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Ramezani A, Molazem H, Entezari M, Nikkhah H, Rezanejad S, Yaseri M. Short-Term Effects of Adding Topical Ketorolac to Intravitreal Bevacizumab in Diabetic Macular Edema: A Crossover Randomized Clinical Trial. JOVR [Internet]. 2024Mar.10 [cited 2024Apr.27];19(1):25–32. Available from: https://knepublishing.com/index.php/JOVR/article/view/15424
https://doi.org/10.18502/jovr.v19i1.15424
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authors
-
Alireza Ramezani
Alireza Ramezani
Ophthalmic Epidemiology Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Hossein Molazem
Hossein Molazem
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Morteza Entezari
Morteza Entezari
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Homayoun Nikkhah
Homayoun Nikkhah
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Saman Rezanejad
Saman Rezanejad
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Mehdi Yaseri
Mehdi Yaseri
Department of Epidemiology and Biostatistics, Tehran University of Medical Sciences, Tehran, Iran
Published Date
- Mar 10, 2024
Short-Term Effects of Adding Topical Ketorolac to Intravitreal Bevacizumab in Diabetic Macular Edema: A Crossover Randomized Clinical Trial
Abstract
Purpose: To evaluate the short-term additive effects of topical ketorolac to intravitreal bevacizumab (IVB) in the management of center-involved diabetic macular edema (CI-DME).
Methods: In a randomized double-masked placebo-controlled crossover clinical trial, eyes with CI-DME and the best-corrected visual acuity (BCVA) between (20/40) and (20/400) were included. These eyes should have had at least one intravitreal anti-VEGF injection in the preceding two months. They were randomized into two groups; while both groups received two IVB injections with a six-week interval, one group received topical ketorolac every 6 hr in the first interval and artificial tears every 6 hr as a placebo in the second interval and the other group received the same medications using a crossover method. The main outcome measures were changes in BCVA and central macular thickness (CMT) .
Results: Fifty-seven eyes of 35 patients with CI-DME were included in the study. The mean BCVA improvement was –0.09 ± 0.47 logMAR in the periods of receiving ketorolac and –0.03 ± 0.12 logMAR in the periods of placebo treatment, respectively (P = 0.99). Corresponding changes in CMT were –13.1 ± 170.1 and +11.7 ± 157.7 µm in the ketorolac and placebo periods, respectively (P = 0.322). The treatment effect was not statistically significant regarding both BCVA and CMT changes. Statistical analysis also disclosed that the carryover effect was insignificant for BCVA and CMT. Although the period effect was not significant for BCVA, it was at a meaningful level for CMT changes (P = 0.012).
Conclusion: This crossover clinical trial demonstrated that in the course of DME treatment with IVB injections, topical ketorolac did not have any additive beneficial effect at least during a six-week period.
Keywords:
Bevacizumab, Diabetic Macular Edema, Intravitreal, Topical Ketorolac
References
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2. Abramoff MD, Lou Y, Erginay A, Clarida W, Amelon R, Folk JC, et al. Improved automated detection of diabetic retinopathy on a publicly available dataset through integration of deep learning. Invest Ophthalmol Vis Sci 2016;57:5200–5206.
3. Paulus YM, Gariano RF. Diabetic retinopathy: A growing concern in an aging population. Geriatrics 2009;64:16–20.
4. Holekamp NM. Overview of diabetic macular edema. Am J Manag Care 2016;22:s284–s91.
5. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806.
6. Maeshima K, Utsugi-Sutoh N, Otani T, Kishi S. Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina 2004;24:507–511.
7. Kim EJ, Lin WV, Rodriguez SM, Chen A, Loya A, Weng CY. Treatment of diabetic macular edema. Curr Diab Rep 2019;19:68.
8. Soheilian M, Karimi S, Ramezani A, Montahai T, Yaseri M, Soheilian R, et al. Intravitreal diclofenac versus intravitreal bevacizumab in naive diabetic macular edema: A randomized double-masked clinical trial. Int Ophthalmol 2015;35:421–428.
