Background/Aims: To compare retrospectively the incidence of arterial thromboembolic events (ATEs) in patients treated with bevacizumab or ranibizumab for exudative age-related macular degeneration. Methods: Charts of 378 patients treated with at least 1 intravitreal injection of ranibizumab or bevacizumab were reviewed to calculate the incidence of ATEs. Only patients under monotherapy were analyzed. Results: ATEs occurred in 15 patients: 12 (12/97) with bevacizumab (12.4%) and 3 (3/219) with ranibizumab (1.4%) – odds ratio 10.16; 95% confidence interval 2.80–36.93; p < 0.0001. ATEs in the bevacizumab and ranibizumab cohorts included stroke, myocardial infarction, angina pectoris, peripheral thromboembolic disease, transient ischemic attack, sudden death and lethal stroke. Conclusion: In this series, bevacizumab raised the risk of ATEs when compared to ranibizumab. In an elderly population with multiple cardiovascular risk factors, the new ATEs may not be attributed exclusively to the intravitreal bevacizumab administration. These findings raise an issue that must be confirmed in randomized clinical trials.

1.
Klein R, Peto T, Bird A, Vannewkirk MR: The epidemiology of age-related macular degeneration. Am J Ophthalmol 2004;137:486–495.
2.
Mitchell P, Smith W, Attebo K, Wang JJ: Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995;102:1450–1460.
3.
Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT: The prevalence of age-related maculopathy in the Rotterdam study. Ophthalmology 1995;102:205–210.
4.
Yannuzzi LA, Guyer DR, Green WR: The Retina Atlas. St Louis, Mosby, 1995.
5.
Ferrara N, Kerbel RS: Angiogenesis as a therapeutic target. Nature 2005;438:967–974.
6.
Gariano RF, Gardner TW: Retinal angiogenesis in development and disease. Nature 2005;438:960–966.
7.
Ferrara N, Mass RD, Campa C, Kim R: Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu Rev Med 2007;58:491–504.
8.
Ferrara N, Damico L, Shams N, Lowman H, Kim R: Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859–870.
9.
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S: Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444.
10.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431.
11.
Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816.
12.
Triano LR, Deshpande H, Gettinger SN: Management of patients with advanced non-small cell lung cancer: current and emerging options. Drugs;70:167–179.
13.
Labianca R, Beretta GD, Kildani B, Milesi L, Merlin F, Mosconi S, Pessi MA, Prochilo T, Quadri A, Gatta G, de Braud F, Wils J: Colon cancer. Crit Rev Oncol Hematol 2010;74:106–133.
14.
Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D: Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat 2010;122:1–7.
15.
Rosenfeld PJ, Moshfeghi AA, Puliafito CA: Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331–335.
16.
Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Pruente C, Schmidt-Erfurth UM, Tano Y, Wolf S: Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 2010;94:2–13.
17.
Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz H: Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007;99:1232–1239.
18.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ: Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855–859.
19.
Sheybani A, Kymes S, Schlief S, Apte R: Vascular events in patients with age-related macular degeneration treated with intraocular bevacizumab. Retina 2009;29:1404–1408.
20.
Fung AE, Rosenfeld PJ, Reichel E: The international intravitreal bevacizumab safety survey: using the Internet to assess drug safety worldwide. Br J Ophthalmol 2006;90:1344–1349.
21.
Carneiro AM, Falcao MS, Brandao EM, Falcao-Reis FM: Intravitreal bevacizumab for neovascular age-related macular degeneration with or without prior treatment with photodynamic therapy: one-year results. Retina 2010;30:85–92.
22.
Saint-Geniez M, Maharaj AS, Walshe TE, Tucker BA, Sekiyama E, Kurihara T, Darland DC, Young MJ, D’Amore PA: Endogenous VEGF is required for visual function: evidence for a survival role on Muller cells and photoreceptors. PLoS One 2008;3:e3554.
23.
Los M, Roodhart JM, Voest EE: Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer. Oncologist 2007;12:443–450.
24.
Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, Di Pietro LA: Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol 1998;152:1445–1452.
25.
Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N: VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5:623–628.
26.
