Drilling Deeper for Treatment Choices in Diabetic Macular Edema
Invited Commentary
Invited Commentary
Drilling Deeper for Treatment Choices in Diabetic Macular Edema Emily Y. Chew, MD
After decades of using focal/grid laser photocoagulation to reduce the risk of vision loss with diabetic macular edema (DME), the current therapy has shifted to intravitreal injections of anti– vascular endothelial growth factor (VEGF) agents, which Related article can result in gains in visual acuity (VA). Investigators from the Diabetic Retinopathy Clinical Research Network1 report in this issue of JAMA Ophthalmology the findings from the secondary analyses of data previously reported in a comparative trial of 3 anti-VEGF agents—aflibercept, bevacizumab, and ranibizumab—for the treatment of DME.2 The current report examines the 1-year outcomes of subgroups that were both prespecified and post hoc.1 The comparative trial randomized 660 participants with DME into 3 groups: participants received 0.05-mL intravitreal injections of 2 mg of aflibercept, 1.25 mg of bevacizumab, or 0.3 mg of ranibizumab.2 All 3 drugs resulted in substantial improvement, on average, in VA at 1 year, with mean improvement occurring by 1 month. Prespecified subgroup analyses were based on baseline VA, worse VA (Snellen equivalent of 20/50 or worse), or better VA (Snellen equivalent of 20/32 or 20/40). All 3 agents were considered to have similar effects on VA for participants whose baseline VA was 20/30 or 20/40. However, for participants whose baseline VA was 20/50 or worse, improvement in VA was greatest with aflibercept while the effects of ranibizumab and bevacizumab on VA were similar. In addition, the participants who received aflibercept also required less supplemental focal/grid laser photocoagulation than did the patients who received ranibizumab or bevacizumab. In the current report, additional exploratory analyses were conducted, again stratified by baseline VA, to evaluate the 1-year VA outcomes in greater detail.1 In addition to the mean VA gain at 1 year, the proportion of participants experiencing visual gain or loss of 10, 15, or more letters were previously published.2 The additional data presented included an unusual detailed listing of VA outcomes at 1 year, including analyses of the proportion of participants achieving VA of 20/20 at 1 year in each of the treatment groups. Post hoc analyses were also conducted based on stratification by baseline retinal thickness as measured by optical coherence tomography in addition to baseline VA. Central subfield thickness was divided into thicker (>400 μm) or thinner (250-399 μm) categories. The scatter plot in eFigure 1 in the current report1 showed only a modest correlation of retinal thickness with VA, similar to the scatter plot published in a study previously reported by the Diabetic Retinopathy Clinical Research Network.3 Participants with thickened or thinned retina may have a wide range of VAs. The current analyses showed separate interactions of baseline VA with treatment and baseline central subfield thickness with jamaophthalmology.com
treatment, but when both 2-way interactions were included in the analyses, only baseline VA remained statistically significant.1 It is not surprising that, regardless of central subfield thickness, baseline VA remains the most important factor in determining the visual outcomes at 1 year for the treatment, given the modest correlation with VA of retinal thickness as measured by optical coherence tomography. Despite these findings in the subgroup analyses, the investigators expressed concern about the efficacy of bevacizumab.1 As noted in the abstract, for the subgroup of eyes with better initial VA and thicker central subfield thickness, “some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups.”1 Do these new data persuade us that there are clinically important differences among the 3 anti-VEGF agents, especially for bevacizumab? I concur with the investigators’ own statements about these data: “Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients.”1 These data cannot provide support to further differentiate the effects of the 3 treatments. In fact, these data fully support the investigators’ initial conclusion that, for persons with DME presenting with better initial VA, all 3 antiVEGF agents were appropriate while the greatest visual gain was achieved with aflibercept treatment in participants presenting with the poorest VA. The proportion of persons in the general population presenting with DME with visual impairment of 20/50 or worse is difficult to ascertain because clinical trials have limitations on the degree of VA for patient eligibility. Population-based studies do not have sufficient numbers of persons affected with DME to provide reliable statistics (R. Klein, MD, written communication, August 13, 2015). However, the Early Treatment Diabetic Retinopathy Study,4 which was a clinical trial conducted in the 1980s that accepted participants with DME with a variety of levels of VA and with no lower limits on VA, suggested that 75% of patients presenting to a general clinic with DME have a VA of 20/40 or better. One could assume that this proportion would be markedly increased in the present, as the medical care of glycemic and blood pressure control and management of dyslipidemia for persons with diabetes mellitus have vastly improved over the decades. Regardless of the precise number of persons with varying degrees of baseline VA seeking treatment for DME, the issues surrounding compounding pharmacies for bevacizumab, or types of health insurance coverage, bevacizumab remains an important player in this trio of anti-VEGF therapies. Because of its markedly reduced cost and because of the findings from this comparative trial, bevacizumab still can be a first-line treatment for a large proportion of persons with DME. Although the (Reprinted) JAMA Ophthalmology Published online November 25, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Chinese University of Hong Kong User on 11/25/2015
E1
Invited Commentary
Drilling Deeper for Treatment Choices in Diabetic Macular Edema
medical care of persons with diabetes has improved, the numbers of individuals affected with diabetes are increasing markedly worldwide. The cost of treatment to the patient, their families, and to society will be an enormous burden. The Diabetic Retinopathy Clinical Research Network has provided a more detailed set of data for physicians caring for
patients with DME. They have also affirmed the prior conclusion that all 3 anti-VEGF therapies result in improvement in VA, with differences seen in the subgroups stratified by presenting VA. Their previous conclusions from this important comparative trial still hold. These data provide physicians the best level 1 evidence in determining treatment choices for DME.
