laser rescue treatment in IVR-treated eyes. CONCLUSIONS:This trial suggests that the use of IVR is safe and may have a beneficial effect in the treatment of eyes with high-risk PDR. MESSAGE:Ranibizumab appears to have a place in the treatment of PDR.
Impact of baseline Diabetic Retinopathy Severity Scale scores on visual outcomes in the VIVID-DME and VISTA-DME studies.
Staurenghi Giovanni,Feltgen Nicolas,Arnold Jennifer J,Katz Todd A,Metzig Carola,Lu Chengxing,Holz Frank G,
The British journal of ophthalmology
BACKGROUND/AIMS:To evaluate intravitreal aflibercept versus laser in subgroups of patients with baseline Diabetic Retinopathy Severity Scale (DRSS) scores ≤43, 47, and ≥53 in VIVID-DME and VISTA-DME. METHODS:Patients with diabetic macular oedema were randomised to receive intravitreal aflibercept 2 mg every 4 weeks (2q4), intravitreal aflibercept 2 mg every 8 weeks after five initial monthly doses (2q8), or macular laser photocoagulation at baseline with sham injections at every visit. These post hoc analyses evaluate outcomes based on baseline DRSS scores in patients in the integrated dataset. The 2q4 and 2q8 treatment groups were also pooled. RESULTS:748 patients had a baseline DRSS score based on fundus photographs (≤43, n=301; 47, n=153; ≥53, n=294). At week 100, the least squares mean difference between treatment groups (effect of intravitreal aflibercept above that of laser, adjusting for baseline best-corrected visual acuity) was 8.9 (95% CI 5.99 to 11.81), 9.7 (95% CI 5.54 to 13.91), and 11.0 (95% CI 7.96 to 14.1) letters in those with baseline DRSS scores ≤43, 47, and ≥53, respectively. The proportions of patients with ≥2 step DRSS score improvement were greater in the intravitreal aflibercept group versus laser, respectively, for those with baseline DRSS scores of ≤43 (13% vs 5.9%), 47 (25.8% vs 4.5%), and ≥53 (64.5% vs 28.4%). CONCLUSIONS:Regardless of baseline DRSS score, functional outcomes were superior in intravitreal aflibercept-treated patients, demonstrating consistent treatment benefit across various baseline levels of retinopathy. TRIAL REGISTRATION NUMBERS:NCT01331681 and NCT01363440, Post-results.
Mechanistic Evaluation of Panretinal Photocoagulation Versus Aflibercept in Proliferative Diabetic Retinopathy: CLARITY Substudy.
Nicholson Luke,Crosby-Nwaobi Roxanne,Vasconcelos Joana C,Prevost A Toby,Ramu Jayashree,Riddell Amy,Bainbridge James W,Hykin Philip G,Sivaprasad Sobha
Investigative ophthalmology & visual science
Purpose:The purpose of this study was to study the effects of panretinal photocoagulation (PRP) and intravitreal aflibercept on retinal vessel oxygen saturations, area of retinal nonperfusion, and area of neovascularization in proliferative diabetic retinopathy. Methods:This is a prospective randomized single center study. Forty patients with proliferative diabetic retinopathy were randomized to PRP or intravitreal aflibercept treatment for 52 weeks. Retinal oximetry and ultra-widefield angiography were performed at baseline and week 52. Ultra-widefield color fundus imaging was performed at baseline, week 12, and week 52. The outcomes were retinal arterio-venous oximetry differences (AVD), area of retinal nonperfusion, and area of neovascularization in disc areas (DA). Results:The AVD in the PRP group increased from 36.7% at baseline to 39.7%, whereas it decreased from 33.4% to 32.5% in the aflibercept group. The difference in AVD between groups at week 52 was 4.0% (95% confidence interval, -0.08, 8.8; P = 0.10). The baseline mean area of retinal nonperfusion of 125.1 DA and 131.2 DA in the PRP and aflibercept groups increased to 156.1 DA and 158.4 DA, respectively, at week 52 (P = 0.46). The median baseline area of neovascularization decreased from 0.98 DA to 0.68 DA in the PRP group and from 0.70 DA to 0 DA in the aflibercept group at week 12 (P = 0.019). At week 52, this measured 0.24 DA in the PRP group and 0 DA in the aflibercept group (P = 0.45). Conclusions:Intravitreal aflibercept achieved an earlier and complete regression of neovascularization in proliferative diabetic retinopathy compared with PRP. There were no significant differences in global change in intravascular oxygen saturation or areas of retinal nonperfusion between the two groups by 52 weeks.
Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy.
Dhoot Dilsher S,Avery Robert L
Current diabetes reports
The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser.
CHOROIDAL THICKNESS CHANGES IN PROLIFERATIVE DIABETIC RETINOPATHY TREATED WITH PANRETINAL PHOTOCOAGULATION VERSUS PANRETINAL PHOTOCOAGULATION WITH INTRAVITREAL BEVACIZUMAB.
Roohipoor Ramak,Sharifian Elaheh,Ghassemi Fariba,Riazi-Esfahani Mohammad,Karkhaneh Reza,Fard Masoud Aghsaei,Zarei Mohammad,Modjtahedi Bobeck S,Moghimi Sasan
Retina (Philadelphia, Pa.)
PURPOSE:To compare choroidal thickness (CT) and retinal thickness (RT) between eyes with proliferative diabetic retinopathy treated with panretinal photocoagulation (PRP) or PRP with intravitreal bevacizumab (PRP + IVB). METHODS:Thirty-three patients with proliferative diabetic retinopathy were randomized to have one eye treated with PRP and the other with PRP + IVB. Change in CT was compared with baseline using enhanced depth imaging-optical coherence tomography at baseline and Months 1, 3, 6, and 10 after treatment. Change in RT was similarly assessed using spectral domain optical coherence tomography. Changes in both CT and RT were assessed in all nine macular areas as defined by Early Treatment Diabetic Retinopathy Study subfields. RESULTS:The PRP + IVB group had a significant decrease in subfoveal CT at 3 and 10 months (323.9 ± 62 μm at baseline vs. 320.7 ± 64.8 μm at Month 3 [P = 0.024] and 304.7 ± 65.6 μm at Month 10 [P = 0.003]). Subfoveal CT significantly decreased at 10 months compared with baseline in the PRP group (320.8 ± 57.7 at baseline to 297 ± 66.3 μm at 10 months, P = 0.01). Subfoveal CT was not significantly different between the 2 groups at 10 months. The best-corrected visual acuity did not change after treatment in the two groups, and there was no correlation between BCVA and CT changes (r = 0.222, P = 0.37 in the PRP group and r = 0.387, P = 0.12 in the PRP + IVB group). Significant increases in RT were seen in the PRP + IVB group at 6 months and in the PRP group at Months 1, 3, 6, and 10. A correlation between changes in CT and RT was only seen in the PRP group at 10 months after treatment. CONCLUSION:Eyes with proliferative diabetic retinopathy treated with PRP + IVB and PRP both had significant reduction in CT at 10 months; however, the eyes that were also treated with IVB also underwent an earlier but transient reduction at 3 months. Patients treated with IVB underwent less increase in RT.
Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial.
Bressler Susan B,Qin Haijing,Melia Michele,Bressler Neil M,Beck Roy W,Chan Clement K,Grover Sandeep,Miller David G,
IMPORTANCE:The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation, an inherently destructive treatment that can cause iatrogenic vision loss. Therefore, evaluating the effects of therapies for diabetic macular edema on development or worsening of PDR might lead to new therapies for PDR. OBJECTIVE:To evaluate the effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat diabetic macular edema, on worsening of diabetic retinopathy. DESIGN:Exploratory analysis was performed on worsening of retinopathy, defined as 1 or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having panretinal photocoagulation, (4) experiencing vitreous hemorrhage, or (5) undergoing vitrectomy for the treatment of PDR. SETTING:Community- and university-based ophthalmology practices. PARTICIPANTS:Individuals with central-involved diabetic macular edema causing visual acuity impairment. INTERVENTIONS:Eyes were assigned randomly to sham with prompt focal/grid laser, 0.5 mg of intravitreal ranibizumab with prompt or deferred (≥24 weeks) laser, or 4 mg of intravitreal triamcinolone acetonide with prompt laser. MAIN OUTCOMES AND MEASURES:Three-year cumulative probabilities for retinopathy worsening. RESULTS:For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham with prompt laser) were 23% using sham with prompt laser, 18% with ranibizumab with prompt laser (P = .25), 7% with ranibizumab with deferred laser (P = .001), and 37% with triamcinolone with prompt laser (P = .10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = .05), 18% (P = .02), and 12% (P < .001), respectively. CONCLUSIONS AND RELEVANCE Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and the fact that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time.
