Evaluation of Injection Frequency and Visual Acuity Outcomes for Ranibizumab Monotherapy in Exudative Age-related Macular Degeneration

doi:10.1016/j.ophtha.2009.05.033

Ophthalmology

Volume 116, Issue 9, September 2009, Pages 1740-1747

Presented in part as a poster presentation at the American Academy of Ophthalmology meeting, November 2008, Atlanta, Georgia.

https://doi.org/10.1016/j.ophtha.2009.05.033 Get rights and content

Objective

To evaluate the visual outcomes for intravitreal ranibizumab administered on an as-needed basis for exudative age-related macular degeneration (AMD) and to investigate the relationship between injection frequency and visual outcome in this setting.

Design

Retrospective, interventional case series.

Participants

A total of 131 eyes with treatment-naïve, exudative AMD undergoing ranibizumab monotherapy.

Methods

Intravitreal ranibizumab was administered on an as-needed basis guided by clinical examination and optical coherence tomography (OCT). The OCT scans were evaluated by the treating physicians for the presence of intraretinal fluid, subretinal fluid, intraretinal cysts, or increasing pigment epithelial detachment size. Clinical data including visual acuity (VA), choroidal neovascularization lesion morphology, and treatment course were collected retrospectively for analysis.

Main Outcome Measures

Mean change in best-corrected Snellen VA.

Results

The mean age was 81.3 years, mean follow-up was 12±4.3 months (minimum 6 months, median 12 months), and mean number of injections was 5.2±2.8. Mean baseline Snellen VA for the entire population was 20/110 and significantly improved at 6 months (20/80; P = 0.0002) and at last follow-up (20/90; P = 0.0066). At 6 months, 31% of eyes had gained at least 3 lines of VA and 90.5% had avoided loss of 3 lines. On average, it took 3.0 injections and 3.5 months to achieve a “dry” or “flat” macula on OCT after initiating treatment. Resolution of intra- and subretinal fluid on OCT did not correlate with the degree of vision improvement. Eyes receiving more frequent injections (defined as <2 months mean inter-injection interval) gained more vision (+2.3 lines at 6 months) than eyes receiving injections less frequently (+0.46 lines at 6 months; P = 0.012). At 6 months, 3.1% of those in the more frequent injection group lost >3 lines of vision compared with 15.9% in the >2 months interval group (P = 0.011).

Conclusions

In a population receiving as-needed injections of ranibizumab for exudative AMD, visual improvement was related to the frequency of injections received but not to the resolution of fluid by OCT. Treatment with ranibizumab on a strictly as-needed basis may result in undertreatment and significantly less visual gain.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Materials and Methods

After Cleveland Clinic Institutional Review Board approval, the charts of all patients with CNV due to exudative AMD receiving their first ranibizumab injection at the Cole Eye Institute (Cleveland, OH) between April 2006 and December 2007 were retrospectively reviewed. Patients were included in the study if they were older than 50 years of age, were treatment naïve and receiving their first ranibizumab injection for exudative AMD, and had at least 6 months of follow-up. Patients were excluded

Results

A total of 446 patients were reviewed, and 131 treatment-naïve eyes in 124 patients met the inclusion criteria and were included in the analysis. Demographic and clinical data for these patients are summarized in Table 1. The mean age was 81.3±8.3 years, and the gender distribution was 64.5% female. Baseline FAs were available for 104 eyes, and these revealed a mix of baseline lesion types (16.3% predominantly classic CNV, 16.3% minimally classic CNV, 66.3% occult with no classic CNV) that were

Discussion

Determining the optimal dosing schedule for anti-VEGF therapy for exudative AMD remains a challenge because neither the effect of the drugs in human eyes nor the nature of the disease itself is fully understood. On the basis of the MARINA and ANCHOR trial data, the best reported efficacy, in terms of VA preservation and gain, is seen with mandated monthly dosing.3, 4 However, these trials did not follow a clinical end point for treatment cessation, and such a regimen raises concerns for

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Cited by (119)

