Skip to main content
SpringerLink
Log in

Association Between Intravitreal Aflibercept and Serious Non-ocular Haemorrhage Compared with Intravitreal Ranibizumab: A Multicentre Observational Cohort Study

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Introduction

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs aflibercept and ranibizumab are used in neovascular retinal diseases but may be associated with non-ocular haemorrhage.

Aims

Our objective was to compare the risk of non-ocular haemorrhage with intravitreal aflibercept versus intravitreal ranibizumab and with individual intravitreal anti-VEGFs versus intravitreal dexamethasone.

Methods

A retrospective cohort study was conducted using four Italian claims databases, covering 18 million inhabitants from 2011 to 2016. Incident aflibercept users were matched 1:4 to incident ranibizumab users. The outcome was incident non-ocular haemorrhage requiring hospitalisation. Incidence per 1000 person-years (PYs) was estimated. Patients were followed for 180 days using an intention-to-treat (ITT) approach. An as-treated (AT) approach was also employed, using grace periods of 60 or 90 days. Analyses were repeated for aflibercept versus dexamethasone and ranibizumab versus dexamethasone. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.

Results

We identified incident users of intravitreal ranibizumab (n = 21,766), aflibercept (n = 3150) and dexamethasone (n = 3900). The incidence of haemorrhage was four events per 1000 PYs for each drug. Aflibercept was not associated with increased risk versus ranibizumab at 180 days (HR 0.97 [95% CI 0.37–2.56]). Results were consistent in the AT analysis (HR 1.19 [95% CI 0.52–2.75]). No increased risk was found for aflibercept and ranibizumab at 180 days versus dexamethasone (HR 0.70 [95% CI 0.30–2.60] and HR 0.67 [95% CI 0.33–1.38], respectively).

Conclusion

No association was identified between intravitreal aflibercept and non-ocular haemorrhage versus ranibizumab. A comparable risk for these intravitreal anti-VEGFs and intravitreal dexamethasone was observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004;291(15):1900–1.

    Article  CAS  PubMed  Google Scholar 

  2. Brand CS. Management of retinal vascular diseases: a patient-centric approach. Eye (Lond). 2012;26(Suppl 2):S1–.

    Article  CAS  Google Scholar 

  3. Friedman DS, O'Colmain BJ, Muñoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J, Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–72.

    Article  PubMed  Google Scholar 

  4. Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004;82(11):844–51.

    PubMed  PubMed Central  Google Scholar 

  5. Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006;142(6):961–9.

    Article  CAS  PubMed  Google Scholar 

  6. Pe'er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Vascular endothelial growth factor upregulation in human central retinal vein occlusion. Ophthalmology. 1998;105(3):412–6.

    Article  CAS  PubMed  Google Scholar 

  7. Pe'er J, Shweiki D, Itin A, Hemo I, Gnessin H, Keshet E. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest. 1995;72(6):638–45.

    CAS  PubMed  Google Scholar 

  8. Shima DT, Gougos A, Miller JW, Tolentino M, Robinson G, Adamis AP, D'Amore PA. Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis. Invest Ophthalmol Vis Sci. 1996;37(7):1334–400.

    CAS  PubMed  Google Scholar 

  9. Roche Products Limited. Avastin 25mg/ml concentrate for solution for infusion: summary of product characteristics. https://www.medicines.org.uk/emc/product/3885/smpc#POSOLOGY. Accessed 22 Mar 2019.

  10. Steinbrook R. The price of sight–ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006;355(14):1409–12.

    Article  CAS  PubMed  Google Scholar 

  11. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.

    Article  Google Scholar 

  12. Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, Recchia FM, American Academy of Ophthalmology. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(10):1837–46.

    Article  PubMed  Google Scholar 

  13. Virgili G, Parravano M, Menchini F, Brunetti M. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for diabetic macular oedema. Cochrane Database Syst Rev. 2012;12:CD007419.

    PubMed  Google Scholar 

  14. Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC, Murahashi WY, Rubio RG, BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102–1112.e1.

    Article  PubMed  Google Scholar 

  15. Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124–1133.e1.

    Article  PubMed  Google Scholar 

  16. He Y, Ren XJ, Hu BJ, Lam WC, Li XR. A meta-analysis of the effect of a dexamethasone intravitreal implant versus intravitreal anti-vascular endothelial growth factor treatment for diabetic macular edema. BMC Ophthalmol. 2018;18(1):121.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chang-Lin JE, Attar M, Acheampong AA, Robinson MR, Whitcup SM, Kuppermann BD, Welty D. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52(1):80–6.

    Article  CAS  PubMed  Google Scholar 

  18. Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF. Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol. 2013;97(4):454–9.

    Article  PubMed  Google Scholar 

  19. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, Couvillion S, Nasir MA, Rabena MD, Maia M, Van Everen S, Le K, Hanley WD. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina. 2017;37(10):1847–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cutroneo PM, Giardina C, Ientile V, Potenza S, Sottosanti L, Ferrajolo C, Trombetta CJ, Trifirò G. Overview of the safety of anti-VEGF drugs: analysis of the italian spontaneous reporting system. Drug Saf. 2017;40(11):1131–40.

