Repeated intravitreal injections of anti-vascular endothelial growth factor-A (VEGF) pharmaceuticals are the cornerstone of neovascular age-related macular degeneration (nAMD) management.1–4 Multiple attempts have been made to reduce the burden of nAMD care delivery by decreasing the dosing frequency of anti-VEGF pharmaceuticals.
Quarterly dosing with intravitreal anti-VEGF injections is a relatively common approach to managing eyes with nAMD and has been studied using both fixed5–7 and treat-and-extend strategies.8–14 Fixed quarterly ranibizumab (Lucentis; Genentech, South San Francisco, CA) treatments in the phase 3 PIER trial maintained baseline visual acuity (VA) through 1 year but did not achieve the VA gains observed with fixed monthly treatment.5 EXCITE and SAILOR similarly concluded that quarterly ranibizumab dosing was insufficient to maintain the VA gains achieved with monthly dosing.6,7
Prospective treat-and-extend trials have demonstrated that a meaningful proportion of eyes can maintain a dry macula with quarterly dosing and achieve similar VA gains as observed with monthly dosing. Cumulatively, using bevacizumab (Avastin; Genentech, South San Francisco, CA), ranibizumab or aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY), these studies have reported that 22% to 38% of patients are able to achieve an interval of 11 weeks or more between re-treatments.8–14
The current study aimed to characterize the clinical course and rates of exudative disease recurrence among nAMD eyes receiving quarterly anti-VEGF dosing in real-world practice.
Patients and Methods
Records of 6,809 patients receiving intravitreal anti-VEGF injections for nAMD from 2005 through 2017 within a large retina-only practice, Retina Consultants of Houston, Houston, Texas, were retrospectively reviewed. Institutional review board (Houston Methodist Hospital, Houston, Texas) approval for chart review was obtained. All study procedures adhered to the tenets set forth in the Declaration of Helsinki and the Health Insurance Portability and Accountability Act.
Patients were included if they had been managed exclusively within the same practice since initial nAMD treatment and received five or more consecutive injections intentionally at intervals of 11 to 15 weeks, defined as quarterly dosing, without exudative disease recurrence during this time. Patients unintentionally treated at an interval of 11 to 15 weeks due to missed visits were excluded. Demographics, clinical variables, and documented reason(s) for transition to and from quarterly dosing were recorded.
Prior to quarterly dosing, patients were predominately managed using a treat-and-extend regimen with a low tolerance for fluid. Specifically, monthly anti-VEGF injections were given until a dry macula was achieved, without intraretinal hemorrhage (IRH), subretinal hemorrhage (SRH), subretinal fluid (SRF), or intraretinal fluid (IRF) that was believed to be anti-VEGF responsive. Fluid status was followed most commonly with spectral-domain optical coherence tomography (OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany) imaging. Once a dry macula was achieved, the interval between injections was increased systematically, most commonly by 2-week increments, to a maximum of quarterly dosing. If there was a recurrence of exudative disease activity, as evidenced by recurrent or new IRH, SRH, SRF, or IRF, the interval between injections was reduced to the maximum tolerated interval. In general, specified loading doses were not used, although most patients received monthly injections until a dry macula was achieved.
Categorical data including gender and anti-VEGF agent used during quarterly dosing were collected and analyzed using chi-square and Fisher's exact tests. The anti-VEGF agent used most recently was recorded when the anti-VEGF agent had been changed during the course of quarterly treatment. Clinical data including VA and OCT-determined central subfield thickness (CST) were collected at four key visits: initial nAMD diagnosis, initiation of quarterly dosing, final visit, and, where relevant, termination of quarterly dosing. VA was converted to approximate Early Treatment Diabetic Retinopathy Study letter equivalent for analysis.15 Changes in VA and CST were analyzed along with continuous variables such as age and number of injections using Student's t-tests, ANOVA, and Wilcoxon signed-rank tests. Kaplan-Meier survival analysis was performed to calculate cumulative disease recurrence rates during quarterly dosing.
The primary outcome measure was defined as the proportion of patients maintained on quarterly dosing. Eyes were divided into three major groups for data analysis: (1) eyes maintained on quarterly dosing through their final visit, (2) eyes transitioned from quarterly dosing to more frequent dosing, and (3) eyes that stopped receiving anti-VEGF therapy following quarterly dosing. Statistical analyses were conducted using R version 3.5.2 (R Project for Statistical Computing, www.r-project.org). All tests were two-sided, and P values less than .05 were considered statistically significant.