[Intravitreal triamcinolone combined with grid laser photocoagulation for patients with cystoid macular edema and advanced diabetic retinopathy: pilot study].
Arévalo J F,Fernández C F,Mendoza A J,García R A,Arévalo F A
Archivos de la Sociedad Espanola de Oftalmologia
BACKGROUND:To determine if primary intravitreal injection of triamcinolone acetonide (TA) plus grid laser photocoagulation (GLP) is effective in treating cystoid diabetic macular edema (DME). METHODS:Prospective comparative non-randomized clinical trial. Fourteen eyes (14 patients) diagnosed with cystoid DME were treated with GLP according to the Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines, plus an intravitreal injection of 4 mg of TA. A matched control group (16 eyes [16 patients]) treated with GLP was selected retrospectively from our medical records. Best-corrected visual acuity (BCVA), and quantitative change in optical coherence tomography (OCT) macular thickness were assessed. RESULTS:Mean follow up was 14.9 months (12 to 19 months). In 3 (21.4%) eyes BCVA increased > 2 ETDRS lines, in 5 (35.7%) eyes BCVA remained the same, and BCVA decreased >2 ETDRS lines in 6 (42.8%) eyes. Central macular thickness, as measured by OCT, decreased a mean of 106.2 μm (30.2%). The difference with the control group was not statistically significant (P = .2). Four (28.5%) eyes developed an increased in intraocular pressure in our study group. CONCLUSIONS:Although all of our patients showed an improvement of cystoid DME by means of OCT and fluorescein angiography, 42.8% (6 eyes) lost 2 or more lines in BCVA with primary intravitreal injection of TA plus GLP. Primary intravitreal injection of TA plus GLP may not be effective for cystoid DME at 12-months.
Factors Associated with Worsening Proliferative Diabetic Retinopathy in Eyes Treated with Panretinal Photocoagulation or Ranibizumab.
Bressler Susan B,Beaulieu Wesley T,Glassman Adam R,Gross Jeffrey G,Jampol Lee M,Melia Michele,Peters Mark A,Rauser Michael E,
PURPOSE:To compare rates and identify predictive factors for events that represent worsening of proliferative diabetic retinopathy (PDR) in eyes treated with panretinal photocoagulation (PRP) or ranibizumab. DESIGN:Randomized clinical trial (55 United States sites). PARTICIPANTS:Three hundred ninety-four study eyes from 305 adults with PDR, visual acuity (VA) 20/320 or better, and no history of PRP. INTERVENTION:Panretinal photocoagulation or intravitreous ranibizumab injections (0.5 mg/0.05 ml). MAIN OUTCOME MEASURES:Time from randomization to a composite PDR-worsening outcome defined as the first occurrence of vitreous hemorrhage, retinal detachment, anterior segment neovascularization, or neovascular glaucoma. RESULTS:Through 2 years, the cumulative probability of worsening PDR was 42% (PRP) versus 34% (ranibizumab; hazard ratio [HR], 1.33; 99% confidence interval [CI], 0.90 to 1.98; P = 0.063). Worse baseline levels of diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study scale) were associated with increased risk of worsening PDR, regardless of treatment group (64% [high-risk PDR or worse] vs. 23% [moderate PDR or better]; HR, 3.97; 99% CI, 2.48 to 6.36; P < 0.001). In the PRP group, eyes receiving pattern scan versus conventional single-spot PRP also were at higher risk for worsening PDR (60% vs. 39%; HR, 2.04; 99% CI, 1.02 to 4.08; P = 0.008), regardless of the number of spots placed or the number of sittings to complete the initial PRP. Eyes in both groups with vision-impairing (VA 20/32 or worse) center-involved diabetic macular edema (DME) at baseline were required to receive ranibizumab for center-involved DME. Therefore the composite outcome was compared by treatment in the subgroup of eyes that did not have vision-impairing center-involved DME at baseline. For these eyes, the rate of PDR-worsening was greater with PRP than ranibizumab (45% vs. 31%; HR, 1.62; 99% CI, 1.01 to 2.60; P = 0.008). CONCLUSIONS:In eyes with PDR, ranibizumab resulted in less PDR worsening compared with PRP, especially in eyes not required to receive ranibizumab for center-involved DME. Although anti-vascular endothelial growth factor therapy requires a more frequent visit schedule than PRP, these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through 2 years.
