The "Treat and Extend" Dosing Regimen of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration
While monthly injections of intravitreal anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (AMD) have produced visual outcomes superior to prior therapies,1,2 the frequency of office visits and injections can place a tremendous burden on patients and the health care system. Unfortunately, the PIER trial,3 which is the only randomized, double-blind, sham-controlled trial investigating a less frequent dosing regimen, yielded inferior visual outcomes compared to outcomes reported after monthly dosing. Patients in the PIER trial were examined and treated quarterly following an initial series of three monthly injections. The open-label, non-randomized PrONTO study also employed three initial monthly injections but was followed by "as needed" dosing based on changes in visual acuity, clinical findings and optical coherence tomography (OCT) evaluation.4,5 The PrONTO regimen appeared to achieve visual results similar to monthly dosing with fewer injections, but patients still required monthly visits, examinations, and OCTs. Furthermore, after the initial mandated series of three injections, this protocol allowed fluid to re-accumulate at the fovea before treatment was repeated, raising concerns regarding incremental long-term vision loss and the possibility of new hemorrhages during periods without VEGF inhibition.6,7,8
The "Treat and Extend" dosing regimen is a tailored maintenance regimen intended to achieve optimal visual results with two additional goals.9 Like PIER and PrONTO, it consists of at least three initial monthly injections, but, once stable visual acuity, an absence of macular hemorrhage, and a dry OCT have been achieved, patients continue to receive regular maintenance injections at increasing intervals. Once stability is achieved with monthly dosing, the patient is instructed to return in six weeks. Visual acuity, clinical findings, and OCT changes are recorded again and patients receive an injection regardless of the presence or absence of disease activity. However, the interval to the next visit (and scheduled injection) is based on an observed change in the above parameters. If there are no changes, the interval to the next visit is extended to seven or eight weeks (hence the term "Treat and Extend"). However, if there is evidence of renewed disease activity, the interval for the next scheduled injection and examination is shortened. In our own clinical practice, we rarely extend the interval between injections and examination beyond 8-9 weeks.
One goal of "Treat and Extend" is to reduce the treatment burden by reducing number of patient visits and the number of imaging studies performed by eliminating the need for the monthly visits necessitated by alternative dosing strategies. We recently reported success in achieving this goal in two small cohorts of eyes with newly diagnosed type 1 (occult)10 and type 3 (retinal angiomatous proliferation)11 neovascularization. In these reports, the eyes with type 3 vessels had a sustained visual improvement of approximately 2 Snellen lines while the eyes with type 1 vessels achieved visual stabilization. The number of office visits and injections was reduced by 25-50% compared to a monthly dosing regimen.
A second goal of the "Treat and Extend" dosing regimen is to reduce the risk of new sight-threatening submacular hemorrhages. We recently demonstrated a statistically significant increase in macular hemorrhages when patients in the PIER trial were switched from a monthly to quarterly dosing regimen.6 Unfortunately, large and potentially devastating submacular hemorrhages may occur almost immediately after a high-quality OCT examination showing an absence of fluid.7, 8 Theoretically, eyes treated with an OCT-guided "as needed" regimen, in which patients may go long intervals without VEGF suppression, could be at a greater risk for sight-threatening submacular hemorrhages compared to eyes receiving more frequent and regular anti-VEGF treatments. In our two retrospective series, we did not observe any sight-threatening macular hemorrhages. Also, unlike the ANCHOR, MARINA and PrONTO studies which are limited to 24 months of follow-up, 17 of our 28 patients completed 36 month follow-up. We are not aware of any other dosing regimen of anti-VEGF therapy that has demonstrated stable or improved VA out to three years.
While initial results of the "Treat and Extend" dosing regimen appear promising, the strategy requires further validation in a larger randomized trial. Clinicians should view the current data regarding different regimens critically when deciding which dosing strategy is best for individual patients.
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 PM, Michels M, et al. Ranibizumab versus verteporforin for neovascular age-related macular degeneration. N Engel J Med 2006; 355: 1432-1444
Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. Feb 2008;145(2):239-248.
Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. Apr 2007;143(4):566-583.
Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009 Jul;148(1):43-58.e1. Epub 2009 Apr 18.
Barbazetto I, Saroj N, Freund KB. Dosing regimen and the frequency of macular hemorrhages in neovascular age-related macular degeneration treated with ranibizumab. Presented at the Annual Meeting of the Retina Society, September 2008.
Margolis R, Freund KB. Hemorrhagic recurrence of neovascular age-related macular degeneration not predicted by spectral domain optical coherence tomography. Retinal Cases and Brief Reports, in press.
Levine JP, Marcus I, Sorenson JA, Spaide RF, Cooney MJ, Freund KB. Macular hemorrhage in neovascular age-related macular degeneration after stabilization with antiangiogenic therapy. Retina. 2009 Sep;29(8):1074-9.
Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol. 2007 Apr;143(4):679-80.
Engelbert M, Zweifel SA, Freund KB. Long-term Follow-up for Type 1 (sub-RPE) Neovascularization using a "Treat and Extend" Dosing Regimen of Intravitreal Anti-vascular Endothelial Growth Factor Therapy". Retina, accepted for publication.
Engelbert M, Zweifel SA, Freund KB. "Treat and extend" dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina. 2009 Nov-Dec;29(10):1424-31.
About our author(s):
Michael Engelbert, MD
K. Bailey Freund, MD
Edward S. Harkness Eye Institute, Columbia University College of Physicians & Surgeons, New York, NY,
Vitreous-Retina-Macula Consultants of New York, New York, NY
LuEsther T. Mertz Retinal Research Center, New York, NY
This work is supported by The Macula Foundation, Inc..