Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an update

References

• Ozaki E, Campbell M, Kiang AS, et al. Inflammation of age related macular degeneration. Adv Exp Med Bio. 2014;801:229–235.
   PubMed Web of Science ®Google Scholar
• Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):106–116.
   PubMed Web of Science ®Google Scholar
• Bakri SJ, Thorne JE, Ho AC, et al. Safety and efficacy of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration: a report by the American academy of ophthalmology. Ophthalmology. 2019;126(1):55–63.
   PubMed Web of Science ®Google Scholar
• Zarbin MA. Anti-VEGF agents and the risk of arteriothrombotic events. Asia Pac J Ophthalmol (Phila). 2018;7(1):63–67.
   PubMed Web of Science ®Google Scholar
• Lee JH, Canny MD, De Erkenez A, et al. A therapeutic aptamer inhibits angiogenesis by specifically targeting the heparin binding domain of VEGF165. Proc Natl Acad Sci USA. 2005;102(52):18902–18907.
   PubMed Web of Science ®Google Scholar
• Goldbaum M, Cunningham M. Aptamers and intramers: pegaptanib. In: Retin Pharmacother. 2010. p. 265–272.
   Google Scholar
• Macugen - pfizer: one of the world’s premier biopharmaceutical companies www.pfizer.com/products/rx_product_macugen.jsp;.
   Google Scholar
• Rosenfeld PJ, Brown DM, Heirer JS, et al. MARINA study group. ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–1431.
   PubMed Web of Science ®Google Scholar
• Brown DM, Michels M, Kaiser PK, et al. ANCHOR study group. ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 5; 355(14):1432–1444.
   PubMed Web of Science ®Google Scholar
• Avery LR, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina. 2017;37(10):1847–1858.
   PubMed Web of Science ®Google Scholar
• Kazazi-Hyseni L, Beinjein JH, Schellens JHM. Bevacizumab. Oncologist. 2010;15(8):819–825.
   PubMed Web of Science ®Google Scholar
• Aisenbrey S, Ziemssen F, Volker M, et al. Intravitreal bevacizumab (Avastin) for occult choroidal neovascularisation in age-related macular degeneration. Graefe’s Arch Clin Exp Ophthalmol. 2007;245:941–948.
   PubMed Web of Science ®Google Scholar
• Heiduschka P, Fietz H, Hofmeister S, et al. Penetration of bevacizumab through the retina after intravitreal injection in the monkey. Invest Ophthalmol Vis Sci. 2007;48:2814–2823.
   PubMed Web of Science ®Google Scholar
• Ziemssen F, Zhu Q, Peters S, et al. Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: preliminary findings of a pilot study. Int Ophthalmol. 2009;29(4):213–224.
   PubMedGoogle Scholar
• Ranibizumab intravitreal injection. Initial U.S. Approval: 2006. 2006;4–33. [cited 2019 July 8]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125156s105lbl.pdf
   Google Scholar
• Yu L, Liang XH, Ferrara N. Comparing protein VEGF inhibitors: in vitro biological studies. Biochem Biophys Res Commun. 2011;408:276–281.
   PubMed Web of Science ®Google Scholar
• Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–11398.
   PubMed Web of Science ®Google Scholar
• Semeraro F, Morescalchi F, Duse S, et al. Aflibercept in wet AMD: specific role and optimal use. Drug Des Devel Ther. 2013;7:711–722.
   PubMed Web of Science ®Google Scholar
• Dixon JA, Oliver OJL, Mandava N. VEGF trap-eye for the treatment of age-related macular degeneration. Expert Opin Investig Drug. 2009;18(10):1573–1580.
   PubMed Web of Science ®Google Scholar
• Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study. Ophthalmology. 2014;121(9):1740–1747.
   PubMed Web of Science ®Google Scholar
• Li H, Lei N, Zhang M, et al. Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit. Exp Eye Res. 2012;97(1):154–159.
   PubMed Web of Science ®Google Scholar
• Zhang M, Yu D, Yang C, et al. The pharmacology study of a new recombinant human VEGF receptor-fc fusion protein on experimental choroidal neovascularization. Pharm Res. 2009;26(1):204–210.
   PubMed Web of Science ®Google Scholar
• Vazquez-Lombardi R, Phan TG, Zimmermann C, et al. Challenges and opportunities for non-antibody scaffold drugs. Drug Discov Today. 2015;20:1271–1283.