The current study identified 150 eyes from 134 patients receiving five or more consecutive injections for nAMD at quarterly dosing (Figure 1). Mean patient age was 82.1 years, 79 patients (59%) were female, and 70 (47%) were right eyes. Demographics were similar between the three predefined clinical groups (P > .1).
Flowchart illustrating the disposition of patients by quarterly dosing outcome and recurrence of exudative disease activity. VEGF = vascular endothelial growth factor; nAMD = neovascular age-related macular degeneration
Baseline VA was significantly different between the three clinical groups (P = .01). Eyes maintained on quarterly dosing began at a mean 55 letters (20/80), eyes transitioned to more frequent dosing began at a mean 51 letters (20/100), and eyes for which treatment was stopped completely began at a lower mean of 39 letters (20/160). Mean baseline CST also appeared numerically different between the groups, and these differences paralleled the VA observations (P = .05); eyes maintained on quarterly dosing began with the lowest mean CST of 353 μm, followed by eyes transitioned to more frequent dosing at 392 μm, and eyes for which treatment was stopped completely had the highest CST of 475 μm (Table 1).
Baseline Demographic and Treatment Data
Among all 150 eyes, a mean 16.1 injections were given over a mean of 31 months prior to initiation of quarterly dosing. During this time, mean CST decreased significantly (379 μm to 261 μm; P < .001), and mean VA increased, although this increase in VA was not statistically significant (51 to 55 letters; P = .08). A mean of 9.8 injections (range: five injections to 29 injections) were then given over a mean of 29 months (range: 12 months to 98 months) of quarterly dosing. CST improvements achieved prior to initiation of quarterly dosing were maintained (255 μm) whereas VA decreased at final visit or termination of quarterly dosing (55 to 51 letters; P < .001) (Figure 2). During quarterly dosing, 22 eyes (15%) received intravitreal bevacizumab, 75 eyes (50%) received ranibizumab, and 53 eyes (35%) received aflibercept. The anti-VEGF agent used did not vary among the three predefined clinical groups (P = .40).
Graphs showing mean visual and anatomic outcomes from diagnosis through termination of quarterly dosing or final visit for all 150 eyes treated with quarterly anti-VEGF dosing for neovascular age-related macular degeneration management. A. Visual acuity (Early Treatment Diabetic Retinopathy Study letters). B. Optical coherence tomography determined central subfield thickness (μm). Solid line = dosing interval before initiation of quarterly dosing. Dashed line = quarterly dosing interval.
Group 1: Eyes Maintained on Quarterly Dosing
Ninety-one eyes (61%) were maintained on quarterly dosing through the final visit without recurrence of exudative activity. Among the eyes that continued quarterly dosing, a mean 10.7 quarterly anti-VEGF injections were administered over a mean of 31 months (range: 13 months to 98 months) of follow-up. VA remained stable from baseline to quarterly dosing initiation (55 to 56 letters; P = .71) then decreased to final visit (56 to 52 letters; P = .009). CST decreased significantly (353 μm to 257 μm; P < .001) from baseline to quarterly dosing initiation, and these gains were maintained during quarterly dosing (249 μm).
Group 2: Eyes Transitioned to More Frequent Dosing
After a mean 8.9 quarterly injections, 33 eyes (22%) were treated more frequently due to the development of increased exudative disease activity. Of the 24 eyes that had imaging at the time of recurrence identification, 92% (n = 22 eyes) had new IRF, 54% (n = 13 eyes) had new SRF, and 25% (n = 6 eyes) had new IRH or SRH. At the time of recurrent exudative disease activity, these eyes had lost a mean of 6 letters of VA from initiation of quarterly dosing (59 to 53 letters; P = .01) and had gained a mean of 10 μm CST, although this change was not significant (261 to 271 μm; P = .39). VA for this group decreased further to final visit (53 to 49 letters; P = .007). Of these 33 recurrences of exudative nAMD activity during quarterly dosing, by definition, none occurred within the first year of quarterly dosing because the prespecified inclusion criteria required five or more consecutive quarterly injections. A 12% mean cumulative yearly recurrence rate was observed for years 2 through 5 following initiation of quarterly dosing (Figure 3). Additionally, two eyes (1%) transitioned to more frequent dosing due to the development of macular edema secondary to new-onset retinal vascular occlusions.
