- Email: [email protected]
Re: Lepore et al.: Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings (Ophthalmology 2014;121:2212-9)
Correspondence zinc and antioxidants of the AREDS supplement may be associated with specific genotypes.4 We then assembled a separate group of AREDS participants not included in the analyses by Awh et al and attempted to replicate their analyses. In this newly assembled group of AREDS participants, every genotype benefited from the AREDS supplements,5 contrary to the findings of Awh et al.4 Wittes and Musch provided an excellent guideline for interpreting all the data that have been presented. They specifically criticized Awh et al for doing multiple testing that, in essence, allowed them to shoot multiple arrows at a target, which provide even a poor archer a high probability of hitting a bull’s eye. To be statistically rigorous, one would have to adjust for the large number of arrows (i.e., the many multiple tests). However, it is not possible to adjust in the case of Awh et al as they do not report the number of subgroups examined and whether they were prespecified or post hoc (after the fact). To quote Wittes and Musch, “Post hoc exploration of subgroups is treacherous because one never knows whether the results are due to inadvertent selection bias or if they are ‘true.’ Many people search post hoc for subgroup effects. Such ‘data dredging’ rewards the searcher with a high probability of finding differences between subgroups, but the probability is high that the finding is spurious. Replication is the only reliable way of assessing the validity of a post hoc finding.” Our analyses of an independent cohort did not validate the results of the second set of analyses by Awh et al. If we were to find similar results as Awh et al, despite all the biases, we would agree that their conclusions might be reasonable. But this was not the case. The authors of the editorial then explain that Awh et al based their subgroup analyses on the outcome. This was conducting the analyses “after the fact.” Thus, Awh et al have ensured themselves of finding significant results. Wittes and Musch agreed with our clinical recommendation. Treatment with the AREDS supplement is indicated in persons with bilateral intermediate age-related macular degeneration (AMD) or those with late AMD in 1 eye. In fact, if they personally had ocular findings that warrant AREDS supplement, Wittes and Musch state that they hope their ophthalmologists would prescribe the AREDS supplement without genetic testing. We, the AREDS investigators, and Wittes and Musch, agree: genotype testing before advising treatment with AREDS supplements for a patient at risk of developing late AMD is not recommended. The current letter from Drs Awh and Zanke criticized the lack of finding a beneficial effect of the AREDS supplement in AREDS Report 38.3 This insignificant finding is not surprising, because the report was based on a subgroup analysis, utilizing less than onequarter of the original cohort required to show a beneficial effect in the original AREDS report. Their letter also contains a new claim based on further subgroup analyses to support their mistaken view of genetic testing. This quote reinforces the thoughts expressed by Wittes and Musch: “While postulating subgroup effects a priori allows formal statistical hypothesis testing, much less credence is due to formulating hypotheses after examining the data. Such analysis smacks of betting on a horse after the race is over.” Let’s not bet again. 1
EMILY Y. CHEW, MD MICHAEL L. KLEIN, MD2 TRACI E. CLEMONS, PHD3 ELVIRA AGRÓN, MA1 GONÇALO R. ABECASIS, PHD4 1 Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Eye Institute/National Institutes of Health, Bethesda, Maryland; 2Casey Eye Institute, Oregon Health & Science
University, Portland, Oregon; 3The EMMES Corporation, Rockville, Maryland; 4Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan Financial Disclosure(s): The authors have made the following disclosures: This study was sponsored by the NIH. The NIH holds a royalty-bearing license issued to Bausch & Lomb for the Age-Related Eye Disease Study Supplement. Dr. Abecasis received royalties from patents held by University of Michigan. None of the other authors have financial disclosure. Supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda Maryland (contract HHS-NOIEY-0-2127) The sponsor and funding organization participated in the design and conduct of the study; data collection, management, analysis and interpretation; and the preparation, review and approval of the manuscript. Correspondence: Emily Y. Chew, MD, National Eye Institute, National Institutes of Health, Building 10, CRC Room 3-2531, 10 Center Drive, MSC 1204, Bethesda, MD 20892-1204. E-mail: [email protected].