   PubMed Web of Science ®Google Scholar
• Pluckthun A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu Rev Pharmacol Toxicol. 2015;55:489–511.
   PubMed Web of Science ®Google Scholar
• Eggel A, Buschor P, Baumann MJ, et al. Inhibition of ongoing allergic reactions using a novel anti-IgEDARPin- Fc fusion protein. Allergy. 2011;66:961–968.
   PubMed Web of Science ®Google Scholar
• Souied EH, Devin F, Mauget-Fay¨sse M, et al. Treatment of exudative age-related macular degeneration with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol. 2014;158:724–732.
   PubMed Web of Science ®Google Scholar
• Campochiaro PA, Channa R, Berger BB, et al. Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol. 2013;155:697–704.
   PubMed Web of Science ®Google Scholar
• Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15:171–185.
   PubMed Web of Science ®Google Scholar
• Krohne TU, Liu Z, Holz FG, et al. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012;154:682–686.
   PubMed Web of Science ®Google Scholar
• Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. VEGF inhibition study in ocular neovascularization clinical trial group. pegaptanib for neovascular age related macular degeneration. N Engl J Med. 2004;351:2805–2816.
   PubMed Web of Science ®Google Scholar
• VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr, 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.
   Web of Science ®Google Scholar
• Singerman LJ, Masonson H, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in ocular neovascularisation (VISION) trial. Br J Ophthalmol. 2008;92(12):1606–1611.
   PubMed Web of Science ®Google Scholar
• Rinaldi M, Chiosi F, DellʼOmo R, et al. Intravitreal pegaptanib sodium (Macugen) for treatment of myopic choroidal neovascularization: a morphologic and functional study. Retina. 2013;33(2):397–402.
   PubMed Web of Science ®Google Scholar
• Rinaldi M, Chiosi F, dell’Omo R, et al. Intravitreal pegaptanib sodium (Macugen®) for treatment of diabetic macular oedema: a morphologic and functional study. Br J Clin Pharmacol. 2012;74(6):940–946.
   PubMed Web of Science ®Google Scholar
• van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA. 2005;293:1509–1513.
   PubMed Web of Science ®Google Scholar
• Ko J, Ross J, Awad H, et al. The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice. J Surg Res. 2005;129:251–259.
   PubMed Web of Science ®Google Scholar
• Battaglia Parodi M, Di Bartolo E, Brue C, et al. Pegaptanib: choroidal neovascularization in patients with age-related macular degeneration and previous arterial thromboembolic events. Eur J Ophthalmol. 2018;28(1):58–62.
   PubMed Web of Science ®Google Scholar
• Semeraro F, Morescalchi F, Duse S, et al. Pharmacokinetic and pharmacodynamic properties of anti-vegf drugs after intravitreal injection. Curr Drug Metab. 2015;16(7):572–584.
   PubMed Web of Science ®Google Scholar
• Holz FG, Amoaku W, Donate J, et al. SUSTAIN study group. safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology. 2011;118(4):663–671.
   PubMed Web of Science ®Google Scholar
• Antoszyk AN, Tuomi L, Chung CY, et al. FOCUS study group. ranobizumab combined with verteporfin photodynaimc therapy in age-realted neovascular generation (FOCUS): year 2 results. Am J Ophthalmol. 2008;145(5):862–874.
   PubMed Web of Science ®Google Scholar
• Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year2. Am J Ophthalmol. 2010;150(3):315–324.
   PubMed Web of Science ®Google Scholar
• Schmidt-Erfurth U, Eldem B, Guymer R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology. 2011;118(5):831–839.
   PubMed Web of Science ®Google Scholar
• Mitchell P, Korobelnik JF, Lanzetta P, et al. Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol. 2010;94(1):2–13.
   PubMed Web of Science ®Google Scholar
• Chong NV. Should avastin be used to treat age-related macular degeneration in the NHS? No Eye (Lond). 2009;23:1250–1253.
   PubMed Web of Science ®Google Scholar
• Schmidt-Erfurth U. Clinical safety of ranibizumab in age-related macular degeneration. Expert Opin Drug Saf. 2010;9:149–165.
   PubMed Web of Science ®Google Scholar
• Boyer DS, Heier JS, Brown DM, et al. A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology. 2009;116(9):1731–1739.
