Real-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti–VEGF Drug Type for 1 Year in the IRIS Registry

doi:10.1016/j.ophtha.2017.10.010

Ophthalmology

Volume 125, Issue 4, April 2018, Pages 522-528

https://doi.org/10.1016/j.ophtha.2017.10.010 Get rights and content

Purpose

The purpose of this study is to compare real-world visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) treated with a single anti–vascular endothelial growth factor (VEGF) drug monotherapy for 1 year from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry.

Design

Retrospective, nonrandomized, comparative study.

Participants

IRIS Registry patients with nAMD who received bevacizumab, ranibizumab, or aflibercept only for 1 year between 2013–2016.

Methods

Participants were divided into 3 groups based on monotherapy type. Multivariate analysis of covariance models (ANCOVA) was constructed in a stepwise fashion.

Main Outcome Measures

The logarithm of the minimum angle of resolution (logMAR) VA at 1 year and mean change in logMAR VA between baseline and 1 year were compared between drug types.

Results

Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year. A total of 84 828 injections were performed. The mean number of injections (standard deviation) at 1 year was higher in the ranibizumab (6.4 [±2.4]) and aflibercept groups (6.2 [±2.4]) compared to bevacizumab group (5.9 [±2.4]; P < 0.0001). In the age-adjusted model, both ranibizumab and aflibercept achieved better logMAR VA at 1 year compared with bevacizumab (0.50 [±0.49], 0.49 [±0.44], 0.55 [±0.57]; P < 0.0001). However, this difference was not significant after multivariate adjustment (age, baseline VA, diabetes, posterior vitreous detachment, number of injections, race, insurance). There was no statistical difference in the age-adjusted or multivariate-adjusted mean logMAR VA change (standard deviation) at 1 year among treatment groups (−0.048 [0.44] bevacizumab, −0.053 [0.46] ranibizumab, −0.040 [0.39] aflibercept; P = 0.46). A higher percentage of patients achieved a ≥3-line VA improvement at 1 year in the bevacizumab group (22.7%) compared with ranibizumab (20.1%; P = 0.0093) and aflibercept (17.8%; P < 0.0001). However, after multivariate adjustment, aflibercept exhibited a greater log odds of a ≥3-line VA loss compared with bevacizumab only (1.25 log odds ratio; P < 0.0016).

Conclusions

This study suggests that all 3 drugs improve VA similarly over 1 year of monotherapy.

Section snippets

Study Sample

This was a nonrandomized, retrospective, comparative review of patients with nAMD who received a single anti-VEGF drug (1.25 mg bevacizumab, 0.5 mg ranibizumab, or 2 mg aflibercept) for 1 year between January 1, 2013, and September 30, 2016. Individuals were part of the AAO IRIS Registry, the first US-based national comprehensive eye disease database. The IRIS Registry's electronic health record (EHR) base consisted of approximately 1790 ophthalmologist-based practices with 7791 participating

Participant Characteristics

A total of 204 749 patients were identified who underwent at least 3 intravitreal injections during the study period. Of those, 94 881 exhibited nAMD at the time of the first injection. Further exclusions consisted of those with an age <50 years (n = 800); those with fewer than 180 days of follow-up (n = 14 379); those with a history of anti-VEGF or steroid injection within 6 months of their first injection or prior ocular disease, photodynamic therapy, vitrectomy, or laser in the study eye

Discussion

We present the real-world VA results of treatment-naïve patients with nAMD who received a single anti-VEGF drug without switching for 1 year in a cohort of the AAO IRIS Registry. To date, this is the largest nonrandomized comparative review that compares VA outcomes among 3 anti-VEGF agents head-to-head in nAMD over 1 year in US clinical practice. We demonstrated that all 3 drugs improve VA after 1 year of monotherapy. However, there was no overall difference in the mean VA change between

