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What Is Chronic or Persistent Diabetic Macular Edema and How Should It Be Treated?

What Is Chronic or Persistent Diabetic Macular Edema and How Should It Be Treated? Diabetes mellitus can cause significant tissue damage as manifested by nephropathy, neuropathy, and, in the eye, diabetic retinopathy. Vision loss in patients with diabetes is often associated with diabetic macular edema (DME). Because 3 different modalities of therapy, including focal laser photocoagulation, intravitreal anti–vascular endothelial growth factor (VEGF) agents, and corticosteroids, have been approved by regulatory authorities worldwide, physicians and patients are in a new era with diverse options to prevent moderate and severe vision loss from DME.1-5 The Diabetic Retinopathy Clinical Research Network (DRCR.net) has published several studies4,5 regarding the natural history of DME and the efficacy of diverse therapeutic interventions on anatomical and functional outcomes in DME. Before the study by Bressler et al6 reported in this issue of JAMA Ophthalmology, several questions remained regarding the role of anti-VEGF agents in DME. First, how do you define chronic DME? Second, what proportion of patients had persistent DME despite long-term therapy? Third, what are the long-term visual outcomes in patients who have persistent DME despite treatment with anti-VEGF agents with or without additional focal laser photocoagulation? Fourth, do therapies with reduced treatment frequency, including regimens that allow significant physician discretion, have adverse outcomes compared with long-term, monthly anti-VEGF injections? Fifth, is there a role for a reevaluation of alternative approaches, including VEGF-independent and surgical approaches in treating DME? This issue contains an excellent article by Bressler et al6 from the DRCR.net that asks some of these questions using exploratory data from a well-designed, previously published study (protocol 1). For the exploratory analysis, the investigators focused on study arms from protocol 1 that received intravitreal ranibizumab with prompt or deferred focal laser photocoagulation to pose 2 important questions: what participants have persistent DME (pDME) at 24 weeks into the study, and what proportion have chronic persistent DME (cpDME) at 1, 2, and 3 years into the study? For the definition of pDME, the authors used time domain optical coherent tomography (OCT)–guided criterion of persistent central subfield thickening (CST) of 250 µm or greater. They defined cpDME as failure to achieve less than 250 µm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits. Although the authors discuss that there is no universal definition of cpDME, their definition is an unusual one without a clear rationale except to account for partial treatment response beyond 24 weeks. It is likely that there would be more eyes in the cpDME cohort had the authors used the anatomical definition (same as pDME) instead of requiring the additional criterion of treatment responsiveness. The effects of this factor on the ultimate outcomes reported in the study are unclear. Of the eligible eyes in the study, 40% had pDME at 24 weeks, of which 81%, 56%, and 40% had cpDME at 1, 2, and 3 years, respectively. A critical finding of this analysis was that visual acuity improved in pDME eyes with or without cpDME by a mean of 7 and 13 letters, respectively. In addition, 43% of eyes with cpDME gained 10 or more letters at 3 years and only 13% lost 10 or more letters. This finding has significant implications for physicians as they counsel patients with cpDME on the benefit of continued therapy, especially when following treatment algorithms similar to those described here. Eyes with cpDME at the 3-year visit also had a median improvement of OCT CST of 118 µm while receiving a moderate number of injections (mean, 16-17 for 3 years), which highlights an important aspect of the anatomical response in these eyes. It is tempting to compare these findings with other well-designed trials, such as RIDE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus) and RISE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus), that had more intensive therapeutic regimens and open-label extension protocols.7 This comparison would be inappropriate given the different enrollment criteria, treatment regimens, and analysis strategies. A single point that highlights why such comparisons are fraught with peril is that of the participants randomized to receiving ranibizumab in RISE and RIDE: approximately 20% to 25% had a central foveal thickness greater than 250 µm at 24 months after receiving monthly injections compared with 56% in the current study that met the definition of cpDME at 2 years. The authors are careful in outlining the potential for bias, including the effect of natural history and investigator discretion on the outcomes analyzed. One concern is the effect of the strict censoring of participants eligible for this exploratory analysis on the outcomes of the study. Participants were censored if they received alternative treatments, were lost to follow-up, or missed too many visits. It may be appropriate to conduct a separate analysis in the future without such stringent censoring given the exploratory and fact-finding nature of this type of study. Current strategies rely on higher-resolution spectral domain OCT in defining persistent macular edema and may find that a higher proportion of patients have cpDME. The findings reported here should provide an excellent benchmark to guide physicians and patients regarding outcomes associated with therapeutic regimens that involve a significant component of discretion in the presence of cpDME. In summary, the study results suggest that continuation of anti-VEGF therapy after 24 weeks in eyes that have pDME may lead to long-term visual and anatomical improvement even in the setting of cpDME. How is this relevant to the evolution of DME therapy, especially in patients with cpDME? These data suggest that there may be VEGF-independent molecular mechanisms that are involved in the development and sustenance of macular edema. Because the pathobiology of DME is complex, the need for investigating synergistic, multitargeted pharmacotherapeutic strategies is still highly relevant. The role of vitreous surgery in treating DME has been studied by a number of investigators, including those involved in protocol D from the DRCR.net. These studies have been plagued with design, technique, or analysis flaws, but it may be time to reconsider the role of surgery in the pathogenesis of this complex disease. Back to top Article Information Corresponding Author: Rajendra S. Apte, MD, PhD, Washington University School of Medicine, 660 S Euclid Ave, PO Box 8096, St Louis, MO 63110 (apte@vision.wustl.edu). Published Online: January 7, 2016. doi:10.1001/jamaophthalmol.2015.5469. Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103(12):1796-1806.PubMedGoogle ScholarCrossref 2. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.PubMedGoogle ScholarCrossref 3. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.e2.PubMedGoogle ScholarCrossref 4. Elman MJ, Aiello LP, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.e35.PubMedGoogle ScholarCrossref 5. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203.PubMedGoogle ScholarCrossref 6. Bressler SB, Ayala AR, Bressler NM, et al. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment [published online January 7, 2016]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2015.5346.Google Scholar 7. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Ophthalmology American Medical Association