ARTICLE INFORMATION
REFERENCES
Author Affiliation: Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute/National Institutes of Health, Bethesda, Maryland.
1. Wells JA, Glassman AR, Jampol LM, et al; Diabetic Retinopathy Clinical Research Network. Association of baseline visual acuity and retinal thickness with 1-year efficacy of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema [published online November 26, 2015]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol .2015.4599.
Corresponding Author: Emily Y. Chew, MD, Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute/National Institutes of Health, Bldg 10–Clinical Research Center, Room 3-2531, 10 Center Dr, Mailstop Code 1204, Bethesda, MD 20892 ([email protected]). Published Online: November 25, 2015. doi:10.1001/jamaophthalmol.2015.4652.
2. 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.
3. Browning DJ, Glassman AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography–measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114(3):525-536. 4. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema: relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS Report No. 19. Arch Ophthalmol. 1995;113(9): 1144-1155.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
E2
JAMA Ophthalmology Published online November 25, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Chinese University of Hong Kong User on 11/25/2015
jamaophthalmology.com
Invited Commentary
Invited Commentary
Drilling Deeper for Treatment Choices in Diabetic Macular Edema Emily Y. Chew, MD
After decades of using focal/grid laser photocoagulation to reduce the risk of vision loss with diabetic macular edema (DME), the current therapy has shifted to intravitreal injections of anti– vascular endothelial growth factor (VEGF) agents, which Related article can result in gains in visual acuity (VA). Investigators from the Diabetic Retinopathy Clinical Research Network1 report in this issue of JAMA Ophthalmology the findings from the secondary analyses of data previously reported in a comparative trial of 3 anti-VEGF agents—aflibercept, bevacizumab, and ranibizumab—for the treatment of DME.2 The current report examines the 1-year outcomes of subgroups that were both prespecified and post hoc.1 The comparative trial randomized 660 participants with DME into 3 groups: participants received 0.05-mL intravitreal injections of 2 mg of aflibercept, 1.25 mg of bevacizumab, or 0.3 mg of ranibizumab.2 All 3 drugs resulted in substantial improvement, on average, in VA at 1 year, with mean improvement occurring by 1 month. Prespecified subgroup analyses were based on baseline VA, worse VA (Snellen equivalent of 20/50 or worse), or better VA (Snellen equivalent of 20/32 or 20/40). All 3 agents were considered to have similar effects on VA for participants whose baseline VA was 20/30 or 20/40. However, for participants whose baseline VA was 20/50 or worse, improvement in VA was greatest with aflibercept while the effects of ranibizumab and bevacizumab on VA were similar. In addition, the participants who received aflibercept also required less supplemental focal/grid laser photocoagulation than did the patients who received ranibizumab or bevacizumab. In the current report, additional exploratory analyses were conducted, again stratified by baseline VA, to evaluate the 1-year VA outcomes in greater detail.1 In addition to the mean VA gain at 1 year, the proportion of participants experiencing visual gain or loss of 10, 15, or more letters were previously published.2 The additional data presented included an unusual detailed listing of VA outcomes at 1 year, including analyses of the proportion of participants achieving VA of 20/20 at 1 year in each of the treatment groups. Post hoc analyses were also conducted based on stratification by baseline retinal thickness as measured by optical coherence tomography in addition to baseline VA. Central subfield thickness was divided into thicker (>400 μm) or thinner (250-399 μm) categories. The scatter plot in eFigure 1 in the current report1 showed only a modest correlation of retinal thickness with VA, similar to the scatter plot published in a study previously reported by the Diabetic Retinopathy Clinical Research Network.3 Participants with thickened or thinned retina may have a wide range of VAs. The current analyses showed separate interactions of baseline VA with treatment and baseline central subfield thickness with jamaophthalmology.com
