Abstract
Choroidal neovascularisation (CNV) often leads to severe vision loss and is becoming increasingly prevalent as the aging population grows. Age-related macular degeneration (AMD) is the most common cause of CNV, but CNV also affects younger people with pathological myopia, ocular histoplasmosis syndrome, angioid streaks and idiopathic disorders. The monotherapies available worldwide to treat patients with CNV have primarily been studied in CNV due to AMD, and all have their drawbacks. Combination therapy takes advantage of the strengths of each therapy and their different mechanisms of action to achieve good treatment outcomes with few repeated treatments. For example, combination (triple) therapy with verteporfin photodynamic therapy, anti-vascular endothelial growth factor (VEGF) therapy and anti-inflammatory therapy addresses three main targets of CNV development: the CNV itself, VEGF expression (which promotes CNV growth) and inflammation (which exacerbates the disease process). Such triple therapy has been shown to result in sustained improved vision after only one treatment. Vision outcomes similar to those observed with ranibizumab, the most promising and rigorously proven anti-VEGF monotherapy, may be possible with combination therapy without the need for continued monthly intravitreal injections, which are required if sustained outcomes are to be achieved with ranibizumab. The goal of CNV therapy is improved vision outcomes after one course of treatment. Combination therapy may lead to this goal. Such treatment could also result in fewer safety issues (fewer treatments are required and the unknown effects of continued long-term treatment are avoided), lower cost to both the patient and the medical system and greater convenience for patients (fewer clinic visits). However, combination therapy is beset with several challenges: different therapies, doses, timing and treatment sequences are possible, and it is therefore difficult to conduct large, definitive clinical trials to determine which treatment regimen is safest and most effective. Large controlled studies are needed to more clearly define effective and safe combination regimens for CNV.
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References
Delcourt C, Lacroux A, Carriere I, et al. The three-year incidence of age-related macular degeneration: the ‘Pathologies Oculaires Liees a l’Age’ (POLA) prospective study. Am J Ophthalmol 2005; 140(5): 924–6
Buch H, Nielsen NV, Vinding T, et al. 14-year incidence, progression, and visual morbidity of age-related maculopathy: the Copenhagen City Eye Study. Ophthalmology 2005; 112(5): 787–98
Bjornsson OM, Syrdalen P, Bird AC, et al. The prevalence of age-related maculopathy (ARM) in an urban Norwegian population: the Oslo Macular study. Acta Ophthalmol Scand 2006; 84(5): 636–41
Li Y, Xu L, Jonas JB, et al. Prevalence of age-related maculopathy in the adult population in China: the Beijing eye study. Am J Ophthalmol 2006; 142(5): 788–93
Mukesh BN, Dimitrov PN, Leikin S, et al. Five-year incidence of age-related maculopathy: the Visual Impairment Project. Ophthalmology 2004; 111(6): 1176–82
Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122(4): 564–72
Klein R, Klein BE, Knudtson MD, et al. Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 2007; 114(2): 253–62
Varma R, Fraser-Bell S, Tan S, et al. Prevalence of age-related macular degeneration in Latinos: the Los Angeles Latino eye study. Ophthalmology 2004; 111(7): 1288–97
Munoz B, Klein R, Rodriguez J, et al. Prevalence of age-related macular degeneration in a population-based sample of Hispanic people in Arizona: Proyecto VER. Arch Ophthalmol 2005; 123(11): 1575–80
Augood CA, Vingerling JR, de Jong PT, et al. Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol 2006; 124(4): 529–35
Schrader WF. Age-related macular degeneration: a socioeconomic time bomb in our aging society [in German]. Ophthalmologe 2006; 103(9): 742–8
Glacet-Bernard A, Benyelles N, Dumas S, et al. Photodynamic therapy vs limited macular translocation in the management of subfoveal choroidal neovascularization in pathologic myopia: a two-year study. Am J Ophthalmol 2007; 143: 68–76
Miller DG, Singerman LJ. Vision loss in younger patients: a review of choroidal neovascularization. Optom Vis Sci 2006; 83: 316–25
Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials. TAP Report 2. Arch Ophthalmol 2001; 119: 198–207
Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization. Verteporfin in Photodynamic Therapy Report 2. Am J Ophthalmol 2001; 131: 541–60