Kaplan-Meier analysis of 150 eyes treated with quarterly anti-vascular endothelial growth factor dosing for neovascular age-related macular degeneration management. Trajectory illustrates the probability of remaining exudative disease recurrence-free during quarterly dosing. Because only patients with five or more quarterly injections were included in the current analysis, by definition, there were no recurrences observed until after month 12. There was a mean 12% cumulative yearly recurrence rate from the beginning of year 2 through the start of year 5. At years 2, 3, 4, and 5 following initiation of quarterly dosing, survival rates were 87%, 75%, 67%, and 53%, respectively (n= 83, 32, 15, and 4).
Group 3: Eyes for Which Treatment Was Stopped
Twenty-four eyes (16%) intentionally stopped receiving treatment after a mean 8.1 quarterly injections, due to prolonged apparent disease inactivity or development of widespread macular atrophy. For this population, VA was maintained during quarterly dosing (45 to 44 letters; P = .83), and mean CST decreased from 283 μm to 256 μm (P = .001). After stopping treatment, this population was then followed for a mean of 30 months, during which nine eyes (38%) had recurrent exudative activity after a mean of 21 months (range: 6 months to 58 months) and were reinitiated on anti-VEGF treatment following a mean 8-letter loss relative to VA at the time of quarterly dosing termination (64 to 56 letters; P = .03). Of the seven eyes that had imaging at the time of recurrence identification, 71% (n = 5 eyes) had new IRF, 43% (n = 3 eyes) had new SRF, and 43% (n = 3 eyes) had new IRH or SRH.
Fixed Follow-Up Analysis
Separate analyses were performed using fixed windows of follow-up from initiation of quarterly dosing. One hundred ten eyes completed 24 months from quarterly dosing initiation: 55 eyes (50%) were maintained on quarterly dosing, 32 eyes (29%) transitioned to more frequent dosing due to recurrent exudative nAMD activity, 21 eyes (19%) stopped anti-VEGF therapy completely due to apparent disease inactivity, and two eyes (2%) developed macular edema secondary to a new-onset retinal vascular occlusion. Of the eyes that stopped treatment, one (5%) experienced eventual exudative disease activity recurrence after 6 months of observation.
Sixty-seven eyes completed 36 months from quarterly dosing initiation: 25 eyes (37%) were maintained on quarterly dosing, 23 eyes (34%) transitioned to more frequent dosing, 18 eyes (27%) stopped anti-VEGF therapy completely, and one eye (1%) ] developed macular edema secondary to a new-onset retinal vascular occlusion. Of the eyes that stopped treatment, six (33%) experienced eventual exudative disease activity recurrence after a mean of 11 months (range: 6 months to 18 months).
Forty-six eyes completed 48 months from quarterly dosing initiation: 12 eyes (26%) were maintained on quarterly dosing, 19 eyes (41%) transitioned to more frequent dosing, and 15 eyes (33%) stopped anti-VEGF therapy completely. Of the eyes that stopped treatment, six (40%) experienced eventual exudative disease activity recurrence after a mean of 11 months (range: 6 months to 18 months).
The current real-world study considered the treatment course and outcomes of 150 eyes with nAMD managed with quarterly dosing for a minimum of five injections. Among the entire population, over the full 90 mean months of follow-up including the periods of management before and after quarterly dosing initiation, having received a mean of 26 anti-VEGF injections, there was no significant change in VA (51 to 51 letters; P = .89).
During the quarterly dosing period spanning a mean 29 months, 33 eyes (22%) experienced recurrent exudative disease activity, and Kaplan-Meier survival analysis found a mean 12% cumulative annual recurrence rate from the start of year 2 through the start of year 5. These overall and yearly exudative disease recurrence rates are consistent with prior reports. A retrospective analysis by Hwang et al.16 involving 57 nAMD eyes extended to quarterly dosing following a treat-and-extend regimen found a 16% recurrence rate during a mean of 19 months of follow-up, with a mean cumulative recurrence rate of 10% per year.