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Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice
2024, Ophthalmology Science
To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision.
Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study.
At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries).
Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions.
Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety.
Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually.
VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Impact of Anti-VEGF Treatment and Patient Characteristics on Vision Outcomes in Neovascular Age-related Macular Degeneration: Up to 6-Year Analysis of the AAO IRIS® Registry
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To evaluate anti-VEGF treatment patterns and the influence of patient demographic and clinical characteristics on up to 6-year vision outcomes in neovascular age-related macular degeneration.
Retrospective, multicenter, noninterventional registry study with up to 6 years of follow-up.
A cohort of 254 655 eyes (226 767 patients) with first anti-VEGF injection and at least 2 years of follow-up; 160 423 eyes had visual acuity (VA) data.
Anonymized patient data were collected in the United States through the IRIS® Registry (Intelligent Research in Sight).
Changes in VA from baseline; frequency of and gaps between intravitreal anti-VEGF injections; treatment discontinuations; switching anti-VEGF agents; and influence of baseline clinical and demographic characteristics on VA.
After a mean VA increase of 3.0 ETDRS letters at year 1, annual decreases led to a net loss from baseline of 4.6 letters after 6 years. Patients with longer follow-ups had better baseline and follow-up VA. From a mean of 7.2 in year 1 and 5.6 in year 2, mean injections plateaued between 4.2 to 4.6 in years 3 through 6. Treatment was discontinued in 38.8% of eyes and switched in 32.3%. When adjusting for differences at baseline, every additional injection resulted in a 0.68 letter improvement from baseline to year 1; thus, multiple injections in a year have the potential to be clinically meaningful. Older age, male gender, Medicaid insurance, and not being treated by a retina specialist were associated with a higher likelihood of vision loss at year 1. Of the patients, 58.5% lost ≥ 10 letters VA at least once during follow-up, with 14.5% of patients experiencing sustained poor vision after a median of 3.4 years.
After modest mean VA improvement with intravitreal anti-VEGF injections at year 1, patients netted a loss of VA by year 6. Injection frequency decreased over time, and this was paired with a relatively high rate of discontinuation. Modeling suggested that more frequent injections were associated with better VA. Difficulty with continuous adherence to frequent intravitreal injections may have contributed to undertreatment resulting in less-than-optimal vision outcomes.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Magnitude of Visual Acuity Change with ETDRS versus Snellen Testing in Clinical Trials: Implications for Clinic-Based Outcomes
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To compare visual acuity (VA) changes using standardized ETDRS best-corrected visual acuity (BCVA) and nonstandardized Snellen VA among subjects enrolled in clinical trials.
Retrospective study.
Patients enrolled in prospective clinical trials at 3 urban retina practices.
Best available Snellen VA at the clinic visit before study entry and after exit were compared with the ETDRS BCVA at trial entry and exit. The correlation and discrepancies between Snellen VA and ETDRS methods as well as the VA changes from trial entry to exit were evaluated.
The discrepancy between VA change from trial entry to exit using Snellen VA versus ETDRS BCVA methods.
A total of 273 eyes were included. The mean (standard deviation [SD]) Snellen VA was 58.1 (20) ETDRS-equivalent letters (Snellen 20/69) at the clinic visit before trial entry and 61.6 (21) ETDRS-equivalent letters (Snellen 20/59) at the visit after trial exit. The mean (SD) ETDRS BCVA was 65.5 (16) letters (Snellen 20/49) at trial entry and 70.5 (17) letters (Snellen 20/39) at trial exit. The mean VA change from trial entry to exit was not significantly different for ETDRS (5 letters of vision gain) compared with Snellen (3.6 letters of vision gain) methods (P = 0.061). Eyes with baseline Snellen VA 20/50 or worse gained significantly more letters using Snellen (9.3 ± 22.3 letters) compared with ETDRS (5.2 ± 18.7 letters; P = 0.012). Among eyes with baseline Snellen VA of > 20/50, VA gain was significantly greater with the ETDRS method (4.9 ± 12.3 letters) compared with Snellen (−1.5 ± 12.3 letters; P < 0.001).
The mean VA change from clinical trial entry to exit was similar between the ETDRS and Snellen methods. However, among patients with worse baseline Snellen vision, the magnitude of VA change was greater with Snellen compared with ETDRS, whereas among those with better baseline vision, this magnitude was greater with the ETDRS method. Understanding the proportion of the study population with varying VA levels may have implications for interpreting VA outcomes from retrospective clinic-based studies compared with those reported in clinical trials.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Exudation in Patients With Neovascular Age-Related Macular Degeneration Treated With the Port Delivery System or Monthly Injections
2024, American Journal of Ophthalmology
To evaluate for the presence, severity, and type of exudation at each study visit for a subgroup of patients with neovascular age-related macular degeneration from the Archway and Portal trials.