treatment, but when both 2-way interactions were included in the analyses, only baseline VA remained statistically significant.1 It is not surprising that, regardless of central subfield thickness, baseline VA remains the most important factor in determining the visual outcomes at 1 year for the treatment, given the modest correlation with VA of retinal thickness as measured by optical coherence tomography. Despite these findings in the subgroup analyses, the investigators expressed concern about the efficacy of bevacizumab.1 As noted in the abstract, for the subgroup of eyes with better initial VA and thicker central subfield thickness, “some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups.”1 Do these new data persuade us that there are clinically important differences among the 3 anti-VEGF agents, especially for bevacizumab? I concur with the investigators’ own statements about these data: “Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients.”1 These data cannot provide support to further differentiate the effects of the 3 treatments. In fact, these data fully support the investigators’ initial conclusion that, for persons with DME presenting with better initial VA, all 3 antiVEGF agents were appropriate while the greatest visual gain was achieved with aflibercept treatment in participants presenting with the poorest VA. The proportion of persons in the general population presenting with DME with visual impairment of 20/50 or worse is difficult to ascertain because clinical trials have limitations on the degree of VA for patient eligibility. Population-based studies do not have sufficient numbers of persons affected with DME to provide reliable statistics (R. Klein, MD, written communication, August 13, 2015). However, the Early Treatment Diabetic Retinopathy Study,4 which was a clinical trial conducted in the 1980s that accepted participants with DME with a variety of levels of VA and with no lower limits on VA, suggested that 75% of patients presenting to a general clinic with DME have a VA of 20/40 or better. One could assume that this proportion would be markedly increased in the present, as the medical care of glycemic and blood pressure control and management of dyslipidemia for persons with diabetes mellitus have vastly improved over the decades. Regardless of the precise number of persons with varying degrees of baseline VA seeking treatment for DME, the issues surrounding compounding pharmacies for bevacizumab, or types of health insurance coverage, bevacizumab remains an important player in this trio of anti-VEGF therapies. Because of its markedly reduced cost and because of the findings from this comparative trial, bevacizumab still can be a first-line treatment for a large proportion of persons with DME. Although the (Reprinted) JAMA Ophthalmology Published online November 25, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Chinese University of Hong Kong User on 11/25/2015
E1
Invited Commentary
Drilling Deeper for Treatment Choices in Diabetic Macular Edema
medical care of persons with diabetes has improved, the numbers of individuals affected with diabetes are increasing markedly worldwide. The cost of treatment to the patient, their families, and to society will be an enormous burden. The Diabetic Retinopathy Clinical Research Network has provided a more detailed set of data for physicians caring for
patients with DME. They have also affirmed the prior conclusion that all 3 anti-VEGF therapies result in improvement in VA, with differences seen in the subgroups stratified by presenting VA. Their previous conclusions from this important comparative trial still hold. These data provide physicians the best level 1 evidence in determining treatment choices for DME.
ARTICLE INFORMATION
REFERENCES
Author Affiliation: Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute/National Institutes of Health, Bethesda, Maryland.
1. Wells JA, Glassman AR, Jampol LM, et al; Diabetic Retinopathy Clinical Research Network. Association of baseline visual acuity and retinal thickness with 1-year efficacy of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema [published online November 26, 2015]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol .2015.4599.
Corresponding Author: Emily Y. Chew, MD, Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute/National Institutes of Health, Bldg 10–Clinical Research Center, Room 3-2531, 10 Center Dr, Mailstop Code 1204, Bethesda, MD 20892 ([email protected]). Published Online: November 25, 2015. doi:10.1001/jamaophthalmol.2015.4652.
2. 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.
3. Browning DJ, Glassman AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research Network. Relationship between optical coherence tomography–measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology. 2007;114(3):525-536. 4. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema: relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS Report No. 19. Arch Ophthalmol. 1995;113(9): 1144-1155.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
E2
JAMA Ophthalmology Published online November 25, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a Chinese University of Hong Kong User on 11/25/2015
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