Safety of intravitreal ziv-aflibercept in choroido-retinal vascular diseases: A randomised double-blind intervention study

Autoři: Imoro Zeba Braimah aff001;  Ernest Kenu aff003;  Kwesi N. Amissah-Arthur aff001;  Stephen Akafo aff001;  Kwaku Oppong Kwarteng aff002;  Winfried M. Amoaku aff004
Působiště autorů: Department of Surgery (Eye), School of Medicine and Dentistry, College of Health Sciences, University of Ghana, Accra, Ghana aff001;  Eye Centre, Korle- Bu Teaching Hospital, Korle- Bu, Accra, Ghana aff002;  Department of Epidemiology, School of Public Health, University of Ghana, Accra, Ghana aff003;  Academic Ophthalmology, DCN, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, England, United Kingdom aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article



To evaluate the safety of 1.25mg and 2mg intravitreal ziv-aflibercept (IVZ) in Ghanaian eyes with choroido-retinal vascular diseases.


Prospective, randomised, double blind, interventional study.


Twenty patients with centre involving macular oedema in diabetic retinopathy, retinal vein occlusion, and neovascular age-related macular degeneration were assigned to 2 groups receiving 3 doses of 1.25mg/0.05ml (group 1) and 2mg/0.08ml IVZ (Group 2) at 4 weekly intervals. Safety data was collected after 30 minutes, 1 and 7 days, and 4, 8 and 12 weeks after injection. Changes in continuous variables were compared using paired t-test and categorical variables were compared using chi-square test of proportions. Repeated-Measures ANOVA with nesting test was used to compare variations in continuous variables by IVZ dose over time. Primary outcome measures were ocular and systemic adverse events at 4 weeks.


Eleven females and nine males, with mean age of 63.2± 7.3 years were included. Ocular adverse events included subconjunctival haemorrhage in 1 eye, intraocular pressure (IOP) >21mmHg at 30 minutes in 6 eyes and mild pain in 3 eyes at 1-day. There was no significant difference in IOP rise between the 2 groups at 30 minutes (p = 0.21). No other ocular or systemic adverse events were observed. There was significant improvement in the best corrected visual acuity (LogMAR) from 0.95±0.6 to 0.6±0.4 (p<0.01) and 0.47±0.3 (p<0.01), reduction in central subfield foveal thickness from 405.9±140 um at baseline to 255.6±75 um (p<0.01) and 238±88 um (p<0.01) at 4 and 12 weeks respectively, although no difference was observed between the 2 groups (p = 0.34).


IVZ at 1.25mg and 2mg had similar safety profiles, and did not have any major unexpected adverse events. Further studies with larger cohorts are required to confirm efficacy.

Klíčová slova:

Adverse events – Eye diseases – Eyes – Ghana – Intraocular pressure – Ocular anatomy – Ocular system – Visual acuity


1. Dalal S, Beunza JJ, Volmink J, Adebamowo C, Bajunirwe F, Njelekela M, et al. Non-communicable diseases in sub-Saharan Africa: what we know now. Int J Epidem. 2011; 40(4):885–901.

2. Nazimul H, Rohit K, Anjli H. Trend of retinal diseases in developing countries. Exp Rev Ophthalmol. 2008; 3(1):43–50.

3. Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol. 2012;96(5):614–8. doi: 10.1136/bjophthalmol-2011-300539 22133988

4. Hera R, Keramidas M, Peoc’h M, Mouillon M, Romanet JP, Feige JJ. Expression of VEGF and angiopoietins in subfoveal membranes from patients with age-related macular degeneration. Am J Ophthalmol. 2005; 139(4):589–96. doi: 10.1016/j.ajo.2004.11.064 15808152

5. Ho AC, Scott IU, Kim SJ, Brown GC, Brown MM, Ip MS, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology. 2012; 119(10):2179–88. doi: 10.1016/j.ophtha.2012.07.058 22917890

6. Wang S, Park JK, Duh EJ. Novel targets against retinal angiogenesis in diabetic retinopathy. Curr diab rep. 2012; 12(4):355–63. doi: 10.1007/s11892-012-0289-0 22638940

7. Chung C, Pherwani N. Ziv-aflibercept: a novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer. Am J Health Syst Pharm. 2013; 70(21):1887–96 doi: 10.2146/ajhp130143 24128964

8. Shah GK ST. 2017 Global Trends in Retina Survey. Chicago, IL.; 2017.

9. Amoaku WM, Chakravarthy U, Gale R, Gavin M, Ghanchi F, Gibson J, et al. Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond). 2015; 29(10):1397–8.

10. Andrade GC, Dias JR, Maia A, Farah ME, Meyer CH, Rodrigues EB. Intravitreal injections of ziv-aflibercept for diabetic macular edema: A Pilot Study. Retina (Philadelphia, Pa). 2016; 36(9):1640–5.

11. Braimah IZ, Agarwal K, Mansour A, Chhablani J. One-year outcome of intravitreal ziv-aflibercept therapy for non-responsive neovascular age-related macular degeneration. Br J Ophthalmol. 2018; 102(1):91–96. doi: 10.1136/bjophthalmol-2017-310318 28596286

12. Chhablani J, Narayanan R, Mathai A, Yogi R, Stewart M. Short-term safety profile of intravitreal ziv-aflibercept. Retina (Philadelphia, Pa). 2016; 36(6):1126–31.