   PubMed Web of Science ®Google Scholar
• Ciulla TA, Rosenfeld PJ. Antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. CurrOpinOphthalmol. 2009;20(3):158–165.
   Web of Science ®Google Scholar
• CHMP. Ranibizumab (lucentis). Annex I summary of product characteristics. [cited 2019 July 8]. Available from: https://www.ema.europa.eu/en/documents/product-information/lucentis-epar-product-information_en.pdf
   Google Scholar
• Ueta T, Yanagi Y, Tamaki Y, et al. Cerebrovascular accidents in ranibizumab. Ophthalmology. 2009;116:362.
   PubMed Web of Science ®Google Scholar
• Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175–1183.
   PubMed Web of Science ®Google Scholar
• Silva R, Axer-Siegel R, Eldem B, et al. SECURE study group. the SECURE study: long-termsafety of ranibizumab 0.5 mg in neovascular age-related macular degeneration. Ophthalmology. 2013;120(1):130–139.
   PubMed Web of Science ®Google Scholar
• Rakic J-M, Leys A, Brié H, et al. Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study. Clin Ophthalmol. 2013;7:1849–1858.
   PubMedGoogle Scholar
• Igaki T TNS opinion and social. Special Eurobarometer. 2018. [cited 2019 July 8]. Available from: https://data.europa.eu/euodp/de/data/dataset/S790_72_3_EBS332
   Google Scholar
• LUMINOUS: study to observe the effectiveness and safety of ranibizumab through individualized patient treatment and associated outcomes. [cited 2019 July 8]. Available from: http://clinicaltrials.gov/show/NCT01318941.
   Google Scholar
• Finger RP, Wiedemann P, Blumhagen F, et al. Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study - a non interventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol. 2013;91(6):540–546.
   PubMed Web of Science ®Google Scholar
• Ueta T, Noda Y, Toyama T, et al. Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials. Ophthalmology. 2014;121(11):2193–203.1–7.
   Web of Science ®Google Scholar
• Steinbrook R. The price of sight-ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006;355(14):1409–1412.
   PubMed Web of Science ®Google Scholar
• Semeraro F, Morescalchi F, Duse S, et al. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview. Expert Opin Drug Saf. 2014;13(6):1–18.
   PubMed Web of Science ®Google Scholar
• Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, et al. for the Pan American Collaborative Retina Group (PACORES). twelve-month safety of intravitreal injections of bevacizumab (Avastin(R)): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008;246:81–87.
   PubMed Web of Science ®Google Scholar
• Hwang DJ, Kim YW, Woo SJ, et al. Comparison of systemic adverse events associated with intravitreal anti-VEGF injection: ranibizumab versus bevacizumab. J Korean Med Sci. 2012;27(12):1580–1585.
   PubMed Web of Science ®Google Scholar
• Biswas P, Sengupta S, Choudhary R, et al. Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration. Indian J Ophthalmol. 2011;59(3):191–196.
   PubMed Web of Science ®Google Scholar
• Brechner RJ, Rosenfeld PJ, Babish JD, et al. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011;151(5):887–95e1.
   PubMed Web of Science ®Google Scholar
• Curtis LH, Hammill BG, Schulman KA, et al. Risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration. Arch Ophthalmol. 2010;128(10):1273–1279.
   PubMed Web of Science ®Google Scholar
• Alexander SL, Linde-Zwirble WT, Werther W, et al. Annual rates of arterial thromboembolic events in medicare neovascular age-related macular degeneration patients. Ophthalmology. 2007;114(12):2174–2178.
   PubMed Web of Science ®Google Scholar
• Nguyen-Khoa BA, Goehring EL Jr, Werther W, et al. Hospitalized cardiovascular diseases in neovascular age-related macular degeneration. Arch Ophthalmol. 2008;126(9):1280–1286.
   PubMed Web of Science ®Google Scholar
• Campbell RJ, Gill SS, Bronskill SE, et al. Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study. Br Med J. 2012;345:e4203.
   PubMed Web of Science ®Google Scholar
• CATT Research Group, DF M, MG M, GS Y, et al. Ranibizumab and Bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897–1908.
   PubMed Web of Science ®Google Scholar
• Chakravarthy U, Harding SP, Rogers CA, et al. IVAN Study Investigators. Alternative treatments to inhibit VEGF in age related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382:1258–1267.
