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Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T.

ABSTRACT: PURPOSE:Assess associations of 2-year visual acuity (VA) outcomes with VA and optical coherence tomography central subfield thickness (CST) after 12 weeks of anti-vascular endothelial growth factor treatment for diabetic macular edema in DRCR.net Protocol T. DESIGN:Randomized clinical trial. METHODS:Setting: Multicenter (89 U.S. sites). PATIENT POPULATION:Eyes with VA and CST data from baseline and 12-week visits (616 of 660 eyes randomized [93.3%]). INTERVENTION:Six monthly injections of 2.0 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab; subsequent injections and focal/grid laser as needed for stability. MAIN OUTCOME MEASURES:Change in VA from baseline and VA letter score at 2 years. RESULTS:Twelve-week VA response was associated with 2-year change in VA and 2-year VA letter score for each drug (P < .001) but with substantial individual variability (multivariable R2 = 0.38, 0.29, and 0.26 for 2-year change with aflibercept, bevacizumab, and ranibizumab, respectively). Among eyes with less than 5-letter gain at 12 weeks, the percentages of eyes gaining 10 or more letters from baseline at 2 years were 42% (20 of 48), 31% (21 of 68), and 47% (28 of 59), and median 2-year VA was 20/32, 20/32, and 20/25, in the aflibercept, bevacizumab, and ranibizumab groups, respectively. Twelve-week CST response was not strongly associated with 2-year outcomes. CONCLUSIONS:A suboptimal response at 12 weeks did not preclude meaningful vision improvement (ie, ? 10-letter gain) in many eyes at 2 years. Eyes with less than 5-letter gain at 12 weeks often had good VA at 2 years without switching therapies.

SUBMITTER: Bressler NM

PROVIDER: S-EPMC6648655 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T.

Bressler Neil M NM Beaulieu Wesley T WT Maguire Maureen G MG Glassman Adam R AR Blinder Kevin J KJ Bressler Susan B SB Gonzalez Victor H VH Jampol Lee M LM Melia Michele M Sun Jennifer K JK Wells John A JA

American journal of ophthalmology 20180802

<h4>Purpose</h4>Assess associations of 2-year visual acuity (VA) outcomes with VA and optical coherence tomography central subfield thickness (CST) after 12 weeks of anti-vascular endothelial growth factor treatment for diabetic macular edema in DRCR.net Protocol T.<h4>Design</h4>Randomized clinical trial.<h4>Methods</h4>Setting: Multicenter (89 U.S. sites).<h4>Patient population</h4>Eyes with VA and CST data from baseline and 12-week visits (616 of 660 eyes randomized [93.3%]).<h4>Intervention< ...[more]

PMID: 30077569

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Project description:Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

Project description:PURPOSE:To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN:Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS:Participants with available plasma samples (N = 436). METHODS:Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES:Changes in the natural log (ln) of plasma VEGF levels. RESULTS:Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS:These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Project description:PurposeTo evaluate vitrectomy for diabetic macular edema (DME) in eyes with at least moderate vision loss and vitreomacular traction.DesignProspective cohort study.ParticipantsThe primary cohort included 87 eyes with DME and vitreomacular traction based on investigator's evaluation, visual acuity 20/63-20/400, optical coherence tomography (OCT) central subfield >300 microns and no concomitant cataract extraction at the time of vitrectomy.MethodsSurgery was performed according to the investigator's usual routine. Follow-up visits were performed after 3 months, 6 months (primary end point), and 1 year.Main outcome measuresVisual acuity, OCT retinal thickening, and operative complications.ResultsAt baseline, median visual acuity in the 87 eyes was 20/100 and median OCT thickness was 491 microns. During vitrectomy, additional procedures included epiretinal membrane peeling in 61%, internal limiting membrane peeling in 54%, panretinal photocoagulation in 40%, and injection of corticosteroids at the close of the procedure in 64%. At 6 months, median OCT central subfield thickness decreased by 160 microns, with 43% having central subfield thickness <250 microns and 68% having at least a 50% reduction in thickening. Visual acuity improved by > or =10 letters in 38% (95% confidence interval, 28%-49%) and deteriorated by > or =10 letters in 22% (95% confidence interval, 13%-31%). Postoperative complications through 6 months included vitreous hemorrhage (5 eyes), elevated intraocular pressure requiring treatment (7 eyes), retinal detachment (3 eyes), and endophthalmitis (1 eye). Few changes in results were noted between 6 months and 1 year.ConclusionsAfter vitrectomy performed for DME and vitreomacular traction, retinal thickening was reduced in most eyes. Between 28% and 49% of eyes with characteristics similar to those included in this study are likely to have improvement of visual acuity, whereas between 13% and 31% are likely to have worsening. The operative complication rate is low and similar to what has been reported for this procedure. These data provide estimates of surgical outcomes and serve as a reference for future studies that might consider vitrectomy for DME in eyes with at least moderate vision loss and vitreomacular traction.