9. Elbendary AM, Shahin MM. Intravitreal diclofenac versus intravitreal triamcinolone acetonide in the treatment of diabetic macular edema. Retina 2011;31:2058–2064.
10. Reis Ado C, Vianna RN, Reis RS, Cardoso GP. [Intravitreal injection of ketorolac tromethamine in patients with diabetic macular edema refractory to retinal photocoagulation]. Arq Bras Oftalmol 2010;73:338–342.
11. Faghihi H, Yahyapour H, Mahmoudzadeh R, Faghihi S. Comparison of intravitreal bevacizumab and intravitreal diclofenac in the treatment of diabetic macular edema: A 6-month follow-up. Med Hypothesis Discov Innov Ophthalmol 2017;6:67–75.
12. Ghanbari H, Kianersi F, Sonbolestan SA, Abtahi MA, Akbari M, Abtahi ZA, et al. Intravitreal diclofenac plus bevacizumab versus bevacizumab alone in treatmentnaive diabetic macular edema: A randomized double-blind clinical trial. Int Ophthalmol 2017;37:867–874.
13. Maldonado RM, Vianna RN, Cardoso GP, de Magalhaes AV, Burnier MN, Jr. Intravitreal injection of commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser photocoagulation. Curr Eye Res 2011;36:768–773.
14. Soheilian M, Karimi S, Ramezani A, Peyman GA. Pilot study of intravitreal injection of diclofenac for treatment of macular edema of various etiologies. Retina 2010;30:509–515.
15. Semeraro F, Russo A, Gambicorti E, Duse S, Morescalchi F, Vezzoli S, et al. Efficacy and vitreous levels of topical NSAIDs. Expert Opin Drug Deliv 2015;12:1767–1782.
16. Chastain JE, Sanders ME, Curtis MA, Chemuturi NV, Gadd ME, Kapin MA, et al. Distribution of topical ocular nepafenac and its active metabolite amfenac to the posterior segment of the eye. Exp Eye Res 2016;145:58– 67.
17. Pinna A, Blasetti F, Ricci GD, Boscia F. Bromfenac eyedrops in the treatment of diabetic macular edema: A pilot study. Eur J Ophthalmol 2017;27:326–330.
18. Evliyaoglu F, Akpolat C, Kurt MM, Cekic O, Nuri Elcioglu M. Retinal vascular caliber changes after topical nepafenac treatment for diabetic macular edema. Curr Eye Res 2018;43:357–361.
19. Yilmaz U, Kucuk E, Ulusoy DM, Ozkose A, Atas M, Demircan S, et al. The assessment of changes in macular thickness in diabetic and non-diabetic patients: The effect of topical ketorolac on macular thickness change after ND:YAG laser capsulotomy. Cutan Ocul Toxicol 2016;35:58–61.
20. Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, et al. Topical nepafenec in eyes with noncentral diabetic macular edema. Retina 2015;35:944–956.
21. Razo Blanco-Hernandez DM, Lima-Gomez V, Asbun- Bojalil J. [Efficacy of topical ketorolac for improving visual function after photocoagulation in diabetic patients with focal macular edema]. Cir Cir 2014;82:477–488.
22. Sahoo S, Barua A, Myint KT, Haq A, Abas AB, Nair NS. Topical non-steroidal anti-inflammatory agents for diabetic cystoid macular oedema. Cochrane Database Syst Rev 2015:CD010009.
23. Gonzalez VH, Campbell J, Holekamp NM, Kiss S, Loewenstein A, Augustin AJ, et al. Early and longterm responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: Analysis of protocol I data. Am J Ophthalmol 2016;172:72–79.
24. Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year followup of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609–614.
25. Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972–979.
26. Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801.
27. Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: The 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120:2013–2022.