References 1. Wittes J, Musch DC. Should we test for genotype in deciding on Age-Related Eye Disease Study Supplementation? Ophthalmology 2015;122:3–5. 2. Awh CC, Lane A-M, Hawken S, et al. CFH and ARMS2 genetic polymorphism predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology 2013;120:2317–23. 3. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS Report Number 38. Ophthalmology 2014;121:2173–80. 4. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology 2015;122:162–9. 5. Chew EY, Klein ML, Clemons TE. Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? Ophthalmology 2015;122: 212–5.
Re: Lepore et al.: Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings (Ophthalmology 2014;121:2212-9) Dear Editor: We read with interest the article by Lepore et al1 describing the effects of vascular endothelial growth factor (VEGF) suppression on retinal vascularization as characterized by fluorescein angiography. Since the publication of Efficacy of Intravitreal Bevacizumab for Stage 3þ Retinopathy of Prematurity (BEATROP) study,2 the use of bevacizumab in premature eyes has increased exponentially despite little understanding of the longterm effects of VEGF suppression in retinal vascular and neuronal development and, more important, its acute and chronic
e47
Ophthalmology Volume 122, Number 8, August 2015 systemic effects. The fluorescein angiographic findings presented by Lepore et al raise serious concerns about indiscriminate use of bevacizumab for treatment of retinopathy of prematurity, especially when laser ablation, an effective treatment option with proven longterm systemic and ocular safety, exists. We have a few concerns and comments. Infants with aggressive posterior retinopathy of prematurity in zone 1 treated with laser have an increased incidence of high myopia.3 In contrast, those babies who receive intravitreal bevacizumab as monotherapy for retinopathy of prematurity are more likely to be emmetropic.3,4 Therefore, babies who receive bevacizumab monotherapy in 1 eye as opposed to laser in the fellow eye are at great risk for developing severe anisometropia. We understand that assigning 1 eye to laser and the fellow eye to the bevacizumab arm in the same patient creates a good cohort and removes many patient-related factors that may affect the comparison. However, this would be expected to cause anisometropic amblyopia and raises concerns regarding such use in larger, randomized clinical trials. In contrast, infants who receive the same treatment bilaterally, such as bevacizumab, bevacizumab plus laser, or laser only, are less likely to develop such severe anisometropia. The authors mention that 1 of the 13 patients died of pulmonary complications. A detailed explanation, including whether the infant received bevacizumab or not, the type of pulmonary complications, and the respiratory status prior to injection, would have been informative. In our series, we noted pulmonary complications in 1 of 12 babies who received bevacizumab and laser at 2 months after the injection. This baby had respiratory distress and severe aggressive posterior retinopathy of prematurity that resolved completely, but the respiratory difficulties reappeared at 2 months after discharge, leading to the death of the patient from pulmonary complications. Given the importance of VEGF for pulmonary development and the significant systemic suppression of VEGF levels with a single intravitreal injection in infants, close monitoring of the respiratory system after intravitreal bevacizumab administration is of paramount importance. The use of antibiotic drops in addition to 0.5% povidone iodine both before and after injection may be unnecessary. Any topical medication in an infant may have systemic side effects. Because povidone iodine provides excellent antimicrobial prophylaxis for intravitreal treatment,5 using topical antibiotics as an additional measure before or after injection may be counterproductive in premature infants.
TAPAS RANJAN PADHI, MS, DNB1 CAGRI G. BESIRLI, MD, PHD2 1
Consultant, Retina and Vitreous services, LV Prasad Eye Institute, Bhubaneswar, India; 2Assistant Professor, Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Cagri G. Besirli, MD, PhD, Kellogg Eye Center, Ophthalmology and Visual Sciences, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
References 1. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity:
e48
2.
3.
4. 5.
report on fluorescein angiographic findings. Ophthalmology 2014;121:2212–9. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative group. Efficacy of intravitreal bevacizumab for stage 3þ retinopathy of prematurity. N Engl J Med 2011;364: 603–15. Geloneck MM, Chuang AZ1, Clark WL, et al; for the BEATROP Cooperative Group. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol 2014;132:1327–33. Chen YH, Chen SN, Lien RI, et al. Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes. Eye 2014;28:1080–6. Chen RW, Rachitskaya A, Scott IU, Flynn HW Jr. Is the use of topical antibiotics for intravitreal injections the standard of care or are we better off without antibiotics? JAMA Ophthalmol 2013;131:840–2.