Matsunaga T, Warltier DC, Weihrauch DW, Moniz M, Tessmer J, Chilian WM: Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide. Circulation 2000;102:3098–3103.
27.
Wong TY: Age-related macular degeneration and cardiovascular disease in the era of anti-vascular endothelial growth factor therapies. Am J Ophthalmol 2009;148:327–329.
28.
Vingerling JR, Dielemans I, Bots ML, Hofman A, Grobbee DE, de Jong PT: Age-related macular degeneration is associated with atherosclerosis. The Rotterdam study. Am J Epidemiol 1995;142:404–409.
29.
Wong TY, Klein R, Sun C, Mitchell P, Couper DJ, Lai H, Hubbard LD, Sharrett AR: Age-related macular degeneration and risk for stroke. Ann Intern Med 2006;145:98–106.
30.
Wong TY, Tikellis G, Sun C, Klein R, Couper DJ, Sharrett AR: Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities study. Ophthalmology 2007;114:86–91.
31.
Tan JS, Wang JJ, Liew G, Rochtchina E, Mitchell P: Age-related macular degeneration and mortality from cardiovascular disease or stroke. Br J Ophthalmol 2008;92:509–512.
32.
Liao D, Mo J, Duan Y, Klein R, Scott IU, Huang KA, Zhou H: Is age-related macular degeneration associated with stroke among elderly Americans? Open Ophthalmol J 2008;2:37–42.
33.
Duan Y, Mo J, Klein R, Scott IU, Lin HM, Caulfield J, Patel M, Liao D: Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans. Ophthalmology 2007;114:732–737.
34.
Sun C, Klein R, Wong TY: Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. Ophthalmology 2009;116:1913–1919.
35.
Alexander SL, Linde-Zwirble WT, Werther W, Depperschmidt EE, Wilson LJ, Palanki R, Saroj N, Butterworth SL, Ianchulev T: Annual rates of arterial thromboembolic events in Medicare neovascular age-related macular degeneration patients. Ophthalmology 2007;114:2174–2178.
36.
Hu CC, Ho JD, Lin HC: Neovascular age-related macular degeneration and the risk of stroke: a 5-year population-based follow-up study. Stroke 2010;41:613–617.
37.
Ranpura V, Hapani S, Chuang J, Wu S: Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 2010;49:287–297.
38.
Gillies MC, Wong TY: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2007;356:748–749, author reply 749–750.
39.
Spaide RF, Laud K, Fine HF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, Sorenson J, Slakter J, Fisher YL, Cooney MJ: Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383–390.
40.
Bashshur ZF, Haddad ZA, Schakal A, Jaafar RF, Saab M, Noureddin BN: Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249–256.
41.
Bashshur ZF, Haddad ZA, Schakal AR, Jaafar RF, Saad A, Noureddin BN: Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: the second year of a prospective study. Am J Ophthalmol 2009;148:59–65.
42.
Avery RL: Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 2006;26:352–354.
43.
Sassa Y, Hata Y: Antiangiogenic drugs in the management of ocular diseases: focus on antivascular endothelial growth factor. Clin Ophthalmol 2010;4:275–283.
44.
Lee K, Yang H, Lim H, Lew HM: A prospective study of blood pressure and intraocular pressure changes in hypertensive and nonhypertensive patients after intravitreal bevacizumab injection. Retina 2009;29:1409–1417.
45.
Antiplatelet Trialists’ Collaboration: Collaborative overview of randomised trials of antiplatelet therapy.I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106.
46.
Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T: Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116:57–65.
47.
Liew G, Mitchell P: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2007;356:747–748, author reply 749–750.
48.
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N: Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol 2008;145:239–248.
49.
Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG: A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009;116:1731–1739.
50.
Csaky K, Do DV: Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol 2009;148:647–656.
51.
Schmucker C, Ehlken C, Hansen LL, Antes G, Agostini HT, Lelgemann M: Intravitreal bevacizumab (Avastin) vs ranibizumab (Lucentis) for the treatment of age-related macular degeneration: a systematic review. Curr Opin Ophthalmol 2010;21:218–226.
52.
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;128:1273–1279.
53.