13. de Andrade GC, de Oliveira Dias JR, Maia A, Farah ME, Meyer CH, Rodrigues EB. Intravitreal Ziv-Aflibercept for Diabetic Macular Edema: 48-Week Outcomes. Ophthalmic surg, Lasers & Imaging Retina. 2018; 49(4):245–50.

14. de Oliveira Dias JR, Costa de Andrade G, Kniggendorf VF, Novais EA, Takahashi VKL, Maia A, et al.Intravitreal ziv-aflibercept for neovascular age-related macular degeneration: 52-Week Results. Retina (Philadelphia, Pa). 2017.

15. Mansour AM, Al-Ghadban SI, Yunis MH, El-Sabban ME. Ziv-aflibercept in macular disease. Br J Ophthalmol. 2015; 99(8):1055–9. doi: 10.1136/bjophthalmol-2014-306319 25677668

16. Mansour AM, Ashraf M, Charbaji A, Younis MH, Souka AA, Dogra A, et al. Two-year outcomes of intravitreal ziv-aflibercept. Br J Ophthalmol. 2018; 102(10):1387–1390 doi: 10.1136/bjophthalmol-2017-311591 29317400

17. Mansour AM, Chhablani J, Antonios RS, Yogi R, Younis MH, Dakroub R, et al. Three-month outcome of ziv-aflibercept for exudative age-related macular degeneration. Br J Ophthalmol. 2016; 100(12):1629–33. doi: 10.1136/bjophthalmol-2015-308319 27030277

18. Paulose R, Chhablani J, Dedhia CJ, Stewart MW, Mansour AM. Intravitreal ziv-aflibercept for macular edema following retinal vein occlusion. Clin Ophthalmol. 2016; 10:1853–8. doi: 10.2147/OPTH.S116343 27703326

19. Chhablani J, Dedhia CJ, Peguda HK, Stewart M. Short-term safety of 2mg intravitreal ziv-aflibercept. Retina (Philadelphia, Pa). 2017; 37(10):1859–65.

20. Singh SR, Stewart MW, Chattannavar G, Ashraf M, Souka A, ElDardeery M, et al. Safety of 5914 intravitreal ziv-aflibercept injections. Br J Ophthalmol. 2018:bjophthalmol-2018-312453.

21. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005; 140(3):509–16. doi: 10.1016/j.ajo.2005.03.057 16196117

22. Caudle LE, Williams KA, Pesudovs K. The Eye Sensation Scale: an ophthalmic pain severity measure. Optom Vis Sci. 2007; 84(8):752–62. doi: 10.1097/OPX.0b013e31812f7690 17700338

23. Trichonas G, Kaiser PK. Aflibercept for the treatment of age-related macular degeneration. Ophthalmol Ther. 2013; 2(2):89–98. doi: 10.1007/s40123-013-0015-2 25135809

24. Andrade GC, Dias JR, Maia A, Farah ME, Meyer CH, Rodrigues EB. Intravitreal injections of ziv-aflibercept for diabetic macular edema: A Pilot Study. Retina. 2016;36(9):1640–5 doi: 10.1097/IAE.0000000000001000 26991646

25. Ashraf M, Souka AA, El Kayal H, El Manhaly M, Abdallah MH. Three-month outcomes of ziv-aflibercept in the treatment of diabetic macular oedema. Acta Ophthalmol. 2016; 94(7):e669. doi: 10.1111/aos.13111 27227354

26. Chhablani J. Intravitreal ziv-aflibercept for recurrent macular edema secondary to central retinal venous occlusion. Indian J Ophthalmol. 2015; 63(5):469–70. doi: 10.4103/0301-4738.159909 26139820

27. de Oliveira Dias JR, Xavier CO, Maia A, de Moraes NS, Meyer C, Farah ME, et al. Intravitreal injection of ziv-aflibercept in patient with refractory age-related macular degeneration. Ophthalmic Surg, Lasers & Imaging Retina. 2015; 46(1):91–4.

28. Mansour AM, Chhablani J, Antonios RS, Yogi R, Younis MH, Dakroub R, et al. Three-month outcome of ziv-aflibercept for exudative age-related macular degeneration. Br J Ophthalmol. 2016; 100(12):1629–1633. doi: 10.1136/bjophthalmol-2015-308319 27030277

29. Mansour AM, Dedhia C, Chhablani J. Three-month outcome of intravitreal ziv-aflibercept in eyes with diabetic macular oedema. Br J Ophthalmol.2017; 101(2):166–16. doi: 10.1136/bjophthalmol-2016-308679 27190127

30. Marashi A. Three-Month Outcome of Ziv-Aflibercept for Diabetic Macular Edema. Adv Ophthalmol Vis Syst. 2016;4(3).

31. Malik D, Tarek M, Caceres del Carpio J, Ramirez C, Boyer D, Kenney MC, et al. Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol. 2014; 98 Suppl 1:i11–6.

32. de Oliveira Dias JR, Badaro E, Novais EA, Colicchio D, Chiarantin GM, Matioli MM, et al. Preclinical investigations of intravitreal ziv-aflibercept. Ophthalmic Surg, Lasers & Imaging Retina. 2014; 45(6):577–84.

33. Chakravarthy U, Adamis AP, Cunningham ET Jr., Goldbaum M, Guyer DR, Katz B, et al. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006; 113(9):1508.e1–25.

34. 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. Ophthalmology Retina.1 (2):103–10. doi: 10.1016/j.oret.2016.08.007 31047266

35. 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. Ophthalmology Retina. 2018; 2(5):428–40. doi: 10.1016/j.oret.2017.09.010 31047323

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2019 Číslo 10
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