Visual Acuity Outcomes and Anti–Vascular Endothelial Growth Factor Therapy Intensity in Neovascular Age-Related Macular Degeneration Patients: A Real-World Analysis of 49 485 Eyes
2020, Ophthalmology Retina
Citation Excerpt :
Nevertheless, these patients also showed better final VA compared with those patients with worse baseline VA, who gained more letters at 1 year. Multiple reports have suggested a relationship between the number of anti-VEGF injections and letters gained, with fewer injections associated with worse outcomes.6–8,12,15,25,26 Consequently, attempts to limit treatment burden through the adoption of variable frequency anti-VEGF treatment regimens must be approached cautiously.
This study assessed anti–vascular endothelial growth factor (VEGF) therapy intensity and its relationship with visual acuity (VA) change in real-world neovascular age-related macular degeneration (nAMD) patients.
This retrospective analysis was performed on a large database of aggregated, longitudinal, de-identified electronic medical records from a geographically and demographically diverse sample of patients of United States retina specialists (Vestrum Health Retina Database).
Treatment-naïve nAMD patients who underwent anti-VEGF injections between January 1, 2012, and October 31, 2016, were eligible if follow-up data were available before October 31, 2017.
Age, gender, anti-VEGF treatment type, number of treatments, and VA were extracted from the database.
Mean VA change assessed at 1 year and stratified based on number of anti-VEGF injections received over 1 year.
In this analysis, 49 485 eyes were included. The mean age was 80.9 years, and 64% were female. Mean baseline VA was 53.8 letters (Snellen equivalent, 20/80). At 1 year, after a mean of 7.3 anti-VEGF injections, there was a mean gain of 1 letter (0.95 letter; 95% confidence interval [CI] for change in VA, +0.77 to +1.13 letter; P < 0.001). When stratified by anti-VEGF agent, the mean VA changes were nearly identical at 1 year. There was a linear relationship between mean letters gained and mean number of injections, between 4 and 10 injections over 1 year, with 4 or fewer or 10 or more injections associated with loss of vision or a plateau, respectively. Greater mean 1-year change in VA also trended with worse baseline VA; those patients with better VA at presentation tended to be particularly vulnerable to vision loss. Those who received the fewest injections tended to be older and have worse baseline VA.
Real-world nAMD patients receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients receiving fixed, frequent therapy in randomized controlled trials. Mean change in VA correlates with treatment intensity at 1 year, but with ceiling effects related to treatment intensity and baseline VA. Older patients and those with poor baseline VA may be particularly prone to undertreatment.
Central serous chorioretinopathy: Towards an evidence-based treatment guideline
2019, Progress in Retinal and Eye Research
Citation Excerpt :
While complete resolution of SRF should be the principal surrogate endpoint for trials on CSC, this may not be the case in AMD patients with accompanying SRF. In AMD patients with SRF, the BCVA may be relatively preserved and complete resolution of the SRF may not be required to still maintain a relatively favourable BCVA (Dadgostar et al., 2009; Jang et al., 2015). However, CSC and AMD are different disease entities with potentially different types of and rates of leakage and a different composition of the SRF.
Central serous chorioretinopathy (CSC) is a common cause of central vision loss, primarily affecting men 20–60 years of age. To date, no consensus has been reached regarding the classification of CSC, and a wide variety of interventions have been proposed, reflecting the controversy associated with treating this disease. The recent publication of appropriately powered randomised controlled trials such as the PLACE trial, as well as large retrospective, non-randomised treatment studies regarding the treatment of CSC suggest the feasibility of a more evidence-based approach when considering treatment options. The aim of this review is to provide a comprehensive overview of the current rationale and evidence with respect to the variety of interventions available for treating CSC, including pharmacology, laser treatment, and photodynamic therapy. In addition, we describe the complexity of CSC, the challenges associated with treating CSC, and currently ongoing studies. Many treatment strategies such as photodynamic therapy using verteporfin, oral mineralocorticoid antagonists, and micropulse laser treatment have been reported as being effective. Currently, however, the available evidence suggests that half-dose (or half-fluence) photodynamic therapy should be the treatment of choice in chronic CSC, whereas observation may be the preferred approach in acute CSC. Nevertheless, exceptions can be considered based upon patient-specific characteristics.
Recent Innovations in Drug Delivery for Retinal Diseases
2018, Advances in Ophthalmology and Optometry
Real-world Outcomes of Anti–Vascular Endothelial Growth Factor Therapy in Neovascular Age-Related Macular Degeneration in the United States
2018, Ophthalmology Retina
Real-world visual outcomes of anti–vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD) have been reported in cohorts outside of the United States. This study sought to assess the relationship between presenting visual acuity (VA) and visual outcomes, as well as the potential impact of loss to follow-up, in real-world anti-VEGF–treated nAMD patients from the United States.
Retrospective study of aggregated, longitudinal electronic medical records obtained from a geographically diverse sample of US retina specialists and included in the Vestrum Health Retina Database.
Inclusion criteria were a diagnosis of nAMD, no previous treatment, and ≥3 monthly anti-VEGF injections in the first 4 months from diagnosis in patients diagnosed between January 2011 and July 2013.
To model loss to follow-up, mutually exclusive cohorts of nAMD patients with loss to follow-up after specific time points of 6 and 12 months (i.e., no follow-up beyond) were compared with a separate cohort of patients who completed 24 months of follow-up ending prior to July 2015 (n = 2213).
VA outcomes were assessed on each cohort as a whole, with additional stratification by baseline VA.