    Article  CAS  PubMed  Google Scholar 

  21. Thulliez M, Angoulvant D, Le Lez ML, Jonville-Bera AP, Pisella PJ, Gueyffier F, Bejan-Angoulvant T. Cardiovascular events and bleeding risk associated with intravitreal antivascular endothelial growth factor monoclonal antibodies: systematic review and meta-analysis. JAMA Ophthalmol. 2014;132(11):1317–26.

    Article  PubMed  Google Scholar 

  22. Elice F, Rodeghiero F. Bleeding complications of antiangiogenic therapy: pathogenetic mechanisms and clinical impact. Thromb Res. 2010;125(Suppl 2):S55–S57.

    Article  PubMed  Google Scholar 

  23. Maloney MH, Schilz SR, Herrin J, Sangaralingham LR, Shah ND, Barkmeier AJ. Risk of systemic adverse events associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice. Ophthalmology. 2019;126(7):1007–155.

    Article  PubMed  Google Scholar 

  24. Campbell RJ, Bell CM, Bronskill SE, Paterson JM, Whitehead M, Campbell Ede L, Gill SS. Adverse gastrointestinal events with intravitreal injection of vascular endothelial growth factor. Inhibitors: nested case-control study. Drug Saf. 2014;37(9):723–33.

    Article  CAS  PubMed  Google Scholar 

  25. Kemp A, Preen DB, Morlet N, Clark A, McAllister IL, Briffa T, Sanfilippo FM, Ng JQ, McKnight C, Reynolds W, Gilles MC. Myocardial infarction after intravitreal vascular endothelial growth factor inhibitors: a whole population study. Retina. 2013;33(5):920–7.

    Article  CAS  PubMed  Google Scholar 

  26. Curtis LH, Hammill BG, Schulman KA, Cousins SW. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128(10):1273–9.

    Article  PubMed  Google Scholar 

  27. Food and Drug Administration. Letter of Eylea marketing authorization approval on behalf of the Food and Drug Administration. Published in 2011. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/125387s000ltr.pdf. Accessed 23 Jan 2020.

  28. Australian Government. Department of Health, Therapeutic Goods Administration. Australian Public Assessment Report for Aflibercept. 2015. https://www.tga.gov.au/sites/default/files/auspar-aflibercept-150721.pdf. Accessed 23 Jan 2020.

  29. Health Canada. Summary Safety Review–EYLEA (aflibercept)–assessing the risk of side effects outside the eye (systemic side effects). 2016. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/summary-safety-review-eylea-aflibercept-assessing-risk-side-effects-outside-systemic-side.html. Accessed 23 Jan 2020

  30. Yang J, Wang X, Fuh G, Yu L, Wakshull E, Khosraviani M, Day ES, Demeule B, Liu J, Shire SJ, Ferrara N, Yadav S. Comparison of binding characteristics and in vitro activities of three inhibitors of vascular endothelial growth factor A. Mol Pharm. 2014;11(10):3421–30.

    Article  CAS  PubMed  Google Scholar 

  31. Scondotto G, Sultana J, Ientile V, Ingrasciotta Y, Fontana A, Copetti M, Mirabelli E, Trombetta CJ, Rapisarda C, Reibaldi M, Avitabile T, Longo A, Toro PI, Vadalà M, Cillino S, Virgili G, Gini R, Leoni O, Pollina Addario SW, Cananzi P, La Cavera C, Puzo MR, De Sarro G, De Francesco A, Trifirò G. How have intravitreal anti-VEGF and dexamethasone implant been used in Italy? A multiregional, population-based study in the years 2010–2016. Biomed Res Int. 2020;11(2020):7582763.

    Google Scholar 

  32. European Medicines Agency. Osurdex summary of product characteristics. 2010. https://www.ema.europa.eu/en/documents/product-information/ozurdex-epar-product-information_en.pdf. Accessed 23 Jan 2020.

  33. Trifirò G, Gini R, Barone-Adesi F, Beghi E, Cantarutti A, Capuano A, Carnovale C, Clavenna A, Dellagiovanna M, Ferrajolo C, Franchi M, Ingrasciotta Y, Kirchmayer U, Lapi F, Leone R, Leoni O, Lucenteforte E, Moretti U, Mugelli A, Naldi L, Poluzzi E, Rafaniello C, Rea F, Sultana J, Tettamanti M, Traversa G, Vannacci A, Mantovani L, Corrao G. The role of European healthcare databases for post-marketing drug effectiveness, safety and value evaluation: where does Italy stand? Drug Saf. 2019;42(3):347–63.

    Article  PubMed  Google Scholar 

  34. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904–14.

    Article  PubMed  Google Scholar 

  35. Callanan DG, Loewenstein A, Patel SS, Massin P, Corcóstegui B, Li XY, Jiao J, Hashad Y, Whitcup SM. A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2017;255(3):463–73.

