Treatment of age-related macular degeneration
Authors: Chui Ming Gemmy Cheung, Tien Y Wong
Journal: The Lancet (2013)

Age-related macular degeneration is the leading cause of blindness in developed countries.1Lim LS Mitchell P Seddon JM Holz FG Wong TY Age-related macular degeneration.Lancet. 2012; 379: 1728-1738Summary Full Text Full Text PDF PubMed Scopus (1274) Google Scholar Since the mid-2000s, intraocular injections of agents inhibiting vascular endothelial growth factor (VEGF) have become the mainstay of treatment for neovascular (wet) age-related macular degeneration.2Wong TY Liew G Mitchell P Clinical update: new treatments for age-related macular degeneration.Lancet. 2007; 370: 204-206Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 3Rosenfeld PJ Brown DM Heier JS et al.Ranibizumab for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1419-1431Crossref PubMed Scopus (4840) Google Scholar, 4Brown DM Kaiser PK Michels M et al.Ranibizumab versus verteporfin for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1432-1444Crossref PubMed Scopus (3040) Google Scholar Emerging data from national registries show that blindness related to age-related macular degeneration started to fall when anti-VEGF treatment was introduced.5Cheung N Wong TY Changing trends of blindness: the initial harvest from translational public health and clinical research in ophthalmology.Am J Ophthalmol. 2012; 153: 193-195Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar However, three key questions remain unanswered for physicians, their patients, and policy makers. First, what is the most cost-effective drug? Two anti-VEGF agents are available: ranibizumab, which was approved by the US Food and Drug Administration, and bevacizumab, which is a cancer drug widely used off label.1Lim LS Mitchell P Seddon JM Holz FG Wong TY Age-related macular degeneration.Lancet. 2012; 379: 1728-1738Summary Full Text Full Text PDF PubMed Scopus (1274) Google Scholar Bevacizumab costs a fraction of ranibizumab, and is the main drug used in many non-reimbursed settings, such as in US practice.6Levinson DR Review of Medicare part B Avastin and Lucentis treatments for age-related macular degeneration. Department of Health and Human Services, Washington, DCSept 6, 2011http://oig.hhs.gov/oas/reports/region10/11000514.pdfDate: 2011Google Scholar A report6Levinson DR Review of Medicare part B Avastin and Lucentis treatments for age-related macular degeneration. Department of Health and Human Services, Washington, DCSept 6, 2011http://oig.hhs.gov/oas/reports/region10/11000514.pdfDate: 2011Google Scholar suggested that US Medicare could save more than US$1 billion within 2 years if bevacizumab replaced ranibizumab. Second, how often should injections be given? Initial clinical trials3Rosenfeld PJ Brown DM Heier JS et al.Ranibizumab for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1419-1431Crossref PubMed Scopus (4840) Google Scholar, 4Brown DM Kaiser PK Michels M et al.Ranibizumab versus verteporfin for neovascular age-related macular degeneration.N Engl J Med. 2006; 355: 1432-1444Crossref PubMed Scopus (3040) Google Scholar suggested that ranibizumab should be given monthly for the best visual outcome. In clinical practice, physicians and patients would obviously prefer injections with intervals of longer than 1 month, and alternative regimens (eg, as needed) have been proposed. However, whether such alternative regimens have acceptable results is unclear. Third, does long-term treatment have safety issues? Although anti-VEGF agents are injected in small quantities into the eye, concerns about systemic safety have been raised, including possible risk of stroke.7Curtis LH Hammill BG Shulman KA Cousins SW Risks of mortality, myocardial infarction, bleeding and stroke associated with therapies for age-related macular degeneration.Arch Ophthalmol. 2010; 128: 1273-1279Crossref PubMed Scopus (185) Google Scholar, 8Lim LS Cheung CMG Mitchell P Wong TY Emerging evidence concerning systemic safety of anti-VEGF agents—should ophthalmologists be concerned?.Am J Ophthalmol. 2011; 152: 329-331Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar In The Lancet, Usha Chakravarthy and colleagues report 2-year findings of the IVAN randomised controlled trial.9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar This trial, along with the US CATT trial,10The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Crossref PubMed Scopus (2166) Google Scholar, 11The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Summary Full Text Full Text PDF PubMed Scopus (1446) Google Scholar attempts to answer these questions. In IVAN, adults with untreated neovascular age-related macular degeneration were randomly assigned to receive intravitreal injections of ranibizumab or bevacizumab in continuous (monthly) or discontinuous (as needed) regimens.12Chakravarthy U Harding SP et al.IVAN Study InvestigatorsRanibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.Ophthalmology. 