The 6-, 12-, and 24-month cohorts received means of 5.4, 7.3, and 12.1 injections and showed no change, no change, and a mean change of +3.1 letters from baseline (95% confidence interval 1.8–4.4 letters, P < 0.01), respectively. When stratified by baseline VA, nearly all groups lose VA at their respective follow-up periods, except for those with baseline VA of 20/200 or worse.
Real-world nAMD patients in the United States receive fewer anti-VEGF injections and experience worse visual outcomes compared with patients in randomized clinical trials, consistent with non-US studies. Patients with better VA at presentation tend to be particularly vulnerable to vision loss. Compared with other patients, those ultimately lost to follow-up have worse visual outcomes at, or prior to, their final visit, suggesting that loss to follow-up may lead to overestimation of visual outcomes in clinical studies of nAMD.
Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the TREND Study
2018, Ophthalmology
To evaluate the efficacy and safety of ranibizumab 0.5 mg treat-and-extend (T&E) versus monthly regimens in patients with neovascular age-related macular degeneration (nAMD) from the TReat and extEND (TREND) study.
A 12-month phase 3b visual acuity (VA) assessor-masked, multicenter, randomized, interventional study.
Six hundred fifty patients.
Treatment-naïve nAMD patients (age, ≥50 years) were randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n = 323) or monthly (n = 327) regimen.
The primary objective was to show noninferiority of ranibizumab 0.5 mg T&E versus monthly regimen, as assessed by the change in best-corrected VA (BCVA) from baseline to the end of the study. Secondary objectives included change in retinal central subfield thickness (CSFT) from baseline to the end of study, treatment exposure, and safety.
Overall, 89.8% (T&E) and 90.2% (monthly) of patients completed the study. Patient demographic and baseline characteristics were well balanced between the 2 treatment groups. The T&E regimen was noninferior (P < 0.001) to the monthly regimen, with a least squares mean BCVA change from baseline of 6.2 versus 8.1 letters to the end of study, respectively. In both treatment groups, most BCVA improvements occurred during the first 6 months and were maintained until the end of the study. The mean change in CSFT from baseline to the end of study was −169.2 μm and −173.3 μm in the T&E and monthly groups, respectively. Fewer injections were required in patients receiving the T&E (8.7) versus monthly (11.1) regimen, with mean number of postbaseline visits of 8.9 and 11.2, respectively. Types and rates of adverse events were comparable between the treatment groups.
Ranibizumab 0.5 mg administered according to a T&E regimen was statistically noninferior and clinically comparable with a monthly regimen in improving VA from baseline to the end of study. No new safety signals for ranibizumab were identified.
Predictors of Outcome in Patients with Neovascular Age-Related Macular Degeneration Switched from Ranibizumab to 8-Weekly Aflibercept
2016, Ophthalmology
The purpose of this study was to evaluate the outcomes over 12 months in patients with neovascular age-related macular degeneration (nAMD) with insufficient response to ranibizumab who were switched directly to 8-weekly fixed dosing of aflibercept without a loading phase.
Retrospective interventional study.
Consecutive patients with nAMD who were switched from pro re nata (PRN) intravitreal ranibizumab to 8-weekly fixed aflibercept because of persistent disease activity from November 1, 2013, to September 30, 2014, were included.
Demographic data, visual acuity (VA), and spectral-domain optical coherence tomography characteristics over time were evaluated to determine the prognostic indicators of final visual outcome at 12 months.
The VA, central subfield thickness (CST), presence of macular fluid at month 12 compared with baseline, and the definition of prognostic indicators of final visual outcome at month 12.
A total of 431 patients (447 eyes) were included in this study. There was no statistically significant difference in VA between baseline and month 12 (P = 0.79), whereas the CST significantly decreased at month 12 compared with baseline (P < 0.001). At the 12-month follow-up, 48.3% of eyes had no macular fluid compared with 8.5% at baseline. The mean number of injections at month 12 was 6.8±1.75. Poor prognostic indicators included increasing age, increasing CST, the presence of intraretinal fluid, pigment epithelial detachment, and subfoveal thickening.
Patients who have not yet “responded” to PRN ranibizumab seem to exhibit retinal dehydration after switching to aflibercept, whereas there was no demonstration of VA benefit. Baseline features at the point of switching can independently predict outcomes.

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: Manuscript no. 2009-161.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): This research was not supported by commercial funding; however, Dr. Kaiser has received honoraria from Genentech and Carl Zeiss Meditec that have been disclosed to the Conflict of Interest Committee of the Cleveland Clinic. The Cole Eye Institute, Drs. Kaiser's employer, has received research grant support on his behalf from Genentech. None of the other authors have any relevant financial disclosures to report. Dr. Dadgostar is supported by a Heed Foundation fellowship award. The Cole Eye Institute, but none of the authors, receives funding from Research to Prevent Blindness.

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Original articleEvaluation of Injection Frequency and Visual Acuity Outcomes for Ranibizumab Monotherapy in Exudative Age-related Macular Degeneration

Objective

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Materials and Methods

Results

Discussion

J Cataract Refract Surg

Am J Ophthalmol

Ophthalmology

Age-related macular degeneration is the leading cause of blindness

JAMA

The evolving role of vascular endothelial growth factor inhibitors in the treatment of neovascular age-related macular degeneration

Eye

Ranibizumab versus verteporfin for neovascular age-related macular degeneration

N Engl J Med

Original article
Evaluation of Injection Frequency and Visual Acuity Outcomes for Ranibizumab Monotherapy in Exudative Age-related Macular Degeneration