28. Wykoff CC, Ou WC, Khurana RN, Brown DM, Lloyd Clark W, Boyer DS, et al. Long-term outcomes with as-needed aflibercept in diabetic macular oedema: 2-year outcomes of the ENDURANCE extension study. Br J Ophthalmol 2018;102:631–636.
29. Russo A, Costagliola C, Delcassi L, Parmeggiani F, Romano MR, Dell’Omo R, et al. Topical nonsteroidal anti-inflammatory drugs for macular edema. Mediators Inflamm 2013;2013:476525.
30. Schoenberger SD, Kim SJ. Nonsteroidal anti-inflammatory drugs for retinal disease. Int J Inflam 2013;2013:281981.
31. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: A safety review. Drug Saf 2002;25:233–250.
32. Pastore MR, De Giacinto C, Cirigliano G, D’Aloisio R, Riccardo A, Chiara A, et al. Vitreous prostaglandin E2 changes after topical administration of diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, and bromfenac 0.09. Retina 2019.
33. Heier JS, Awh CC, Busbee BG, Waterbury LD, Daniel P, Stoller GL, et al. Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%. Retina 2009;29:1310–1313.
34. Acar U, Acar DE, Tanriverdi C, Acar M, Ozdemir O, Erikci A, et al. Prostaglandin E2 levels of aqueous and vitreous humor in ketorolac 0.4% and nepafenac 0.1% administered healthy rabbits. Ocul Immunol Inflamm 2017;25:323–327.
35. Bucci FA Jr, Waterbury LD. A randomized comparison of to-aqueous penetration of ketorolac 0.45%, bromfenac 0.09% and nepafenac 0.1% in cataract patients undergoing phacoemulsification. Curr Med Res Opin 2011;27:2235– 2239.
36. Bucci FA Jr, Waterbury LD. Prostaglandin E2 inhibition of ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% in patients undergoing phacoemulsification. Adv Ther 2011;28:1089–1095.
37. Walters T, Raizman M, Ernest P, Gayton J, Lehmann R. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg 2007;33:1539–1545.
38. WON B-SLY-WCJ-Y. The effect of a 0.1% bromfenac solution on diabetic macular edema. J Korean Ophthalmol Soc 2020:1273–1278.
39. Sivaprasad S, Crosby-Nwaobi R, Esposti SD, Peto T, Rajendram R, Michaelides M, et al. Structural and functional measures of efficacy in response to bevacizumab monotherapy in diabetic macular oedema: Exploratory analyses of the BOLT study (report 4). PLoS One 2013;8:e72755.
40. Sivaprasad S, Crosby-Nwaobi R, Heng LZ, Peto T, Michaelides M, Hykin P. Injection frequency and response to bevacizumab monotherapy for diabetic macular oedema (BOLT Report 5). Br J Ophthalmol 2013;97:1177– 1180.
41. Michaelides M, Fraser-Bell S, Hamilton R, Kaines A, Egan C, Bunce C, et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study): Report 1. Retina 2010;30:781–786.
42. Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12- month data: Report 2. Ophthalmology 2010;117:1078–86 e2.
43. Pieramici DJ, Wang PW, Ding B, Gune S. Visual and anatomic outcomes in patients with diabetic macular edema with limited initial anatomic response to ranibizumab in RIDE and RISE. Ophthalmology 2016;123:1345–1350.
44. Bandello F, De Benedetto U, Knutsson KA, Parodi MB, Cascavilla ML, Iacono P. Ranibizumab in the treatment of patients with visual impairment due to diabetic macular edema. Clin Ophthalmol 2011;5:1303–1308.
45. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: Results from the Pan- American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007;114:743–750.
46. Baghi A, Jabbarpoor Bonyadi MH, Ramezani A, Azarmina M, Moradian S, Dehghan MH, et al. Two doses of intravitreal ziv-aflibercept versus bevacizumab in treatment of diabetic macular edema: A three-armed, double-blind randomized trial. Ophthalmol Retina 2017;1:103–110.