Gardete-Correia L, Boavida JM, Raposo JF, Mesquita AC, Fona C, Carvalho R, Massano-Cardoso S: First diabetes prevalence study in Portugal: Prevadiab study. Diabet Med 2010;27:879–881.
54.
Macedo ME, Lima MJ, Silva AO, Alcantara P, Ramalhinho V, Carmona J: Prevalence, awareness, treatment and control of hypertension in Portugal: The PAP study. J Hypertens 2005;23:1661–1666.
55.
Correia M, Silva MR, Matos I, Magalhaes R, Lopes JC, Ferro JM, Silva MC: Prospective community-based study of stroke in northern Portugal: incidence and case fatality in rural and urban populations. Stroke 2004;35:2048–2053.
56.
Oliveira A, Lopes C, Rodriguez-Artalejo F: Adherence to the southern European Atlantic diet and occurrence of nonfatal acute myocardial infarction. Am J Clin Nutr 2010;92:211–217.
57.
Sans S, Puigdefabregas A, Paluzie G, Monterde D, Balaguer-Vintro I: Increasing trends of acute myocardial infarction in Spain: The MONICA-Catalonia study. Eur Heart J 2005;26:505–515.
58.
Gabriel R, Alonso M, Reviriego B, Muniz J, Vega S, Lopez I, Novella B, Suarez C, Rodriguez-Salvanes F: Ten-year fatal and non-fatal myocardial infarction incidence in elderly populations in Spain: the Epicardian cohort study. BMC Public Health 2009;9:360.
59.
Mares-Perlman JA, Brady WE, Klein R, Van den Langenberg GM, Klein BE, Palta M: Dietary fat and age-related maculopathy. Arch Ophthalmol 1995;113:743–748.
60.
Schaumberg DA, Christen WG, Hankinson SE, Glynn RJ: Body mass index and the incidence of visually significant age-related maculopathy in men. Arch Ophthalmol 2001;119:1259–1265.
61.
Kroll J, Waltenberger J: VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun 1998;252:743–746.
62.
Murohara T, Horowitz JR, Silver M, Tsurumi Y, Chen D, Sullivan A, Isner JM: Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 1998;97:99–107.
63.
Hata Y, Clermont A, Yamauchi T, Pierce EA, Suzuma I, Kagokawa H, Yoshikawa H, Robinson GS, Ishibashi T, Hashimoto T, Umeda F, Bursell SE, Aiello LP: Retinal expression, regulation, and functional bioactivity of prostacyclin-stimulating factor. J Clin Invest 2000;106:541–550.
64.
Kuenen BC, Levi M, Meijers JC, Kakkar AK, van Hinsbergh VW, Kostense PJ, Pinedo HM, Hoekman K: Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol 2002;22:1500–1505.
65.
Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, Ferrara N, Gerber HP: Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 2004;104:149–158.
66.
Zachary I: Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 2001;280:C1375–C1386.
67.
Carneiro A, Falcao M, Pirraco A, Milheiro-Oliveira P, Falcao-Reis F, Soares R: Comparative effects of bevacizumab, ranibizumab and pegaptanib at intravitreal dose range on endothelial cells. Exp Eye Res 2009;88:522–527.
68.
Yao SK, Ober JC, Krishnaswami A, Ferguson JJ, Anderson HV, Golino P, Buja LM, Willerson JT: Endogenous nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries. Circulation 1992;86:1302–1309.
69.
De Graaf JC, Banga JD, Moncada S, Palmer RM, de Groot PG, Sixma JJ: Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation 1992;85:2284–2290.
70.
Pereg D, Lishner M: Bevacizumab treatment for cancer patients with cardiovascular disease: a double edged sword? Eur Heart J 2008;29:2325–2326.
71.
Meyer T, Robles-Carrillo L, Robson T, Langer F, Desai H, Davila M, Amaya M, Francis JL, Amirkhosravi A: Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J Thromb Haemost 2009;7:171–181.
72.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ: Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179–2182.
73.
Matsuyama K, Ogata N, Matsuoka M, Wada M, Takahashi K, Nishimura T: Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010;94:1215–1218.
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