Author reply Dear Editor: Padhi and Besirli express 3 major concerns about our study1 comparing laser and intravitreal injection of bevacizumab for the treatment of aggressive posterior retinopathy of prematurity. Regarding the risk of anisometropia induced by eye randomization, we informed parents about the risk and performed diligent follow-up. In addition, this within-subject randomization was an important and ethically acceptable component of both the CRYO-ROP and ETROP trials. Long-term results of this aspect of our study will be available soon. Regarding the baby who died of pulmonary complications at a remote hospital, it was quite difficult to obtain complete information from the hospital concerning the pathogenic agent that led to pneumonia and generalized sepsis. This 29-week gestational age, 475-g birth weight infant was a twin who was discharged from our center at 42 weeks. Finally, we agree that 0.5% povidone iodine alone is excellent in preventing infectious complications, although we have been using antibiotics in addition without any significant side effects noted.
DOMENICO LEPORE, MD GRAHAM E. QUINN, MD, MSCE Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Domenico Lepore, MD, Department of Ophthalmology, Catholic University of Sacred Heart, Largo Francesco Vito, 8, Rome 00168, Italy. E-mail: [email protected].
Reference 1. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology 2014;121:2212–9.
EMILY Y. CHEW, MD MICHAEL L. KLEIN, MD2 TRACI E. CLEMONS, PHD3 ELVIRA AGRÓN, MA1 GONÇALO R. ABECASIS, PHD4 1 Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Eye Institute/National Institutes of Health, Bethesda, Maryland; 2Casey Eye Institute, Oregon Health & Science
University, Portland, Oregon; 3The EMMES Corporation, Rockville, Maryland; 4Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan Financial Disclosure(s): The authors have made the following disclosures: This study was sponsored by the NIH. The NIH holds a royalty-bearing license issued to Bausch & Lomb for the Age-Related Eye Disease Study Supplement. Dr. Abecasis received royalties from patents held by University of Michigan. None of the other authors have financial disclosure. Supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, Department of Health and Human Services, Bethesda Maryland (contract HHS-NOIEY-0-2127) The sponsor and funding organization participated in the design and conduct of the study; data collection, management, analysis and interpretation; and the preparation, review and approval of the manuscript. Correspondence: Emily Y. Chew, MD, National Eye Institute, National Institutes of Health, Building 10, CRC Room 3-2531, 10 Center Drive, MSC 1204, Bethesda, MD 20892-1204. E-mail: [email protected].
References 1. Wittes J, Musch DC. Should we test for genotype in deciding on Age-Related Eye Disease Study Supplementation? Ophthalmology 2015;122:3–5. 2. Awh CC, Lane A-M, Hawken S, et al. CFH and ARMS2 genetic polymorphism predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology 2013;120:2317–23. 3. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS Report Number 38. Ophthalmology 2014;121:2173–80. 4. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology 2015;122:162–9. 5. Chew EY, Klein ML, Clemons TE. Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? Ophthalmology 2015;122: 212–5.