47. Jabbarpoor Bonyadi MH, Baghi A, Ramezani A, Yaseri M, Soheilian M. One-year results of a trial comparing 2 doses of intravitreal ziv-aflibercept versus bevacizumab for treatment of diabetic macular edema. Ophthalmol Retina 2018;2:428–440.
48. Korobelnik JF, Daien V, Faure C, Tadayoni R, Giocanti- Auregan A, Dot C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: Results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol 2020;258:521–528.
49. Ozkiris A. Intravitreal bevacizumab (Avastin) for primary treatment of diabetic macular oedema. Eye 2009;23:616– 620.
50. Soheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 2007;27:1187–1195.
51. Sibbald B, Roberts C. Understanding controlled trials. Crossover trials. BMJ 1998;316:1719.
52. Margalit E, Kugler LJ, Brumm MV, Meza JL, Kompella UB, Escobar ER, et al. The safety of intraocular ketorolac in rabbits. Invest Ophthalmol Vis Sci 2006;47:2093–2099.
53. Ling TL, Combs DL. Ocular bioavailability and tissue distribution of [14C]ketorolac tromethamine in rabbits. J Pharm Sci 1987;76:289–294.
2. Abramoff MD, Lou Y, Erginay A, Clarida W, Amelon R, Folk JC, et al. Improved automated detection of diabetic retinopathy on a publicly available dataset through integration of deep learning. Invest Ophthalmol Vis Sci 2016;57:5200–5206.
3. Paulus YM, Gariano RF. Diabetic retinopathy: A growing concern in an aging population. Geriatrics 2009;64:16–20.
4. Holekamp NM. Overview of diabetic macular edema. Am J Manag Care 2016;22:s284–s91.
5. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806.
6. Maeshima K, Utsugi-Sutoh N, Otani T, Kishi S. Progressive enlargement of scattered photocoagulation scars in diabetic retinopathy. Retina 2004;24:507–511.
7. Kim EJ, Lin WV, Rodriguez SM, Chen A, Loya A, Weng CY. Treatment of diabetic macular edema. Curr Diab Rep 2019;19:68.
8. Soheilian M, Karimi S, Ramezani A, Montahai T, Yaseri M, Soheilian R, et al. Intravitreal diclofenac versus intravitreal bevacizumab in naive diabetic macular edema: A randomized double-masked clinical trial. Int Ophthalmol 2015;35:421–428.
9. Elbendary AM, Shahin MM. Intravitreal diclofenac versus intravitreal triamcinolone acetonide in the treatment of diabetic macular edema. Retina 2011;31:2058–2064.
10. Reis Ado C, Vianna RN, Reis RS, Cardoso GP. [Intravitreal injection of ketorolac tromethamine in patients with diabetic macular edema refractory to retinal photocoagulation]. Arq Bras Oftalmol 2010;73:338–342.
11. Faghihi H, Yahyapour H, Mahmoudzadeh R, Faghihi S. Comparison of intravitreal bevacizumab and intravitreal diclofenac in the treatment of diabetic macular edema: A 6-month follow-up. Med Hypothesis Discov Innov Ophthalmol 2017;6:67–75.
12. Ghanbari H, Kianersi F, Sonbolestan SA, Abtahi MA, Akbari M, Abtahi ZA, et al. Intravitreal diclofenac plus bevacizumab versus bevacizumab alone in treatmentnaive diabetic macular edema: A randomized double-blind clinical trial. Int Ophthalmol 2017;37:867–874.
13. Maldonado RM, Vianna RN, Cardoso GP, de Magalhaes AV, Burnier MN, Jr. Intravitreal injection of commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser photocoagulation. Curr Eye Res 2011;36:768–773.
