The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial
Open accessAbstract
BACKGROUND: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. METHODS: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. FINDINGS: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). INTERPRETATION: Ranibizumab 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. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.
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“However, in the IVAN study, the incidence was similar in eyes treated with ranibizumab (28%) and with bevacizumab (31%; p=0.46)”
From Five-Year Outcomes with Anti–Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration (2016) · cites this paper as [9]
In the citing paper
“In CATT and all randomized clinical trials of anti-VEGF treatment for neovascular AMD, most of the improvement in mean visual acuity from baseline occurred within the first 3 to 6 months with little erosion of the benefit through 2 years when a fixed schedule of monthly (ranibizumab, bevacizumab, aflibercept) or bi-monthly (aflibercept) treatment was maintained.1,7,9,17,34”
From Five-Year Outcomes with Anti–Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration (2016) · cites this paper as [9]
In the citing paper
“decreasing the likelihood of a true effect of ranibizumab on development of geographic atrophy.”
From Five-Year Outcomes with Anti–Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration (2016) · cites this paper as [9]
In the citing paper
“In the IVAN study, 34% of eyes that received continuous (monthly) treatment developed geographic atrophy as compared with 26% in the discontinuous (PRN) group (p=0.03).9”
From Five-Year Outcomes with Anti–Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration (2016) · cites this paper as [9]
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“Additionally, there are concerns that there is an increase in lesion-associated atrophy in eyes receiving monthly treatment when compared with those treated less frequently.(2,3) We have previously presented 2-year outcomes of treatand-extend therapy for nAMD in a large registry-based cohort.”
ResultAge-Related Macular Degeneration Preferred Practice Pattern®
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“…factor (VEGF) inhibitor improves visual outcomes to an extent that is dependent mainly on the frequency and timeliness of follow-up injections after initiation of therapy (Martin et al. 2012; Chakravarthy et al. 2013), but also on age, anatomical lesion characteristics and baseline visual acuity.”
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“com first-line anti-VEGF agent and recent head-to-head trials have shown an excellent safety profile comparable with ranibizumab [22,23].”
BackgroundNew and Innovative Treatments for Neovascular Age-Related Macular Degeneration (nAMD)
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“Bevacizumab and ranibizumab have been found to be equally effective in treating neovascular AMD (Martin et al. 2011; Chakravarthy et al. 2013; Kodjikian et al. 2013; Krebs et al. 2013; Berg et al. 2015).”
BackgroundLow, A., Faridi, A., Bhavsar, K. V., Cockerham, G. C., Freeman, M., Fu, R., Paynter, R. A., Kondo, K. K., & Kansagara, D. L. (2018) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2018-312691 · Cited by 45
Kwong, T. Q., & Mohamed, M. D. (2014) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12371 · Cited by 46
MacDonald, D., Martin, J. H., Muthusamy, K., Luo, J.-K., Pyles, E. A., Rafique, A., Huang, T. T., Potocky, T. B., Liu, Y., Cao, J., et al. (2016) · Angiogenesis · doi:10.1007/s10456-016-9515-8 · Cited by 45
“While two additional, but smaller trials (IVAN; n = 610, MANTA; n = 321) individually showed no statistically significant differences in systemic SAEs between ranibizumab and bevacizumab [16, 17], a recent meta-analysis (n = 3665) comprising the above studies as well as six additional trials also found a higher incide…”
ResultLorés‐Motta, L., Riaz, M., Grunin, M. A., Corominas, J., van Asten, F., Pauper, M., Leenders, M., Richardson, A. J., Muether, P. S., Cree, A. J., et al. (2018) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2018.2019 · Cited by 45
Self-citationGune, S., Abdelfattah, N. S., Karamat, A., Balasubramanian, S., Marion, K. M., Morgenthien, E. A., & Sadda, S. R. (2019) · Ophthalmology · doi:10.1016/j.ophtha.2019.09.030 · Cited by 44
15 years of anti-VEGF treatment for nAMD: success or failure or something in between?
Chakravarthy, U., Armendariz, B. G., & Fauser, S. (2022) · Eye · doi:10.1038/s41433-022-02153-9 · Cited by 42
“Early studies suggested that VEGF inhibition itself might promote atrophy [2, 6], however others did not find a correlation between atrophy and treatment frequency [15, 16].”