What Is Chronic or Persistent Diabetic Macular Edema and How Should It Be Treated?

Apte, Rajendra S.
JAMA Ophthalmology , Volume 134 (3) – Mar 1, 2016
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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6165
eISSN
2168-6173
DOI
10.1001/jamaophthalmol.2015.5469
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Abstract

Diabetes mellitus can cause significant tissue damage as manifested by nephropathy, neuropathy, and, in the eye, diabetic retinopathy. Vision loss in patients with diabetes is often associated with diabetic macular edema (DME). Because 3 different modalities of therapy, including focal laser photocoagulation, intravitreal anti–vascular endothelial growth factor (VEGF) agents, and corticosteroids, have been approved by regulatory authorities worldwide, physicians and patients are in a new era with diverse options to prevent moderate and severe vision loss from DME.1-5 The Diabetic Retinopathy Clinical Research Network (DRCR.net) has published several studies4,5 regarding the natural history of DME and the efficacy of diverse therapeutic interventions on anatomical and functional outcomes in DME. Before the study by Bressler et al6 reported in this issue of JAMA Ophthalmology, several questions remained regarding the role of anti-VEGF agents in DME. First, how do you define chronic DME? Second, what proportion of patients had persistent DME despite long-term therapy? Third, what are the long-term visual outcomes in patients who have persistent DME despite treatment with anti-VEGF agents with or without additional focal laser photocoagulation? Fourth, do therapies with reduced treatment frequency, including regimens that allow significant physician discretion, have adverse outcomes compared with long-term, monthly anti-VEGF injections? Fifth, is there a role for a reevaluation of alternative approaches, including VEGF-independent and surgical approaches in treating DME? This issue contains an excellent article by Bressler et al6 from the DRCR.net that asks some of these questions using exploratory data from a well-designed, previously published study (protocol 1). For the exploratory analysis, the investigators focused on study arms from protocol 1 that received intravitreal ranibizumab with prompt or deferred focal laser photocoagulation to pose 2 important questions: what participants have persistent DME (pDME) at 24 weeks into the study, and what proportion have chronic persistent DME (cpDME) at 1, 2, and 3 years into the study? For the definition of pDME, the authors used time domain optical coherent tomography (OCT)–guided criterion of persistent central subfield thickening (CST) of 250 µm or greater. They defined cpDME as failure to achieve less than 250 µm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits. Although the authors discuss that there is no universal definition of cpDME, their definition is an unusual one without a clear rationale except to account for partial treatment response beyond 24 weeks. It is likely that there would be more eyes in the cpDME cohort had the authors used the anatomical definition (same as pDME) instead of requiring the additional criterion of treatment responsiveness. The effects of this factor on the ultimate outcomes reported in the study are unclear. Of the eligible eyes in the study, 40% had pDME at 24 weeks, of which 81%, 56%, and 40% had cpDME at 1, 2, and 3 years, respectively. A critical finding of this analysis was that visual acuity improved in pDME eyes with or without cpDME by a mean of 7 and 13 letters, respectively. In addition, 43% of eyes with cpDME gained 10 or more letters at 3 years and only 13% lost 10 or more letters. This finding has significant implications for physicians as they counsel patients with cpDME on the benefit of continued therapy, especially when following treatment algorithms similar to those described here. Eyes with cpDME at the 3-year visit also had a median improvement of OCT CST of 118 µm while receiving a moderate number of injections (mean, 16-17 for 3 years), which highlights an important aspect of the anatomical