2012; 119: 1399-1411Summary Full Text Full Text PDF PubMed Scopus (658) Google Scholar Unfortunately, the results have not clarified the situation. For best corrected distance visual acuity—the primary outcome—bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference −1·37 letters in favour of ranibizumab, 95% CI −3·75 to 1·01; prespecified non-inferiority limit 3·5 letters).9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar Similarly, discontinuous treatment was neither non-inferior nor inferior to continuous treatment (–1·63 letters in favour of continuous treatment, −4·01 to 0·75).9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar Can the three questions now be answered? Can the cheaper drug (bevacizumab) achieve results that are similar to those of the approved treatment (ranibizumab)? Chakravarthy and colleagues9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar suggest the answer is yes. Although the 2-year IVAN results were inconclusive, the meta-analysis of pooled IVAN and CATT data9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar suggests the difference in mean visual acuity between drugs is only −1·15 letters in favour of ranibizumab (95% CI −2·82 to 0·51). Can injections be given less frequently than every month and yet achieve similar outcomes? The answer is possibly not. CATT showed that the as-needed dosing regimen saved nine injections in 2 years, but resulted in a small but significant reduction in vision (–2·4 letters) compared with monthly treatment.11The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Summary Full Text Full Text PDF PubMed Scopus (1446) Google Scholar Chakravarthy and colleagues' meta-analysis confirmed that injections given as needed led to a small loss of efficacy (–2·23 letters, −3·93 to −0·53).9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar Importantly, patients in both trials assigned to discontinuous treatment still attended monthly monitoring visits, which is often not the case in practice. Therefore, although these studies had reasonable results with injections given as needed, monthly physician visits and monitoring were still necessary, and actual clinical outcomes seem to be progressively worse as monthly monitoring and treatment are lost.13Finger RP Wiedemann P Blumhage F Pohl K Holz FG Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany.Acta Ophthalmol. 2012; (published online Nov 22.)https://doi.org/10.1111/j.1755-3768.2012.02493.xCrossref Scopus (128) Google Scholar, 14Cohen SY Dubois L Tadayoni R Results of one-year's treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting.Am J Ophthalmol. 2009; 148: 409-413Summary Full Text Full Text PDF PubMed Scopus (130) Google Scholar Finally, are there systemic safety concerns? The answer is unclear. Age-related macular degeneration has long been suggested to have similar developmental characteristics to cardiovascular diseases, and studies15Chakravarthy U Wong TY Fletcher A et al.Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis.BMC Ophthalmol. 2010; 10: 31Crossref PubMed Scopus (526) Google Scholar, 16Wong TY Klein R Sun C et al.for the Atherosclerosis Risk in Communities StudyAge-related macular degeneration and risk for stroke.Ann Intern Med. 2006; 145: 98-106Crossref PubMed Scopus (116) Google Scholar have shown that patients with age-related macular degeneration have an increased risk of stroke. An observational study based on US Medicare7Curtis LH Hammill BG Shulman KA Cousins SW Risks of mortality, myocardial infarction, bleeding and stroke associated with therapies for age-related macular degeneration.Arch Ophthalmol. 