    Article  CAS  PubMed  Google Scholar 

  36. Austin PC. Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat. 2011;10(2):150–61.

    Article  PubMed  Google Scholar 

  37. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–107.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium use in pregnancy and the risk of cardiac malformations. N Engl J Med. 2017;376(23):2245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xin X, Sun Y, Li S, Xu H, Zhang D. Age-related macular degeneration and the risk of all-cause and cardiovascular mortality: a meta-analysis of cohort studies. Retina. 2018;38(3):497–507.

    Article  PubMed  Google Scholar 

  40. Xie J, Ikram MK, Cotch MF, et al. Association of diabetic macular edema and proliferative diabetic retinopathy with cardiovascular disease: a systematic review and meta-analysis. JAMA Ophthalmol. 2017;135(6):586–93.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wu CY, Riangwiwat T, Limpruttidham N, Rattanawong P, Rosen RB, Deobhakta A. Association of retinal vein occlusion with cardiovascular events and mortality: a systematic review and meta-analysis. Retina. 2019;39(9):1635–45.

    Article  PubMed  Google Scholar 

  42. Zhang W, Xiong Y, Yu L, Xiong A, Bao H, Cheng X. Meta-analysis of stroke and bleeding risk in patients with various atrial fibrillation patterns receiving oral anticoagulants. Am J Cardiol. 2019;123(6):922–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical and Dental Sciences and of Morphological and Functional Images, University of Messina, Messina, Italy

    Janet Sultana & Gianluca Trifirò

  2. U.O.S.D. Farmacologia Clinica, A.O.U. Policlinico “G. Martino”, Messina, Italy

    Francesco Giorgianni, Giulia Scondotto, Valentina Ientile & Gianluca Trifirò

  3. Centre for Clinical Epidemiology, Jewish General Hospital-Lady Davis Institute, Montreal, Canada

    Francesco Giorgianni & Christel Renoux

  4. Regional Pharmacovigilance Centre, Palermo, Italy

    Pasquale Cananzi

  5. Regional Pharmacovigilance Centre, Lombardy, Italy

    Olivia Leoni

  6. Department of Public Health and Epidemiology, Sicilian Regional Healthcare Centre, Palermo, Italy

    Sebastiano Walter Pollina Addario

  7. Department of Healthcare Science, Catanzaro University, Catanzaro, Italy

    Giovanbattista De Sarro

  8. Mater Domini Hospital, Catanzaro, Italy

    Adele De Francesco

  9. Regional Pharmacovigilance Centre, Potenza, Italy

    Maria Rosa Puzo

  10. Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada

    Christel Renoux

  11. Department of Neurology and Neurosurgery, McGill University, Montreal, Canada

    Christel Renoux

Authors
  1. Janet Sultana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Giorgianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giulia Scondotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valentina Ientile
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pasquale Cananzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Olivia Leoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sebastiano Walter Pollina Addario
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanbattista De Sarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adele De Francesco
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Rosa Puzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christel Renoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gianluca Trifirò
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GT conceived the study. FG, CR and GT contributed to the study design. FG, JS and GT interpreted the data and wrote the first draft of the paper. GS, VI, PC, OL, SWPA, AF, GDS and CR critically revised the manuscript.

Corresponding author

Correspondence to Janet Sultana.

Ethics declarations

Funding

This study was funded by a Grant from the Italian Medicines Agency for the project “Short- and long-term monitoring of the benefit–risk profile of intravitreal use of anti-VEGF drugs through network of clinical and administrative data” (CUP-H56D16000070005) awarded to Gianluca Trifirò.

Availability of data and material

An existing data access agreement governing the use of the data used in this study precludes sharing of the data.

Conflict of interest

JS, FG, GS, VI, PC, OL, SWPA, GDS, ADF, MPP, and CR have no conflicts of interest that are directly relevant to the content of this article. CR holds a Chercheur-Boursier Junior 2 Salary Award from the Fonds de recherche du Québec – Santé (FRQS). GT has attended advisory boards in the last 5 years, on topics unrelated to this paper, organized by Sandoz, Hospira, Sanofi, Biogen, Ipsen, and Shire and is a consultant for Otsuka. He is principal investigator of observational studies conducted at the University of Messina and funded by several pharmaceutical companies (e.g. Amgen, AstraZeneca, Daiichi Sankyo, IBSA) as well as scientific coordinator of the Master programme “Pharmacovigilance, pharmacoepidemiology and pharmacoeconomics: real-world data evaluations” at the University of Messina, which is partly funded by several pharmaceutical companies.

Ethics approval

The study abides by the Declaration of Helsinki. The study protocol was notified to the Ethical Committee of the Academic Hospital of Messina, in agreement with the current national legislation, which does not require full ethics approval for observational retrospective studies of a non-interventional nature using anonymized patient data.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sultana, J., Giorgianni, F., Scondotto, G. et al. Association Between Intravitreal Aflibercept and Serious Non-ocular Haemorrhage Compared with Intravitreal Ranibizumab: A Multicentre Observational Cohort Study. Drug Saf 43, 943–952 (2020). https://doi.org/10.1007/s40264-020-00956-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-020-00956-x

Search

Navigation