BackgroundSelf-citationAmini, M. A., Karbasi, A., Vahabirad, M., Khanaghaei, M., & Alizamir, A. (2023) · Chonnam Medical Journal · doi:10.4068/cmj.2023.59.3.143 · Cited by 44
“The Inhibition of VEGF in Age-Related Choroidal Neovas-cularisation (IVAN) trial 93 in the United Kingdom demonstrated effects comparable to CATT, and the findings were validated by more clinical trials and a systematic study as well.”
MethodRosenfeld, P. J., Windsor, M. A., Feuer, W. J., Sun, S. J. J., Frick, K. D., Swanson, E. A., & Huang, D. (2018) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2018.04.008 · Cited by 42
Sivaprasad, S., Banister, K., Azuara‐Blanco, A., Goulão, B., Cook, J. A., Hogg, R. E., Scotland, G., Heimann, H., Lotery, A. J., Ghanchi, F. D., et al. (2021) · Ophthalmology · doi:10.1016/j.ophtha.2021.07.025 · Cited by 42
Self-citationNguyen, Q. D., Agarwal, A. K., Rhoades, W. R., Hanout, M., Soliman, M. K., Sarwar, S., Sadiq, M. A., Sepah, Y. J., & Diana, V. (2015) · Clinical ophthalmology · doi:10.2147/opth.s74959 · Cited by 42
“64,65 The Multicenter Anti-VEGF Trial in Austria (MANTA) 66 and Groupe d ′ Evaluation Français Avastin versus Lucentis (GEFAL) 67 trials were randomized to compare PRN dosing of BCZ and RBZ.”
Interleukin-17 Induces Angiogenesis in Human Choroidal Endothelial Cells In Vitro
Chen, Y., Zhong, M., Liang, L., Gu, F., & Peng, H. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15029 · Cited by 41
“Treatments for CNV in AMD include injections of humanized anti-vascular endothelial growth factor (VEGF) antibody fragments to inhibit neovascularization.(3,4) However, patients are subjected to numerous intravitreal injections and office visits.”
BackgroundAdvances in the management of macular degeneration
Singer, M. A. (2014) · F1000Prime Reports · doi:10.12703/p6-29 · Cited by 41
Tanaka, E., Chaikitmongkol, V., Bressler, S. B., & Bressler, N. M. (2015) · Ophthalmology · doi:10.1016/j.ophtha.2014.07.046 · Cited by 39
Intravitreal bevacizumab injection in unrecognised early pregnancy
Sullivan, L., Kelly, S. P., Glenn, A., Williams, C. P. R., & McKibbin, M. (2014) · Eye · doi:10.1038/eye.2013.311 · Cited by 39
Chen, E. R., & Kaiser, P. K. (2020) · Clinical ophthalmology · doi:10.2147/opth.s194234 · Cited by 39
Dhrami‐Gavazi, E., Balaratnasingam, C., Lee, W., & Freund, K. B. (2015) · International Journal of Retina and Vitreous · doi:10.1186/s40942-015-0015-6 · Cited by 38
“To date however, a difference in the rate of GA progression between ranibizumab and bevacizumab has not been proven [13].”
BackgroundResultThe safety of intravitreal bevacizumab monotherapy in adult ophthalmic conditions: systematic review
Poku, E. N., Rathbone, J., Wong, R., Everson-Hock, E., Essat, M., Pandor, A., & Wailoo, A. (2014) · BMJ Open · doi:10.1136/bmjopen-2014-005244 · Cited by 38
“An explanation for this observation is the possible role of immunological processes in drug interactions.(97) It is also important to note that the CATT study demonstrated some imbalances at baseline between randomised patients which may need further exploration.”
BackgroundResultWykoff, C. C., Ou, W. C., Croft, D. E., Payne, J. F., Brown, D. M., Clark, W. L., Abdelfattah, N. S., & Sadda, S. R. (2017) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2017-310822 · Cited by 38
Choi, M., Kim, S., Yun, C., & Oh, J. (2020) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2020.01.012 · Cited by 40
The pattern and gender disparity in global burden of age-related macular degeneration
Lin, X., Lou, L., Qi, M., Wang, Y., Jin, K., Shan, P., & Xu, Y. (2020) · European Journal of Ophthalmology · doi:10.1177/1120672120927256 · Cited by 38
Conbercept (KH-902) for the treatment of neovascular age-related macular degeneration
Nguyen, T. T., & Guymer, R. H. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2015.1075879 · Cited by 38
“Conversely, the risk of GA increased with continuous treatment [62].”