Baseline Factors Affecting Changes in Diabetic Retinopathy Severity Scale Score After Intravitreal Aflibercept or Laser for Diabetic Macular Edema: Post Hoc Analyses from VISTA and VIVID.
Dhoot Dilsher S,Baker Keith,Saroj Namrata,Vitti Robert,Berliner Alyson J,Metzig Carola,Thompson Desmond,Singh Rishi P
PURPOSE:To evaluate whether select baseline systemic and ocular factors influence ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score at week 100 in VISTA and VIVID. DESIGN:Post hoc analysis of 2 similarly designed phase 3 trials, VISTA and VIVID. PARTICIPANTS:Total of 456 patients with center-involved diabetic macular edema (DME). METHODS:VISTA and VIVID randomized 872 DME patients to receive intravitreal aflibercept injection (IAI) 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or macular laser photocoagulation. This post hoc analysis evaluated the influence of select baseline factors on ≥2-step DRSS score improvement by logistic regression in an integrated VISTA and VIVID dataset using observed cases (n = 456) with patients in each treatment group divided into tertiles based on each characteristic. MAIN OUTCOME MEASURES:Proportion of patients with ≥2-step improvement in DRSS score from baseline at week 100 by age, duration of diabetes, hemoglobin A1c (HbA1c), body mass index (BMI), best-corrected visual acuity (BCVA), central subfield thickness (CST), and DRSS score. RESULTS:At week 100, 10.1%, 34.3%, and 37.6% of patients in the laser, 2q4, and 2q8 groups experienced a ≥2-step DRSS score improvement, respectively. Age, duration of diabetes, HbA1c, BMI, BCVA, and CST had no impact on the ability to achieve ≥2-step improvement in DRSS score. Initial DRSS score was the only factor significantly associated with ≥2-step DRSS score improvement in all treatment groups at weeks 24, 52, 76, and 100. Relatively higher proportions of IAI-treated patients with worse BCVA or thicker CST experienced ≥2-step DRSS score improvement compared with those with better BCVA or thinner CST, respectively, but these associations were not statistically significant. CONCLUSION:A strong association was present between baseline DRSS score and ≥2-step DRSS score improvement at week 100 for DME patients in VISTA and VIVID.
Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open-Label Extension of RIDE and RISE Studies.
Sun Jennifer K,Wang Pin-Wen,Taylor Sarah,Haskova Zdenka
PURPOSE:To evaluate the durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. DESIGN:Pooled analysis of the open-label extension (OLE) of RIDE and RISE (clinicaltrials.gov identifiers, NCT00473382 and NCT00473330) patients with DR and diabetic macular edema (DME). PARTICIPANTS:Patients who completed 36-month participation in RIDE and RISE and entered the OLE. METHODS:In RIDE and RISE, patients (n = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg PRN based on predefined DME re-treatment criteria. Diabetic retinopathy severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. MAIN OUTCOME MEASURES:Change in DR severity from months 36 to 48 by re-treatment status. RESULTS:Among patients who entered the OLE, 121 of 500 (24%) did not require additional ranibizumab injections. Overall, 367 patients had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. CONCLUSIONS:Diabetic retinopathy severity improvements with ranibizumab were maintained in over 70% of OLE patients after switching from ranibizumab monthly to an individualized ranibizumab 0.5 mg PRN dosing regimen. Because approximately one third of OLE patients experienced DR worsening, careful monitoring should be part of the long-term management of patients with DR.
Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy.
Sun Jennifer K,Glassman Adam R,Beaulieu Wesley T,Stockdale Cynthia R,Bressler Neil M,Flaxel Christina,Gross Jeffrey G,Shami Michel,Jampol Lee M,
PURPOSE:To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. DESIGN:Post hoc analyses from a randomized clinical trial. PARTICIPANTS:Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP). METHODS:Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria. MAIN OUTCOME MEASURES:Neovascularization status through 2 years. RESULTS:At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. CONCLUSIONS:The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
Cost-effectiveness of Intravitreous Ranibizumab Compared With Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Secondary Analysis From a Diabetic Retinopathy Clinical Research Network Randomized Clinical Trial.