14. Soheilian M, Karimi S, Ramezani A, Peyman GA. Pilot study of intravitreal injection of diclofenac for treatment of macular edema of various etiologies. Retina 2010;30:509–515.
15. Semeraro F, Russo A, Gambicorti E, Duse S, Morescalchi F, Vezzoli S, et al. Efficacy and vitreous levels of topical NSAIDs. Expert Opin Drug Deliv 2015;12:1767–1782.
16. Chastain JE, Sanders ME, Curtis MA, Chemuturi NV, Gadd ME, Kapin MA, et al. Distribution of topical ocular nepafenac and its active metabolite amfenac to the posterior segment of the eye. Exp Eye Res 2016;145:58– 67.
17. Pinna A, Blasetti F, Ricci GD, Boscia F. Bromfenac eyedrops in the treatment of diabetic macular edema: A pilot study. Eur J Ophthalmol 2017;27:326–330.
18. Evliyaoglu F, Akpolat C, Kurt MM, Cekic O, Nuri Elcioglu M. Retinal vascular caliber changes after topical nepafenac treatment for diabetic macular edema. Curr Eye Res 2018;43:357–361.
19. Yilmaz U, Kucuk E, Ulusoy DM, Ozkose A, Atas M, Demircan S, et al. The assessment of changes in macular thickness in diabetic and non-diabetic patients: The effect of topical ketorolac on macular thickness change after ND:YAG laser capsulotomy. Cutan Ocul Toxicol 2016;35:58–61.
20. Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, et al. Topical nepafenec in eyes with noncentral diabetic macular edema. Retina 2015;35:944–956.
21. Razo Blanco-Hernandez DM, Lima-Gomez V, Asbun- Bojalil J. [Efficacy of topical ketorolac for improving visual function after photocoagulation in diabetic patients with focal macular edema]. Cir Cir 2014;82:477–488.
22. Sahoo S, Barua A, Myint KT, Haq A, Abas AB, Nair NS. Topical non-steroidal anti-inflammatory agents for diabetic cystoid macular oedema. Cochrane Database Syst Rev 2015:CD010009.
23. Gonzalez VH, Campbell J, Holekamp NM, Kiss S, Loewenstein A, Augustin AJ, et al. Early and longterm responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: Analysis of protocol I data. Am J Ophthalmol 2016;172:72–79.
24. Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year followup of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609–614.
25. Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972–979.
26. Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801.
27. Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: The 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120:2013–2022.
28. Wykoff CC, Ou WC, Khurana RN, Brown DM, Lloyd Clark W, Boyer DS, et al. Long-term outcomes with as-needed aflibercept in diabetic macular oedema: 2-year outcomes of the ENDURANCE extension study. Br J Ophthalmol 2018;102:631–636.
29. Russo A, Costagliola C, Delcassi L, Parmeggiani F, Romano MR, Dell’Omo R, et al. Topical nonsteroidal anti-inflammatory drugs for macular edema. Mediators Inflamm 2013;2013:476525.
30. Schoenberger SD, Kim SJ. Nonsteroidal anti-inflammatory drugs for retinal disease. Int J Inflam 2013;2013:281981.
31. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: A safety review. Drug Saf 2002;25:233–250.
32. Pastore MR, De Giacinto C, Cirigliano G, D’Aloisio R, Riccardo A, Chiara A, et al. Vitreous prostaglandin E2 changes after topical administration of diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, and bromfenac 0.09. Retina 2019.
33. Heier JS, Awh CC, Busbee BG, Waterbury LD, Daniel P, Stoller GL, et al. Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%. Retina 2009;29:1310–1313.
34. Acar U, Acar DE, Tanriverdi C, Acar M, Ozdemir O, Erikci A, et al. Prostaglandin E2 levels of aqueous and vitreous humor in ketorolac 0.4% and nepafenac 0.1% administered healthy rabbits. Ocul Immunol Inflamm 2017;25:323–327.