Re: Lepore et al.: Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings (Ophthalmology 2014;121:2212-9) Dear Editor: We read with interest the article by Lepore et al1 describing the effects of vascular endothelial growth factor (VEGF) suppression on retinal vascularization as characterized by fluorescein angiography. Since the publication of Efficacy of Intravitreal Bevacizumab for Stage 3þ Retinopathy of Prematurity (BEATROP) study,2 the use of bevacizumab in premature eyes has increased exponentially despite little understanding of the longterm effects of VEGF suppression in retinal vascular and neuronal development and, more important, its acute and chronic
e47
Ophthalmology Volume 122, Number 8, August 2015 systemic effects. The fluorescein angiographic findings presented by Lepore et al raise serious concerns about indiscriminate use of bevacizumab for treatment of retinopathy of prematurity, especially when laser ablation, an effective treatment option with proven longterm systemic and ocular safety, exists. We have a few concerns and comments. Infants with aggressive posterior retinopathy of prematurity in zone 1 treated with laser have an increased incidence of high myopia.3 In contrast, those babies who receive intravitreal bevacizumab as monotherapy for retinopathy of prematurity are more likely to be emmetropic.3,4 Therefore, babies who receive bevacizumab monotherapy in 1 eye as opposed to laser in the fellow eye are at great risk for developing severe anisometropia. We understand that assigning 1 eye to laser and the fellow eye to the bevacizumab arm in the same patient creates a good cohort and removes many patient-related factors that may affect the comparison. However, this would be expected to cause anisometropic amblyopia and raises concerns regarding such use in larger, randomized clinical trials. In contrast, infants who receive the same treatment bilaterally, such as bevacizumab, bevacizumab plus laser, or laser only, are less likely to develop such severe anisometropia. The authors mention that 1 of the 13 patients died of pulmonary complications. A detailed explanation, including whether the infant received bevacizumab or not, the type of pulmonary complications, and the respiratory status prior to injection, would have been informative. In our series, we noted pulmonary complications in 1 of 12 babies who received bevacizumab and laser at 2 months after the injection. This baby had respiratory distress and severe aggressive posterior retinopathy of prematurity that resolved completely, but the respiratory difficulties reappeared at 2 months after discharge, leading to the death of the patient from pulmonary complications. Given the importance of VEGF for pulmonary development and the significant systemic suppression of VEGF levels with a single intravitreal injection in infants, close monitoring of the respiratory system after intravitreal bevacizumab administration is of paramount importance. The use of antibiotic drops in addition to 0.5% povidone iodine both before and after injection may be unnecessary. Any topical medication in an infant may have systemic side effects. Because povidone iodine provides excellent antimicrobial prophylaxis for intravitreal treatment,5 using topical antibiotics as an additional measure before or after injection may be counterproductive in premature infants.
TAPAS RANJAN PADHI, MS, DNB1 CAGRI G. BESIRLI, MD, PHD2 1
Consultant, Retina and Vitreous services, LV Prasad Eye Institute, Bhubaneswar, India; 2Assistant Professor, Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Cagri G. Besirli, MD, PhD, Kellogg Eye Center, Ophthalmology and Visual Sciences, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
References 1. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity:
e48
2.
3.
4. 5.
report on fluorescein angiographic findings. Ophthalmology 2014;121:2212–9. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative group. Efficacy of intravitreal bevacizumab for stage 3þ retinopathy of prematurity. N Engl J Med 2011;364: 603–15. Geloneck MM, Chuang AZ1, Clark WL, et al; for the BEATROP Cooperative Group. Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial. JAMA Ophthalmol 2014;132:1327–33. Chen YH, Chen SN, Lien RI, et al. Refractive errors after the use of bevacizumab for the treatment of retinopathy of prematurity: 2-year outcomes. Eye 2014;28:1080–6. Chen RW, Rachitskaya A, Scott IU, Flynn HW Jr. Is the use of topical antibiotics for intravitreal injections the standard of care or are we better off without antibiotics? JAMA Ophthalmol 2013;131:840–2.
Author reply Dear Editor: Padhi and Besirli express 3 major concerns about our study1 comparing laser and intravitreal injection of bevacizumab for the treatment of aggressive posterior retinopathy of prematurity. Regarding the risk of anisometropia induced by eye randomization, we informed parents about the risk and performed diligent follow-up. In addition, this within-subject randomization was an important and ethically acceptable component of both the CRYO-ROP and ETROP trials. Long-term results of this aspect of our study will be available soon. Regarding the baby who died of pulmonary complications at a remote hospital, it was quite difficult to obtain complete information from the hospital concerning the pathogenic agent that led to pneumonia and generalized sepsis. This 29-week gestational age, 475-g birth weight infant was a twin who was discharged from our center at 42 weeks. Finally, we agree that 0.5% povidone iodine alone is excellent in preventing infectious complications, although we have been using antibiotics in addition without any significant side effects noted.
DOMENICO LEPORE, MD GRAHAM E. QUINN, MD, MSCE Department of Ophthalmology, Catholic University of Sacred Heart, Rome, Italy Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Domenico Lepore, MD, Department of Ophthalmology, Catholic University of Sacred Heart, Largo Francesco Vito, 8, Rome 00168, Italy. E-mail: [email protected].
Reference 1. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology 2014;121:2212–9.