Hutton David W,Stein Joshua D,Bressler Neil M,Jampol Lee M,Browning David,Glassman Adam R,
Importance:The Diabetic Retinopathy Clinical Research Network Protocol S randomized clinical trial results suggest that ranibizumab is a reasonable treatment alternative to panretinal photocoagulation (PRP) when managing proliferative diabetic retinopathy (PDR), with or without concomitant baseline diabetic macular edema (DME). However, ranibizumab injections are costly. Thus, it would be useful to examine the relative cost-effectiveness of these 2 treatment modalities. Objective:To evaluate incremental cost-effectiveness ratios of 0.5-mg ranibizumab therapy vs PRP for PDR. Design, Setting, and Participants:Preplanned secondary analysis using efficacy, safety, and resource utilization data through 2 years of follow-up at 55 US sites for 213 adults with PDR. Data were collected from February 2012 to January 2015. Interventions:Intravitreous 0.5-mg ranibizumab at baseline and as frequently as every 4 weeks based on a structured retreatment protocol or PRP at baseline for PDR. Eyes in both groups could receive ranibizumab for concomitant DME. Main Outcomes and Measures:Incremental cost-effectiveness ratios of ranibizumab compared with PRP evaluated within 2 prespecified subgroups for the study eye: with baseline vision-impairing (Snellen equivalent 20/32 or worse) DME and without baseline vision-impairing DME. Results:The study included 305 adults with PDR, the mean age was 52 years, 44% were women, and 52% were white. Of the 46 participants with PDR and vision-impairing DME at baseline, 21 were assigned to the ranibizumab group and 25 to the PRP group (plus ranibizumab for DME). Among the remaining participants without baseline vision-impairing DME, 80 and 87 were in the ranibizumab and PRP groups, respectively. For participants with and without baseline vision-impairing DME, the incremental cost-effectiveness ratios of ranibizumab therapy compared with PRP were $55 568/quality-adjusted life-year and $662 978/quality-adjusted life-year, respectively, over 2 years. Conclusions and Relevance:Over 2 years, compared with PRP, 0.5-mg ranibizumab as given in this trial is within the $50 000/quality-adjusted life-year to $150 000/quality-adjusted life-year range frequently cited as cost-effective in the United States for eyes presenting with PDR and vision-impairing DME, but not for those with PDR without vision-impairing DME. Trial Registration:Clinicaltrials.gov Identifier: NCT01489189.
Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial.
Sivaprasad Sobha,Prevost A Toby,Vasconcelos Joana C,Riddell Amy,Murphy Caroline,Kelly Joanna,Bainbridge James,Tudor-Edwards Rhiannon,Hopkins David,Hykin Philip,
Lancet (London, England)
BACKGROUND:Proliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept. METHODS:In this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as -5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582. FINDINGS:We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters [95% CI 2·3-5·6], p<0·0001) and the per-protocol population (4·0 letters [2·4-5·7], p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of -5 letters at both 12 weeks and 52 weeks. INTERPRETATION:Patients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care. FUNDING:The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
Diabetic Retinopathy: Recent Updates on Different Biomarkers and Some Therapeutic Agents.
Khan Amjad Ali,Rahmani Arshad Husain,Aldebasi Yousef Homood
Current diabetes reviews
BACKGROUND:Diabetic Retinopathy is a leading cause of sight-threatening complication, which occurs due to a number of physiological and metabolic abnormalities during later stages of diabetes. Many of these abnormal changes are consistent with altered oxidative stress, inflammation, genetic set up, advanced glycation end products, and hematological changes. So the altered levels of different biomolecules related to these changes serve as important biomarkers to assess better evaluation and early treatment of this disease. Some treatments like laser therapy may be fast and specific but are more expensive, limited and can result in severe contraindications. Several other novel treatment strategies have been evolved recently besides classical approaches like control over hyperglycemia, hypertension, lipid profile to control diabetic retinopathy. These precise treatments are based on targeting the elevated biomarkers in retina. Such treatments include use of anti-VEGF therapy, intravitreal corticosteroids, gamigliptin and flavonoids. CONCLUSION:The present review discusses the latest updates on diabetic retinopathy, common etiology, different biomarkers and current treatments. In conclusion, perfection and proper supervision of diabetes and early treatment of diabetic retinopathy are crucial in controlling the occurrence and severity of this disease.
Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.