2010; 128: 1273-1279Crossref PubMed Scopus (185) Google Scholar showed significantly lower risk of all-cause mortality, incident myocardial infarction, and stroke with ranibizumab than with bevacizumab. In Chakravarthy and colleagues' report,9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar no difference was recorded in frequency of death (odds ratio 0·96, 95% CI 0·46–2·02) or of an arterial thrombotic event or hospital admission for heart failure (1·69, 0·80–3·57) between drugs. In CATT, however, more serious adverse events were reported in the bevacizumab group than the ranibizumab group, although this risk was not dose dependent.10The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Crossref PubMed Scopus (2166) Google Scholar, 11The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Summary Full Text Full Text PDF PubMed Scopus (1446) Google Scholar Intriguingly, systemic safety seemed to be worse when treatment was given as needed rather than monthly in IVAN: there were fewer deaths (odds ratio 0·47, 0·22-1·03) and fewer arterial thrombotic events (0·42, 0·17-1·03) with continuous than with discontinuous treatment.9Chakravarthy U Harding SP Rogers CA et al.on behalf of the IVAN study investigatorsAlternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.Lancet. 2013; (published online July 19.)http://dx.doi.org/10.1016/S0140-6736(13)61501-9Summary Full Text Full Text PDF Scopus (573) Google Scholar This finding raises possible new mechanisms of systemic interaction—eg, instead of the intuitive dose-dependent link, fluctuation in serum VEGF concentrations might be detrimental to systemic vascular health. Another explanation that has been suggested is the potential protective effect of continuous anti-VEGF therapy, perhaps by suppressing early malignancy. Examination of serum VEGF concentrations and systemic effects in oncology patients could be a way to study this association further. A limitation of Chakravarthy and colleagues' meta-analysis is that only 1-year data from CATT were included for comparison between regimens. Because of the small number of events at 1 year (24 deaths and 27 arterial thrombotic events),10The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration.N Engl J Med. 2011; 364: 1897-1908Crossref PubMed Scopus (2166) Google Scholar incorporation of the 2-year CATT data (68 deaths and 57 arterial thrombotic events)11The CATT Research GroupRanibizumab and bevacizumab for neovascular age-related macular degeneration: two-year results.Ophthalmology. 2012; 119: 1388-1398Summary Full Text Full Text PDF PubMed Scopus (1446) Google Scholar would be important. Thus, the ultimate importance of the IVAN trial remains to be established. Despite the similar efficacy between treatments, the uncertainty about safety (particularly systemic events) means ranibizumab users are unlikely to switch to bevacizumab and policy makers are unlikely to mandate such a switch. A reduction in injection frequency also seems to come at the price of a proportionate reduction in efficacy. Chakravarthy and colleagues' results do not address the newest treatment options. Aflibercept, a VEGF-binding fusion protein given every 2 months after loading, was approved by the US Food and Drug Administration after clinical trials showed its results were non-inferior to those of ranibizumab monotherapy.17Heier JS Brown DM Chong V et al.Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.Ophthalmology. 2012; 119: 2537-2548Summary Full Text Full Text PDF PubMed Scopus (1688) Google Scholar Fovista, an aptamer against platelet-derived growth factor, has better outcomes than ranibizumab monotherapy when used in combination with ranibizumab.18Boyer DS. A Phase 2b study of Fovista, a platelet derived growth factor (PDGF) inhibitor in combination with a vascular endothelial growth factor (VEGF) inhibitor for neovascular age-related macular degeneration (AMD). Association for Research in Vision and Ophthalmology Annual Meeting; Seattle, WA, USA; May 5–9, 2013. 2175.Google Scholar With increasingly complex treatment options, more research will be needed to study combination and sequential treatment—used widely in oncology. Both the IVAN and CATT studies have advanced our understanding of the treatment of age-related macular degeneration. Whether these data can significantly impact on clinical management and eventually lead to adoption of bevacizumab for public health funding remains to be seen. The search for a cheaper, better, and safer treatment continues. CMGC is on advisory boards for Bayer, Novartis, and Roche; and has received honoraria for travel and service on advisory boards, and research support from these companies. TYW is on advisory boards for Abbott, Allergan, Bayer, Novartis, Roche, and Pfizer; has received honoraria for travel and service on advisory boards, and research support from these companies; and has provided expert testimony to Novartis. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trialRanibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought. Full-Text PDF Open Access