BackgroundThorell, M. R., Nunes, R. P., Chen, G. W., Doshi, R. R., Dugar, J., George, M. K., Kim, B. T., Lowrance, M. D., Modi, D., Nahas, Z., et al. (2014) · Ophthalmic surgery, lasers & imaging retina · doi:10.3928/23258160-20141118-07 · Cited by 37
Human IgG1 antibodies suppress angiogenesis in a target-independent manner
Bogdanovich, S., Kim, Y., Mizutani, T., Yasuma, R., Tudisco, L., Cicatiello, V., Bastos-Carvalho, A., Kerur, N., Hirano, Y., Baffi, J., et al. (2016) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2015.1 · Cited by 37
“4,19 Our findings suggest that the dose of bevacizumab required to achieve Fc γ RI-mediated anti-angiogenic activity is roughly eight times higher than the dose used in these trials, which is sufficient only to neutralize human VEGFA, thereby providing a molecular rationale for testing such higher…”
Counterfeit Avastin in India: Punish the Criminals, Not the Patients
Stewart, M. W., Narayanan, R., Gupta, V., Rosenfeld, P. J., Martin, D. F., & Chakravarthy, U. (2016) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2016.05.023 · Cited by 37
Self-citationCole, E. D., Ferrara, D., Novais, E. A., Louzada, R. N., & Waheed, N. K. (2016) · Retina · doi:10.1097/iae.0000000000001338 · Cited by 37
Reeves, B. C., Scott, L. J., Taylor, J., Hogg, R. E., Rogers, C. A., Wordsworth, S., Townsend, D., Muldrew, A., Pető, T., Violato, M., et al. (2016) · Health Technology Assessment · doi:10.3310/hta20800 · Cited by 37
Self-citationTopical antibiotics and intravitreal injections
Hunyor, A. P., Merani, R., Darbar, A., Korobelnik, J., Lanzetta, P., & Okada, A. A. (2017) · Acta Ophthalmologica · doi:10.1111/aos.13417 · Cited by 37
“…to diverge from what is perceived as the ‘standard of care’, despite published guidelines that do not support their use (Avery et al. 2014) and editorials in both the English (Chen et al. 2013) and non-English (Cochereau et al. 2013) literature suggesting that their routine use is not justified.”
BackgroundResultParvin, P., Zola, M., Dirani, A., Ambresin, A., & Mantel, I. (2017) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-017-3762-2 · Cited by 36
Graßmann, F., Fauser, S., & Weber, B. H. F. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2015.04.039 · Cited by 38
Treatment Choice for Diabetic Macular Edema
Martin, D. F., & Maguire, M. G. (2015) · New England Journal of Medicine · doi:10.1056/nejme1500351 · Cited by 37
Chen, G., Li, W., Tzekov, R., Jiang, F., Mao, S., & Tong, Y. (2015) · Retina · doi:10.1097/iae.0000000000000301 · Cited by 36
Metadata
- Authors
- Chakravarthy, U., Harding, S. P., Rogers, C. A., Downes, S. M., Lotery, A. J., Culliford, L. A., & Reeves, B. C.
- Affiliations
- Queen's University Belfast (GB)
- Corresponding author
- Chakravarthy, Usha
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 382
- Issue
- 9900
- Pages
- 1258-1267
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2154073405
- Cited by
- 748
- References
- 45
- Citations by year
- 2026: 13 · 2025: 36 · 2024: 36 · 2023: 36 · 2022: 33 · 2021: 84 · 2020: 66 · 2019: 44 · 2018: 74 · 2017: 66 · 2016: 90 · 2015: 77 · 2014: 75 · 2013: 13
- FWCI
- 84.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion, cc-by-nc-sa)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc-sa)
- ePrints Soton (University of Southampton) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute for Health and Care Research (07/36/01)
- Health Technology Assessment Programme (07/36/01, /36/01)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Health Sciences › Medicine › Ophthalmology › Retinal and Macular Surgery
- Keywords
- neovascular age-related macular degeneration, choroidal neovascularization, bevacizumab, ranibizumab, anti-VEGF therapy, intravitreal injection, treatment regimen comparison, best-corrected visual acuity, non-inferiority, arterial thrombotic events, long-term outcomes
- MeSH terms
- Bevacizumab, Ranibizumab, Aged, Female, Humans, Male, Middle Aged, Treatment Outcome, Choroidal Neovascularization, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor A, Antibodies, Monoclonal, Humanized
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