Gross Jeffrey G,Glassman Adam R,Liu Danni,Sun Jennifer K,Antoszyk Andrew N,Baker Carl W,Bressler Neil M,Elman Michael J,Ferris Frederick L,Gardner Thomas W,Jampol Lee M,Martin Daniel F,Melia Michele,Stockdale Cynthia R,Beck Roy W,
Importance:Ranibizumab is a viable treatment option for eyes with proliferative diabetic retinopathy (PDR) through 2 years. However, longer-term results are needed. Objective:To evaluate efficacy and safety of 0.5-mg intravitreous ranibizumab vs panretinal photocoagulation (PRP) over 5 years for PDR. Design, Setting, and Participants:Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial evaluated 394 study eyes with PDR enrolled February through December 2012. Analysis began in January 2018. Interventions:Eyes were randomly assigned to receive intravitreous ranibizumab (n = 191) or PRP (n = 203). Frequency of ranibizumab was based on a protocol-specified retreatment algorithm. Diabetic macular edema could be managed with ranibizumab in either group. Main Outcomes and Measures:Mean change in visual acuity (intention-to-treat analysis) was the main outcome. Secondary outcomes included peripheral visual field loss, development of vision-impairing diabetic macular edema, and ocular and systemic safety. Results:The 5-year visit was completed by 184 of 277 participants (66% excluding deaths). Of 305 enrolled participants, the mean (SD) age was 52 (12) years, 135 (44%) were women, and 160 (52%) were white. For the ranibizumab and PRP groups, the mean (SD) number of injections over 5 years was 19.2 (10.9) and 5.4 (7.9), respectively; the mean (SD) change in visual acuity letter score was 3.1 (14.3) and 3.0 (10.5) letters, respectively (adjusted difference, 0.6; 95% CI, -2.3 to 3.5; P = .68); the mean visual acuity was 20/25 (approximate Snellen equivalent) in both groups at 5 years. The mean (SD) change in cumulative visual field total point score was -330 (645) vs -527 (635) dB in the ranibizumab (n = 41) and PRP (n = 38) groups, respectively (adjusted difference, 208 dB; 95% CI, 9-408). Vision-impairing diabetic macular edema developed in 27 and 53 eyes in the ranibizumab and PRP groups, respectively (cumulative probabilities: 22% vs 38%; hazard ratio, 0.4; 95% CI, 0.3-0.7). No statistically significant differences between groups in major systemic adverse event rates were identified. Conclusions and Relevance:Although loss to follow-up was relatively high, visual acuity in most study eyes that completed follow-up was very good at 5 years and was similar in both groups. Severe vision loss or serious PDR complications were uncommon with PRP or ranibizumab; however, the ranibizumab group had lower rates of developing vision-impairing diabetic macular edema and less visual field loss. Patient-specific factors, including anticipated visit compliance, cost, and frequency of visits, should be considered when choosing treatment for patients with PDR. These findings support either anti-vascular endothelial growth factor therapy or PRP as viable treatments for patients with PDR. Trial Registration:ClinicalTrials.gov Identifier: NCT01489189.
Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Factors Associated with Vision and Edema Outcomes.
Bressler Susan B,Beaulieu Wesley T,Glassman Adam R,Gross Jeffrey G,Melia Michele,Chen Eric,Pavlica Michael R,Jampol Lee M,
PURPOSE:To identify baseline factors associated with change in visual acuity or development of vision-impairing central-involved diabetic macular edema (DME) over 2 years when treating proliferative diabetic retinopathy (PDR) with ranibizumab or panretinal photocoagulation (PRP). DESIGN:Post hoc analyses of randomized, multicenter clinical trial data. PARTICIPANTS:Eyes completing the 2-year visit (n = 328) or without vision-impairing central-involved DME at baseline (n = 302) in Diabetic Retinopathy Clinical Research Network Protocol S. METHODS:Intravitreous ranibizumab (0.5 mg/0.05 ml) or PRP. MAIN OUTCOME MEASURES:Change in visual acuity (area under the curve) and development of vision-impairing (20/32 or worse) central-involved DME over 2 years. RESULTS:After multivariable model selection with adjustment for baseline visual acuity and central subfield thickness, no factors were identified as associated with change in visual acuity or development of vision-impairing central-involved DME within the ranibizumab group. In the PRP group, worse change in visual acuity was more likely with higher hemoglobin A level (-0.6 letters per 1% increase; 95% confidence interval [CI], -1.2 to -0.1 letters; continuous P = 0.03), more severe diabetic retinopathy (difference between high-risk PDR or worse vs. moderate PDR or better, -2.8 letters [95% CI, -5.5 to -0.2 letters]; continuous P = 0.003), and higher mean arterial pressure (difference between ≥100 mmHg vs. <100 mmHg, -2.0 letters [95% CI, -4.6 to 0.5 letters]; continuous P = 0.009). Development of vision-impairing central-involved DME was more likely with higher hemoglobin A level (hazard ratio [HR] per 1% increase, 1.31 [95% CI, 1.13-1.52]; continuous P < 0.001), more severe diabetic retinopathy (HR for high-risk PDR or worse vs. moderate PDR or better, 1.46 [95% CI, 0.73-2.92]; continuous P = 0.03), and the presence of cystoid abnormalities within 500 μm of the macula center (HR, 2.90 [95% CI, 1.35-6.24]; P = 0.006). CONCLUSIONS:For eyes managed with PRP, higher hemoglobin A level and more severe diabetic retinopathy were associated with less vision improvement and an increased risk of vision-impairing central-involved DME developing. When managing PDR with ranibizumab, eyes gained vision, on average, with no baseline characteristics identified as associated with visual acuity or central-involved DME outcomes.