response in these eyes. It is tempting to compare these findings with other well-designed trials, such as RIDE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus) and RISE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema [ME] With Center Involvement Secondary to Diabetes Mellitus), that had more intensive therapeutic regimens and open-label extension protocols.7 This comparison would be inappropriate given the different enrollment criteria, treatment regimens, and analysis strategies. A single point that highlights why such comparisons are fraught with peril is that of the participants randomized to receiving ranibizumab in RISE and RIDE: approximately 20% to 25% had a central foveal thickness greater than 250 µm at 24 months after receiving monthly injections compared with 56% in the current study that met the definition of cpDME at 2 years. The authors are careful in outlining the potential for bias, including the effect of natural history and investigator discretion on the outcomes analyzed. One concern is the effect of the strict censoring of participants eligible for this exploratory analysis on the outcomes of the study. Participants were censored if they received alternative treatments, were lost to follow-up, or missed too many visits. It may be appropriate to conduct a separate analysis in the future without such stringent censoring given the exploratory and fact-finding nature of this type of study. Current strategies rely on higher-resolution spectral domain OCT in defining persistent macular edema and may find that a higher proportion of patients have cpDME. The findings reported here should provide an excellent benchmark to guide physicians and patients regarding outcomes associated with therapeutic regimens that involve a significant component of discretion in the presence of cpDME. In summary, the study results suggest that continuation of anti-VEGF therapy after 24 weeks in eyes that have pDME may lead to long-term visual and anatomical improvement even in the setting of cpDME. How is this relevant to the evolution of DME therapy, especially in patients with cpDME? These data suggest that there may be VEGF-independent molecular mechanisms that are involved in the development and sustenance of macular edema. Because the pathobiology of DME is complex, the need for investigating synergistic, multitargeted pharmacotherapeutic strategies is still highly relevant. The role of vitreous surgery in treating DME has been studied by a number of investigators, including those involved in protocol D from the DRCR.net. These studies have been plagued with design, technique, or analysis flaws, but it may be time to reconsider the role of surgery in the pathogenesis of this complex disease. Back to top Article Information Corresponding Author: Rajendra S. Apte, MD, PhD, Washington University School of Medicine, 660 S Euclid Ave, PO Box 8096, St Louis, MO 63110 (apte@vision.wustl.edu). Published Online: January 7, 2016. doi:10.1001/jamaophthalmol.2015.5469. Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. References 1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;103(12):1796-1806.PubMedGoogle ScholarCrossref 2. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.PubMedGoogle ScholarCrossref 3. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.e2.PubMedGoogle ScholarCrossref 4. Elman MJ, Aiello LP, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077.e35.PubMedGoogle ScholarCrossref 5. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203.PubMedGoogle ScholarCrossref 6. Bressler SB, Ayala AR, Bressler NM, et al. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment [published online January 7, 2016]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2015.5346.Google Scholar 7. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.PubMedGoogle ScholarCrossref

Journal

JAMA Ophthalmology – American Medical Association

Published: Mar 1, 2016

Keywords: combined modality therapy,fovea centralis,laser coagulation,light coagulation,treatment outcome,macular edema, diabetic,ranibizumab

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