Project description:BackgroundIntravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice.MethodsThis was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models.ResultsThere was a significant improvement in BCVA (p < 0.001) and CMT (p < 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a < 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive "early functional response" (p < 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p < 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an "early anatomical response", (p < 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response.ConclusionsThe study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes.Trial registrationThe study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 - 067).

Project description:Background: Antiangiogenic therapy with anti-vascular endothelial growth factor (VEGF) is commonly used to treat diabetic macular edema (DME), which can reduce edema, improve vision, and prevent further visual loss. There is little head-to-head trial data to guide the selection of an individual VEGF inhibitor. Therefore, we aimed to investigate the efficacy and safety of anti-VEGF for patients with DME and to assess the differences between clinically relevant options by using network meta-analysis (NMA). Methods: MEDLINE, Embase, the Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Wanfang, China National Knowledge Infrastructure, and VIP databases were searched for published randomized controlled trials (RCTs) from their inception to November 2020. We included RCTs of anti-VEGF drugs (intravitreal aflibercept (IVT-AFL), intravitreal ranibizumab (IVR), and intravitreal conbercept (IVC)) treating adult patients who were diagnosed with DME, regardless of stage or duration of the disease. We estimated summary odds ratios (ORs) and mean differences (MDs) with 95% credible intervals (CrIs) using a Bayesian NMA. This study's registration number is CRD42021259335. Results: We identified 43 RCTs comprising 8,234 patients. Beneficial effects were observed in patients who used IVT-AFL compared with those who used other anti-VEGF therapies at 1-year follow-up on corrected visual acuity (BCVA) improvements (all patients: versus IVR: MD 2.83, 95% CrIs 1.64, 4.01, versus IVC: MD 2.41, 95% CrIs -0.52, 5.32; patients with worse baseline visual acuity (VA): versus IVR: MD 3.39, 95% CrIs 1.89, 4.9, versus IVC: MD 3.49, 95% CrIs 0.49, 6.44) and the proportion of patients with a gain of at least 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (all patients: versus IVR: OR 1.55, 95% CrIs 1.11, 2.17, versus IVC: OR 2.78, 95% CrIs 1.23, 6.04; patients with worse baseline VA: versus IVR: OR 2.05, 95% CrIs 1.18, 3.58, versus IVC: OR 2.85, 95% CrIs 1.24, 6.41). The effect of improvement in BCVA was identified for IVT-AFL compared to intravitreal bevacizumab. Based on the surface under the cumulative ranking curve (SUCRA), IVT-AFL had the highest probability of being the most effective option (99.9% and 99.5% in terms of the two primary outcomes, respectively). At the 2-year follow-up, numerical differences were identified favoring IVT-AFL; however, they did not reach statistical significance when comparing IVT-AFL to IVR. In the analysis of adverse events, IVT-AFL showed a lower risk of incidence of ocular adverse events compared to other anti-VEGF therapies at 1-year follow-up (versus IVR: OR 0.45, 95% CrIs 0.28, 0.7; versus IVC: OR 0.36, 95% CrIs 0.21, 0.63). Conclusion: IVT-AFL resulted in greater beneficial effects on BCVA and a higher proportion of patients with a gain of at least 15 ETDRS letters compared to IVR or IVC one year after treatment (especially in DME patients with worse baseline VA). In addition, fewer ocular adverse events occurred in the IVT-AFL group compared to the IVR or IVC groups. After two years, there was insufficient evidence to identify which anti-VEGF has superior efficacy or safety. Clinical Trial Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021259335, CRD42021259335.

Dataset Information

Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T.

Publications

Early Response to Anti-Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T.

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