The effect of laser pan-retinal photocoagulation with or without intravitreal bevacizumab injections on the OCT-measured macular choroidal thickness of eyes with proliferative diabetic retinopathy.
Preti Rony C,Mutti Anibal,Ferraz Daniel A,Zacharias Leandro C,Nakashima Yoshitaka,Takahashi Walter Y,Monteiro Mario L R
Clinics (Sao Paulo, Brazil)
OBJECTIVES::To investigate the effect of laser pan-retinal photocoagulation with or without intravitreal bevacizumab injections on macular choroidal thickness parameters in eyes with high-risk proliferative diabetic retinopathy. METHODS::High-risk proliferative diabetic retinopathy patients undergoing laser treatment were prospectively enrolled in this study. One eye was randomly selected for laser treatment combined with bevacizumab injections, study group, whereas the corresponding eye was subjected to laser treatment alone, control group. Spectral-domain optical coherence tomography with enhanced depth imaging was used to measure the macular choroidal thickness prior to and 1 month after treatment. Measurements in both groups were compared. Clinicaltrials.gov: NCT01389505. RESULTS::Nineteen patients (38 eyes) with a mean±standard deviation age of 53.4±9.3 years were evaluated, and choroidal thickness measurements for 15 patients were used for comparison. The greatest measurement before treatment was the subfoveal choroidal thickness (341.68±67.66 μm and 345.79±83.66 μm for the study and control groups, respectively). No significant difference between groups was found in terms of macular choroidal thickness measurements at baseline or after treatment. However, within-group comparisons revealed a significant increase in choroidal thickness parameters in 10 measurements in the study group and in only 5 temporal measurements in the control group when 1-month follow-up measurements were compared to baseline values. CONCLUSIONS::The macular choroidal thickness does not appear to be significantly influenced by laser treatment alone but increases significantly when associated with bevacizumab injections in patients with proliferative diabetic retinopathy and macular edema. Because bevacizumab injections reduce short-term laser pan-retinal photocoagulation-induced macular edema, our findings suggest that the choroid participates in its pathogenesis.
The Diabetic Retinopathy Clinical Research Network (DRCR.net) and Its Contributions to the Treatment of Diabetic Retinopathy.
Sun Jennifer K,Jampol Lee M
Over the past two decades, the Diabetic Retinopathy Clinical Research Network (now known as the DRCR Retina Network) has contributed to multiple and substantial advances in the clinical care of diabetic eye disease. Network studies helped establish anti-vascular endothelial growth factor (VEGF) agents as an effective alternative to panretinal photocoagulation for eyes with proliferative diabetic retinopathy (PDR) and as first-line therapy for eyes with visual impairment for diabetic macular edema (DME), defined treatment algorithms for the use of intravitreal medications in these conditions, and provided critical data to understand how to better evaluate the diabetic eye using optical coherence tomography and other imaging modalities. Ongoing DRCR.net studies will address whether anti-VEGF therapy is effective at preventing vision-threatening complications in eyes with severe non-proliferative diabetic retinopathy, if photobiomodulation has a beneficial effect in eyes with DME, and whether initiation of DME treatment with bevacizumab and rescue with aflibercept can provide visual outcomes as good as those achieved with aflibercept alone. Future plans for the Network also include the expansion into non-diabetic eye disease in areas such as age-related macular degeneration.