Verteporfin in Photodynamic Therapy (VIP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial. VIP Report No. 3. Ophthalmology 2003; 110: 667–73
Kaiser PK, on behalf of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension. TAP report no. 8. Graefes Arch Clin Exp Ophthalmol 2006; 244(9): 1132–42
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419–31
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1432–4
Genentech. Lucentis® (ranibizumab injection) prescribing information. San Francisco (CA): Genentech, 2006 [online]. Available from URL: http://www.gene.com/gene/products/information/tgr/lucentis/index.jsp [Accessed 2006 Feb 23]
Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with in-travitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007; 143(4): 566–83
Genentech. Avastin® (bevacizumab) prescribing information. San Francisco (CA): Genentech, 2006 [online]. Available from URL: http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp [Accessed 2006 Feb 23]
Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006; 113(3): 363–72
Lazic R, Gabric N. Intravitreally administered bevacizumab (Avastin) in minimally classic and occult choroidal neovascularization secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2007; 245(1): 68–73
Costa RA, Jorge R, Calucci D, et al. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA study): results of a phase 1 dose-escalation study. Invest Ophthalmol Vis Sci 2006; 47(10): 4569–78
Yamamoto I, Rogers AH, Reichel E, et al. Intravitreal bevacizumab (Avastin) as treatment for subfoveal choroidal neovascularisation secondary to pathological myopia. Br J Ophthalmol 2007; 91(2): 157–60
Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006; 142(1): 1–9
Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006; 26(4): 383–90
Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351(27): 2805–16
Chakravarthy U, Adamis AP, Cunningham Jr ET, 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. el-25
Slakter JS, Bochow T, D’Amico DJ, et al. Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration. Ophthalmology 2006; 113(1): 3–13
Russell SR, Hudson HL, Jerdan JA, et al. Anecortave acetate for the treatment of exudative age-related macular degeneration: a review of clinical outcomes. Surv Ophthalmol 2007; 52Suppl. 1: 79–90
Challa J, Gillies M, Penfold P, et al. Exudative macular degeneration and intravitreal triamcinolone: 18 month follow up. Aust N Z J Ophthalmol 1998; 26(4): 277–81
Danis RP, Ciulla TA, Pratt LM, et al. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000; 20(3): 244–50
Jonas JB, Degenring RF, Kreissig I, et al. Exudative age-related macular degeneration treated by intravitreal triamcinolone acetonide: a prospective comparative nonrandomised study. Eye 2004; 19(2): 163–70
Gillies MC, Simpson JM, Billson FA, et al. Safety of an intravitreal injection of triamcinolone: results from a randomized clinical trial. Arch Ophthalmol 2004; 122(3): 336–40
Chakravarthy U, Soubrane G, Bandello F, et al. Evolving European guidance on the medical management of neovascular age related macular degeneration. Br J Ophthalmol 2006; 90(9): 1188–96
Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991; 109: 1220–31
Chauvaud D. The place of surgery in subfoveal neovascular treatment in age-related macular degeneration [in French]. J Fr Ophtalmol 2002; 25(7): 756–9
Gelisken F, Voelker M, Schwabe R, et al. Full macular translocation versus photodynamic therapy with verteporfin in the treatment of neovascular age-related macular degeneration: 1-year results of a prospective, controlled, randomised pilot trial (FMT-PDT). Graefes Arch Clin Exp Ophthalmol 2007; 245(8): 1085–95
Eckardt C, Eckardt U, Conrad HG. Macular rotation with and without counter-rotation of the globe in patients with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 1999; 237(4): 313–25
Marcus DM, Peskin E, Maguire M. The age-related macular degeneration radiotherapy trial (AMDRT): one year results from a pilot study. Am J Ophthalmol 2004; 138(5): 818–28
Feucht M, Fuisting B, Richard G. Status of TTT in the therapy for CNV [in German]. Klin Monatsbl Augenheilkd 2006; 223(10): 802–7
Kaiser PK. Verteporfin photodynamic therapy and anti-angiogenic drugs: potential for combination therapy in exudative age-related macular degeneration. Curr Med Res Opin 2007; 23(3): 477–87
Augustin AJ, Offermann I. Emerging drugs for age-related macular degeneration. Expert Opin Emerg Drugs 2006; 11(4): 725–40
Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007; 27(2): 133–40
Shastry BS. Assessment of the contribution of the LOC387715 gene polymorphism in a family with exudative age-related macular degeneration and heterozygous CFH variant (Y402H). J Hum Genet 2007; 52(4): 384–7
Moshfeghi DM, Blumendranz MS. Role of genetic factors and inflammation in age-related macular degeneration. Retina 2007; 27: 269–75
Narayanan R, Butani V, Boyer DS, et al. Complement factor H polymorphism in age-related macular degeneration. Ophthalmology 2007; 114(7): 1327–31
Shuler Jr RK, Hauser MA, Caldwell J, et al. Neovascular age-related macular degeneration and its association with LOC387715 and complement factor H polymorphism. Arch Ophthalmol 2007; 125(1): 63–7
Spaide RF. Rationale for combination therapies for choroidal neovascularization. Am J Ophthalmol 2006; 141: 149–56
Schmidt-Eurfurth U, Scholtzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2003; 44(10): 4473–80
Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina 2005; 25: 111–8
Tatar O, Shinoda K, Adam A, et al. Effect of verteporfin photodynamic therapy on endostatin and angiogenesis in human choroidal neovascular membranes. Br J Ophthalmol 2007; 91: 166–73
Dorrell MI, Aguilar E, Scheppke L, et al. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci U S A 2007; 104(3): 967–72
Kaiser PK. Verteporfin therapy in combination with triamcinolone: published studies investigating a potential synergistic effect. Curr Med Res Opin 2005; 21(5): 705–13
Augustin AJ, Schmidt-Erfurth U. Verteporfin therapy and triamcinolone acetonide: convergent modes of action for treatment of neovascular age-related macular degeneration. Eur J Ophthalmol 2006; 16(6): 824–34
Chan WM, Lai TY, Wong AL, et al. Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of subfoveal choroidal neovascularisation in age related macular degeneration: a comparative study. Br J Ophthalmol 2006; 90(3): 337–41
Arias L, Garcia-Arumi J, Ramon JM, et al. Photodynamic therapy with intravitreal triamcinolone in predominantly classic choroidal neovascularization: one-year results of a randomized study. Ophthalmology 2006; 113(12): 2243–50
Augustin AJ, Schmidt-Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone in all types of choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006; 113(1): 14–22
Spaide R, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003; 110(8): 1517–25
Rechtman E, Danis RP, Pratt LM, et al. Intravitreal triamcinolone with photodynamic therapy for subfoveal choroidal neovascularisation in age related macular degeneration. Br J Ophthalmol 2004; 88(3): 344–7
Van De Moere A, Sandhu SS, Kak R, et al. Effect of posterior juxtascleral triamcinolone acetonide on choroidal neovascular growth after photodynamic therapy with verteporfin. Ophthalmology 2005; 112(11): 1896–903
Nicolo M, Ghiglione D, Lai S, et al. Occult with no classic choroidal neovascularization secondary to age-related macular degeneration treated by intravitreal triamcinolone and photodynamic therapy with verteporfin. Retina 2006; 26(1): 58–64
Augustin AJ, Schmidt-Erfuth U. Verteporfin and intravitreal triamcinolone acetonide combination therapy for occult choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006; 141: 638–45
Ruiz-Moreno JA, Montera JA, Barile S, et al. Photodynamic therapy and high-dose intravitreal triamcinolone to treat exudative age-related macular degeneration: 1-year outcome. Retina 2006; 26: 602–12
Fackler TK, Reddy S, Bearelly S, et al. Retrospective review of eyes with neovascular age-related macular degeneration treated with photodynamic therapy with verteporfin and intravitreal triamcinolone. Ann Acad Med Singapore 2006; 35(10): 701–5
Marticorena J, Gomez-Ulla F, Fernandez M, et al. Combined photodynamic therapy and intravitreal triamcinolone acetonide for the treatment of myopic subfoveal choroidal neovascularization. Am J Ophthalmol 2006; 142(2): 335–7
Chan WM, Lai TY, Wong AL, et al. Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of choroidal neovascularisation secondary to pathological myopia: a pilot study. Br J Ophthalmol 2007; 91: 174–9
Lazic R, Gabric N. Verteporfin therapy and intravitreal bevacizumab combined and alone in choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2007; 114: 1179–85
Eyetech Study Group. Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology 2003; 110(5): 979–86