Retrospective analysis of prospectively obtained data.
Spectral-domain optical coherence tomography scans from each study visit of 44 patients from the Port Delivery System (PDS) arm and 32 patients from the monthly injection arm of Archway were evaluated, and composites of horizontal scans through the fovea were created. Each composite was graded for the presence, type, and severity of exudation and impact on best-corrected visual acuity.
After PDS implantation, 20 of 44 eyes (45%) never showed any exudation in the fovea, 2 (5%) never showed exudation in the fovea but had several missed visits, whereas 15 (34%), 3 (7%), and 4 (9%) showed mild, moderate, or severe exudation at 1 or more study visits, respectively. When exudation was present, it was most commonly subretinal fluid (50%). Of 32 patients randomized to monthly injections, 15 (47%) had no exudation in the fovea during monthly injections or after PDS implantation. Fluctuation of exudation in the fovea over time was seen in some patients after PDS implantation or during monthly injections with little or no identifiable impact on best-corrected visual acuity. In the 7 eyes with moderate or severe exudation in the fovea after PDS implantation, final vision was good in 5 (20/25 in 3, 20/40 in 1, and 20/50 in 1) and 2 had reduced vision from submacular hemorrhage.
The PDS provides excellent control of exudation in the fovea in patients with neovascular age-related macular degeneration, and when exudation occurs, it often resolves without a negative impact on vision.
Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study
2024, The Lancet
Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD.
For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50–89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 10⁹ genome copies per eye, cohort 2 received 1 × 10¹⁰, and cohort 3 received 6 × 10¹⁰. Two additional dose cohorts (cohort 4: 1·6 × 10¹¹; cohort 5: 2·5 × 10¹¹) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258.
Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 10⁹ to 2·5 × 10¹¹ genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 10¹¹ genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 10¹⁰ genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 10¹⁰ genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants.
Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD.
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Randomised clinical trials (RCTs) are generally considered the gold-standard for providing scientific evidence for treatments' effectiveness and safety but their findings may not always be generalisable to the broader population treated in routine clinical practice. RCTs include highly selected patient populations that fit specific inclusion and exclusion criteria. Although they may have a lower level of certainty than RCTs on the evidence hierarchy, real-world data (RWD), such as observational studies, registries and databases, provide real-world evidence (RWE) that can complement RCTs. For example, RWE may help satisfy requirements for a new indication of an already approved drug and help us better understand long-term treatment effectiveness, safety and patterns of use in clinical practice. Many countries have set up registries, observational studies and databases containing information on patients with retinal diseases, such as diabetic macular oedema (DMO). These DMO RWD have produced significant clinical evidence in the past decade that has changed the management of DMO. RWD and medico-administrative databases are a useful resource to identify low frequency safety signals. They often have long-term follow-up with a large number of patients and minimal exclusion criteria. We will discuss improvements in healthcare information exchange technologies, such as blockchain technology and FHIR (Fast Healthcare Interoperability Resources), which will connect and extend databases already available. These registries can be linked with existing or emerging retinal imaging modalities using artificial intelligence to aid diagnosis, treatment decisions and provide prognostic information. The results of RCTs and RWE are combined to provide evidence-based guidelines.

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: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: HUMAN SUBJECTS: Data from the IRIS Registry are de-identified and do not require patient-level consent. Institutional review board approval was not required.

: Submitted to American Academy of Ophthalmology Annual Meeting, November 11–14, 2017, New Orleans, Louisiana, and IRB/Ethics Committee ruled that approval was not required for this study.

: Author Contributions:

: Conception and design: Rao, Lum, Salman, Hall, Singh, Williams

: Data collection: Rao, Lum, Wood, Williams

: Analysis and interpretation: Rao, Lum, Wood, Salman, Burugapalli, Parke, Williams

: Overall responsibility: Rao, Lum, Parke

: Supplemental material available at www.aaojournal.org.

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Original articleReal-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti–VEGF Drug Type for 1 Year in the IRIS Registry

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Study Sample

Participant Characteristics

Discussion

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmol Retina

Prevalence of age-related macular degeneration in the United States

Arch Ophthalmol

Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Cochrane Database Syst Rev

The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis

Ophthalmology

Original article
Real-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti–VEGF Drug Type for 1 Year in the IRIS Registry