Retinal function in eyes with proliferative diabetic retinopathy treated with intravitreal ranibizumab and multispot laser panretinal photocoagulation.
Messias Katharina,Barroso Rafael de Montier,Jorge Rodrigo,Messias Andre
Documenta ophthalmologica. Advances in ophthalmology
PURPOSE:To compare retinal function changes in eyes with proliferative diabetic retinopathy (PDR) after intravitreal ranibizumab (IVR), combined or not with conventional (ETDRS) or multispot laser panretinal (PASCAL) photocoagulation (PRP). METHODS:This study included laser-naive PDR patients that required PRP. Eyes were randomly and prospectively assigned to receive IVR or IVR combined with PASCAL or EDTRS. PRP was performed at baseline in 1 (PASCAL) or 2 (ETDRS) sessions. In eyes with macular edema, macular short pulse grid laser was associated with IVR at baseline and IVR was repeated monthly or quarterly if neovascularization was detected on angiography. Comprehensive ophthalmological evaluations, including SD-OCT, were performed at baseline and every 4 weeks after treatment. Full-field electroretinography (ERG: extended ISCEV standard) was performed at baseline and at 12, 24 and 48 weeks. RESULTS:IVR = 13, PASCAL = 15 and ETDRS = 15 eyes finished 48-week follow-up. There was a statistically significant BCVA improvement of 0.1-0.3 logMAR in all groups, and fluorescein angiography leakage area (FLA) reduced in 56%, 73%, and 73% from baseline for ETDRS, IVR and PASCAL, respectively, up to 48 weeks without significant differences between groups (p > 0.05). A significant a- and b-wave amplitudes reduction was observed for dark- and light-adapted ERG for ETDRS and PASCAL, but only minor dark-adapted b-wave reduction was found for IVR, up to 48 weeks. As an example, at week 48, combined response b-wave amplitude reduced in 181.5 ± 31.4 µV, 128.0 ± 27.9 µV and 82.4 ± 15.2 µV for ETDRS, PASCAL and IVR (p < 0.05 each group), respectively. No significant difference was observed between ETDRS and PASCAL for any ERG parameter. CONCLUSIONS:IVR combined with single or multiple spot PRP causes similar retinal function impairment during 48 weeks of observation, while IVR alone seems to be similarly effective controlling FLA without changing retinal function.
Posterior subtenon infusion of triamcinolone acetonide as adjunctive treatment to panretinal photocoagulation using pattern scan laser for diabetic retinopathy.
Yamada Yutaka,Takamura Yoshihiro,Matsumura Takehiro,Morioka Masakazu,Gozawa Makoto,Inatani Masaru
Japanese journal of ophthalmology
PURPOSE:To estimate the effect of sub-Tenon's capsule triamcinolone acetonide injection (STTA) combined with panretinal photocoagulation (PRP) using pattern scan laser (PSL) for high risk non-proliferative diabetic retinopathy (NPDR), in terms of the inflammation and the progression of diabetic macular edema (DME). STUDY DESIGN:Retrospective comparative analysis. METHODS:NPDR patients who underwent PRP using PSL with (STTA+PSL group, n=24) or without (PSL group, n=19) pretreatment of STTA were enrolled. We measured anterior flare intensity (AFI) and central retinal thickness (CRT) at day of STTA (day 0), and at 1, 3, 7, 11 and 15 weeks. RESULTS:The CRT of the STTA+PSL group was significantly lower than that of the PSL group at 7 (308.15±69.16 μm versus 340.21±77.91 μm, p = 0.04), 11 (283.8±60.75 μm versus 335.7±67.70 μm, p = 0.01) and 15 weeks (281.13±35.29 μm versus 316.58±54.89 μm, p = 0.02). AFI levels in the STTA+PSL group were significantly lower than those in the PSL group at 11 (10.47±3.40 versus 15.85±8.38, p = 0.007) and 15 weeks (11.38±3.31 versus 14.37±3.85, p = 0.009). The significant improvement in CRT from baseline was noticed through the observational periods in STTA+PSL group, but not in the PSL group. CONCLUSION:Pretreatment of STTA has the potential to not only prevent the worsening of DME, but also reduce the CRT and AFI of eyes with NPDR after PRP using PSL.