Heier JS, Boyer DS, Ciulla TA, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular agerelated macular degeneration: year 1 results of the FOCUS study. Arch Ophthalmol 2006; 124: 1532–42
Dhalla MS, Shah GK, Blinder KJ, et al. Combined photodynamic therapy with verteporfin and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration. Retina 2006; 26(9): 988–93
Schmidt-Erfurth U, Gabel P, Hohman T, et al. Preliminary results from an open-label, multicenter, phase II study assessing the effects of same-day administration of ranibizumab (Lucentis™) and verteporfin PDT (PROTECT Study) [abstract no. 2960]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Funk M, Michels S, Wagner J, et al. Vascular effects of combined ranibizumab (Lucentis®) and verteporfin (Visudyne®) therapy in patients with neovascular age-related macular degeneration [abstract no. 353]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Wagner J, Simader C, Kiss C, et al. Changes in functional macular mapping in patients with neovascular age-related macular degeneration receiving combination of verteporfin (Visudyne™) and ranibizumab (Lucentis®) therapy [abstract no. 363]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Wolf S, Gabel P, Hohman TC, et al. Fluorescein angiographic and OCT results from an open-label, multicenter, phase II study assessing the effects of same-day ranibizumab (Lucentis™) and verteporfin PDT (Visudyne®) [abstract no. 3542]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Eter N, Ladewig M, Hamelmann V, et al. Combined intravitreal bevacizumab (Avastin) and photodynamic therapy for AMD [abstract no. PO341]. Annual meeting of the American Academy of Ophthalmology (AAO); Las Vegas (NV); 2006 Nov 12 [online]. Available from URL: http://www.aao.org/annual_meeting/program/onlineprogram06.cfm [Accessed 2007 Mar 15]
Colina-Luquez Jm, Liggett Pe, Tom D, et al. Prospective and preliminary study evaluating triple therapy of intravitreal triamcinolone, photodynamic therapy and pegaptanib sodium for choroidal neovascularization [abstract no. 349]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Offermann I, Altinay A, Schmidt-Erfurth U, et al. Intravitreal bevacizumab for the treatment of remaining choroidal neovascularization (CNV) activity following combination therapy (PDT and triamcinolone) [abstract no. 2154]. Annual meeting of the Association for Research in Vision and Ophthalmology (ARVO); 2006 Apr 30–May 4; Fort Lauderdale (FL)
Bay Area Retinal Associates, QLT Inc. Triple therapy: PDT plus IVD and intravitreal ranibizumab versus monotherapy: intravitreal ranibizumab alone for the treatment of age-related macular degeneration [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT003902087.order=1 [Accessed 2007 May 31]
Vitreous-Retina-Macula Consultants of New York, QLT Inc. Second line therapy to treat AMD for patients not responding well to Lucentis therapy by itself [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00457678?.order=2 [Accessed 2007 May 31]
Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 2007; 125(3): 309–17
Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am 2006; 19(3): 361–72
Mares JA, La Rowe TL, Blodi BA. Doctor, what vitamins should I take for my eyes? Arch Ophthalmol 2004; 122: 628–35
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119: 1417–36
Desmettre T, Lecerf JM, Souied EH. Nutrition and age-related macular degeneration [in French]. J Fr Ophtalmol 2004; 27 (9 Pt 2): 3S38–56
Moeller SM, Parekh N, Tinker L, et al. Associations between intermediate age-related macular degeneration and lutein and zeaxanthin in the carotenoids in age-related eye disease study (CAREDS): ancillary study of the Women’s Health Initiative. Arch Ophthalmol 2006; 124(8): 1151–62
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No sources of funding were used to assist in the preparation of this article. The authors have no proprietary interest in the therapies discussed. Dr Augustin has acted as a consultant to and received honoraria from Novartis and QLT, and has received research grants from Alcon, Novartis and QLT. Dr Offermann has acted as a consultant to QLT. Assistance with manuscript preparation was provided by Laurie Haynes, ELS, of QLT.
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Augustin, A.J., Offermann, I. Combination Therapy for Choroidal Neovascularisation. Drugs Aging 24, 979–990 (2007). https://doi.org/10.2165/00002512-200724120-00002
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DOI: https://doi.org/10.2165/00002512-200724120-00002