Eyes in the current analysis that experienced recurrent exudative disease activity ultimately lost approximately 10 letters of VA from their maximum VA. Analogously, within the 2-year prospective treat-and-extend LUCAS trial, eyes that experienced exudative disease recurrence while being managed with quarterly dosing ultimately lost VA compared with eyes experiencing recurrence of exudative disease activity while at a shorter interval; in response, Berg et al.9 suggest that treatment intervals be reduced more dramatically for recurrences during quarterly dosing or, alternatively, that treat-and-extend regimens be capped at 10-week intervals to address this risk.
Of the 150 eyes captured within the current study, 24 (16%) stopped receiving treatment altogether. These patients had a notably lower baseline VA than the other populations (39 vs. 51 and 55 letters; P = .01), and cessation of treatment in this population likely reflected a clinical interpretation of futility in the setting of perceived limited visual function from the involved eye. Nevertheless, 38% of these eyes later reinitiated anti-VEGF therapy after a mean of 21 months due to recurrent disease activity. Adrean et al.17 noted a recurrence rate of 29% over a mean of 14 months of follow-up among eyes that stopped receiving treatment after extension to quarterly dosing as part of a “treat-extend-stop” retrospective analysis. In comparison, Hwang et al.16 found that 63% of patients who achieved a quarterly dosing interval using a treat-and-extend regimen with bevacizumab and then immediately stopped dosing exhibited recurrence of exudative disease activity within a mean of just 4 months after cessation of anti-VEGF dosing; this recurrence rate appears notably higher than other reports and is likely driven by the use of just one interval of quarterly dosing before stopping ongoing therapy. Overall, termination of treatment altogether appears to heighten the risk of exudative disease recurrence compared with the risk during ongoing quarterly dosing, consistent with the accepted mechanism of episodic anti-VEGF dosing as a treatment but not a cure for the exudative process underlying nAMD.
Strengths of the current study are the inclusion of all three current anti-VEGF pharmacotherapies, average follow-up of more than 7 years, exclusive management of the studied eyes in one clinical practice from diagnosis through final follow-up, and real-world clinical setting. Key limitations of the current study include the shortcomings associated with a retrospective analysis and limited number of eyes. Additionally, the current retrospective study relied entirely on treating physicians to accurately diagnose nAMD, and this diagnosis at baseline was not verified in all patients by imaging.
In summary, 61% of eyes managed with quarterly dosing were maintained on quarterly dosing, whereas 39% of eyes transitioned away from quarterly dosing through nearly 2.5 mean years of follow-up. Thirty-three eyes (22%) transitioned to more frequent dosing due to increased exudative disease activity, and 24 eyes (16%) stopped treatment completely with nine (38%) of these subsequently reinitiating anti-VEGF dosing due to recurrent exudative disease activity. Cumulatively, a 12% yearly exudative recurrence rate was identified during quarterly dosing, illustrating a steadily increasing probability of recurrence during quarterly dosing with passing years. These findings indicate that recurrence of exudative disease activity is not uncommon, even among patients who initially tolerate 5 or more quarterly injections. Consistent clinical care and monitoring are indicated for the long-term management of patients receiving current-generation quarterly anti-VEGF intravitreal treatments for nAMD.
- Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–1431. doi:10.1056/NEJMoa054481 [CrossRef]17021318
- Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57–65. doi:10.1016/j.ophtha.2008.10.018 [CrossRef]19118696
- Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: Ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193–201. doi:10.1016/j.ophtha.2013.08.011 [CrossRef]
- Maguire MG, Martin DF, Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group et al. Five-year outcomes with anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751–1761. doi:10.1016/j.ophtha.2016.03.045 [CrossRef]27156698
- 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. 2008;145(2):239–248. doi:10.1016/j.ajo.2007.10.004 [CrossRef]18222192
- Schmidt-Erfurth U, Eldem B, Guymer R, et al. EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: The EXCITE study. Ophthalmology. 2011;118(5):831–839. doi:10.1016/j.ophtha.2010.09.004 [CrossRef]
- 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(9):1731–1739. doi:10.1016/j.ophtha.2009.05.024 [CrossRef]19643495
- Berg K, Pedersen TR, Sandvik L, Bragadóttir R. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122(1):146–152. doi:10.1016/j.ophtha.2014.07.041 [CrossRef]
- Berg K, Hadzalic E, Gjertsen I, et al. Ranibizumab or bevacizumab for neovascular age-related macular degeneration according to the Lucentis Compared to Avastin Study treat-and-extend protocol: Two-year results. Ophthalmology. 2016;123(1):51–59. doi:10.1016/j.ophtha.2015.09.018 [CrossRef]
- DeCroos FC, Reed D, Adam MK, et al. Treat-and-extend therapy using aflibercept for neovascular age-related macular degeneration: A prospective clinical trial. Am J Ophthalmol. 2017;180:142–150. doi:10.1016/j.ajo.2017.06.002 [CrossRef]28624325
- Kertes PJ, Galic IJ, Greve M, et al. Canadian treat-and-extend analysis trial with ranibizumab in patients with neovascular age-related macular disease: One-year results of the randomized Canadian Treat-and-Extend Analysis Trial with Ranibizumab Study. Ophthalmology. 2019;126(6):841–848. doi:10.1016/j.ophtha.2019.01.013 [CrossRef]30677465
- Silva R, Berta A, Larsen M, Macfadden W, Feller C, Monés JTREND Study Group. Treat-and-extend versus monthly regimen in neovascular age related macular degeneration: Results with ranibizumab from the TREND study. Ophthalmology. 2018;125(1):57–65. doi:10.1016/j.ophtha.2017.07.014 [CrossRef]
- Wykoff CC, Croft DE, Brown DM, et al. TREX-AMD Study Group. Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results. Ophthalmology. 2015;122(12):2514–2522. doi:10.1016/j.ophtha.2015.08.009 [CrossRef]26391465
- Wykoff CC, Ou WC, Brown DM, et al. TREX-AMD Study Group. Randomized trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: 2-year results of the TREX-AMD Study. Ophthalmol Retina. 2017;1(4):314–321. doi:10.1016/j.oret.2016.12.004 [CrossRef]31047517
- Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing Snellen visual acuity measurements. Retina. 2010;30(7):1046–1050. doi:10.1097/IAE.0b013e3181d87e04 [CrossRef]20559157
- Hwang RY, Santos D, Oliver SCN. Rates of exudative recurrence for eyes with inactivated wet age-related macular degeneration on 12-week interval dosing with bevacizumab therapy. Retina. 2019. doi:. doi:10.1097/IAE.0000000000002446 [CrossRef]
- Adrean SD, Chaili S, Grant S, Pirouz A. Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat-extend-stop protocol. Ophthalmol Retina. 2018;2(3):225–230. doi:10.1016/j.oret.2017.07.009 [CrossRef]31047590
Baseline Demographic and Treatment Data
|Maintained Quarterly Dosing (n = 91 eyes)||Increased Frequency (n = 35 eyes)||Stopped Injections (n = 24 eyes)||Total (n = 150 eyes)||P Value|
|Mean Age, Years||82.4||83||79.9||82.1||.37|
|Females, n (%)||42 (55)||23 (66)||14 (61)||79 (59)||.57|
|Right Eyes, n (%)||41 (45)||17 (49)||12 (50)||70 (47)||.88|
|Mean Baseline VA, ETDRS Letters||55||51||39||51||.01*|
|Approximate Snellen Equivalent||20/80||20/100||20/160||20/100||-|
|Mean Baseline CST, μm||357||392||475||380||.05|
|Mean Injections Prior to Quarterly Dosing, n||17.3||16.4||11.7||16.2||.11|
|Mean Follow-up Prior to Quarterly Dosing, Months||33||32||22||31||.17|
|Mean Quarterly Injections, n||10.7||8.9||8.1||9.8||.008*|
|Mean Quarterly Follow-up, Months||31||25||23||29||.02*|
|Anti-VEGF Agent Used During Quarterly Dosing||-||-||-||-||.41|
|Quarterly Bevacizumab, n (%)||13 (14)||4 (11)||5 (21)||22 (15)||-|
|Quarterly Ranibizumab, n (%)||41 (45)||21 (60)||13 (54)||75 (50)||-|
|Quarterly Aflibercept, n (%)||37 (41)||10 (29)||6 (25)||53 (35)||-|
|Mean Follow-up After Quarterly Dosing Termination, Months||-||30||34||33||.59|