   PubMed Web of Science ®Google Scholar
• Kodjikian L, Souied EH, Mimoun G, et al. GEFAL study group. ranibizumab versus bevacizumab for neovascular agerelated macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120:2300–2309.
   PubMed Web of Science ®Google Scholar
• Maguire MG, Martin DF, Ying GS, et al. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) research group. five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123:1751–1761.
   PubMed Web of Science ®Google Scholar
• Ahfat FG, Zaidi FH. Bevacizumab vs ranibizumab-an appraisal of the evidence from CATT and IVAN. Eye (Lond). 2013 Mar;27(3):289–290.
   PubMed Web of Science ®Google Scholar
• Krebs I, Schmetterer L, Boltz A, et al. MANTA research group. a randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration. Br J Ophthalmol. 2013;97(3):266–271.
   PubMed Web of Science ®Google Scholar
• Maguire MG, Shaffer J, Ying G, et al. Serious adverse events with bevacizumab or ranibizumab for age-related macular degeneration: meta-analysis of individual patient data. Ophthalmol Retin. 2017;1(5):375–381.
   PubMedGoogle Scholar
• Sangroongruangsri S, Chaikledkaew U, Kumluang S, et al. Real-world safety of intravotreal bevacizumab and ranibizumab treatments for retinal diseases in Thailand: a prospective obervational study. Clin Drug Investig. 2018;38:853–860.
   PubMed Web of Science ®Google Scholar
• Enseleit F, Michels S, Sudano I, et al. SAVE-AMD: safety of VEGF inhibitors in age-related macular degeneration. Ophthalmologica. 2017;238(4):205–216.
   PubMed Web of Science ®Google Scholar
• Mikačič I, Bosnar D. Intravitreal bevacizumab and cardiovascular risk in patients with age-related macular degeneration: systematic review and meta-analysis of randomized controlled trials and observational studies. Drug Saf. 2016;39:517–541.
   PubMed Web of Science ®Google Scholar
• Moja L, Lucenteforte E, Kwag KH, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;(9):CD011230.
   PubMed Web of Science ®Google Scholar
• Stewart MW, Rosenfeld PJ, Penha FM, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor trap-eye). Retina. 2012;32(3):343–457.
   Web of Science ®Google Scholar
• Heier JS, Brown DM, Chong V, et al. VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–2548. Erratum in: Ophthalmology. 2013;120(1):209-10.
   PubMed Web of Science ®Google Scholar
• Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular geberation: ninty-six-week results of the VIEW studies. Ophthalmology. 2014;121:193–201.
   PubMed Web of Science ®Google Scholar
• Liu K, Song Y, Xu G, et al. Conbercept for treatment of neovascular age-related macular degeneration: results of the randomized phase 3 PHOENIX study. Am J Ophthalmol. 2019;197:156–167.
   PubMed Web of Science ®Google Scholar
• Callanan D, Kunimoto D, Maturi RK, et al. Double-masked, randomized, phase 2 evaluation of abicipar pegol (an Anti-VEGF DARPin Therapeutic) in neovascular age-related macular degeneration. J Ocul Pharmacol Ther. 2018;34(10):700–709.
   PubMed Web of Science ®Google Scholar
• Gentile R. More research is needed to support the association of AMD and stroke. SurvOphthalmol. 2007;52(5):551–553.
   Google Scholar
• Zehetner C, Kirchmair R, Huber S, et al. 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):454–459.
   PubMed Web of Science ®Google Scholar
• Matsuyama K, Ogata N, Matsuoka M, et al. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol. 2010;94(9):1215–1218.
   PubMed Web of Science ®Google Scholar
• Dalvin LA, Starr MR, AbouChehade JE, et al. Association of intravitreal anti-vascular endothelial growth factor therapy with risk of stroke, myocardial infarction, and death in patients with exudative age-related macular degeneration. JAMA Ophthalmol. 2019;137(5):483.
   PubMed Web of Science ®Google Scholar
• Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300(19):2277–2285.
   PubMed Web of Science ®Google Scholar
• Etulan J, Negrotto S, Tribulatti MV, et al. Control of angiogenesis by galectins involves the release of platelet derived proangiogenic factors. PLoS One. 2014;9(4):e96402.
   PubMed Web of Science ®Google Scholar