35. Bucci FA Jr, Waterbury LD. A randomized comparison of to-aqueous penetration of ketorolac 0.45%, bromfenac 0.09% and nepafenac 0.1% in cataract patients undergoing phacoemulsification. Curr Med Res Opin 2011;27:2235– 2239.
36. Bucci FA Jr, Waterbury LD. Prostaglandin E2 inhibition of ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% in patients undergoing phacoemulsification. Adv Ther 2011;28:1089–1095.
37. Walters T, Raizman M, Ernest P, Gayton J, Lehmann R. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg 2007;33:1539–1545.
38. WON B-SLY-WCJ-Y. The effect of a 0.1% bromfenac solution on diabetic macular edema. J Korean Ophthalmol Soc 2020:1273–1278.
39. Sivaprasad S, Crosby-Nwaobi R, Esposti SD, Peto T, Rajendram R, Michaelides M, et al. Structural and functional measures of efficacy in response to bevacizumab monotherapy in diabetic macular oedema: Exploratory analyses of the BOLT study (report 4). PLoS One 2013;8:e72755.
40. Sivaprasad S, Crosby-Nwaobi R, Heng LZ, Peto T, Michaelides M, Hykin P. Injection frequency and response to bevacizumab monotherapy for diabetic macular oedema (BOLT Report 5). Br J Ophthalmol 2013;97:1177– 1180.
41. Michaelides M, Fraser-Bell S, Hamilton R, Kaines A, Egan C, Bunce C, et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study): Report 1. Retina 2010;30:781–786.
42. Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12- month data: Report 2. Ophthalmology 2010;117:1078–86 e2.
43. Pieramici DJ, Wang PW, Ding B, Gune S. Visual and anatomic outcomes in patients with diabetic macular edema with limited initial anatomic response to ranibizumab in RIDE and RISE. Ophthalmology 2016;123:1345–1350.
44. Bandello F, De Benedetto U, Knutsson KA, Parodi MB, Cascavilla ML, Iacono P. Ranibizumab in the treatment of patients with visual impairment due to diabetic macular edema. Clin Ophthalmol 2011;5:1303–1308.
45. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, Sanchez JG, Wu L, Maia M, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: Results from the Pan- American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007;114:743–750.
46. Baghi A, Jabbarpoor Bonyadi MH, Ramezani A, Azarmina M, Moradian S, Dehghan MH, et al. Two doses of intravitreal ziv-aflibercept versus bevacizumab in treatment of diabetic macular edema: A three-armed, double-blind randomized trial. Ophthalmol Retina 2017;1:103–110.
47. Jabbarpoor Bonyadi MH, Baghi A, Ramezani A, Yaseri M, Soheilian M. One-year results of a trial comparing 2 doses of intravitreal ziv-aflibercept versus bevacizumab for treatment of diabetic macular edema. Ophthalmol Retina 2018;2:428–440.
48. Korobelnik JF, Daien V, Faure C, Tadayoni R, Giocanti- Auregan A, Dot C, et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: Results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol 2020;258:521–528.
49. Ozkiris A. Intravitreal bevacizumab (Avastin) for primary treatment of diabetic macular oedema. Eye 2009;23:616– 620.
50. Soheilian M, Ramezani A, Bijanzadeh B, Yaseri M, Ahmadieh H, Dehghan MH, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina 2007;27:1187–1195.
51. Sibbald B, Roberts C. Understanding controlled trials. Crossover trials. BMJ 1998;316:1719.
52. Margalit E, Kugler LJ, Brumm MV, Meza JL, Kompella UB, Escobar ER, et al. The safety of intraocular ketorolac in rabbits. Invest Ophthalmol Vis Sci 2006;47:2093–2099.
53. Ling TL, Combs DL. Ocular bioavailability and tissue distribution of [14C]ketorolac tromethamine in rabbits. J Pharm Sci 1987;76:289–294.