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AMD Essentials and an RVO Review

By: Aleksandra V. Rachitskaya, MD; Jorge A. Fortun, MD; Mitul Mehta, MD MS; Hemang K. Pandya, MD; Veeral Sheth, MD, MBA, FACS; Lejla Vajzovic, MD; Jeremy Wolfe, MD

Webinar Credits: .5

This activity focuses primarily on studies that highlight all of the anti-VEGF dosing paradigms investigated in large, randomized clinical trials for the treatment of neovascular age-related macular degeneration plus two case presentations. A brief review of study results for retinal vein occlusion is also included.

PRIMARY AUDIENCE:
Retina specialists involved in the treatment and management of patients with retina disorders.


Expiration Date: Friday, April 30, 2021
Release Date: April 2020

Learning Objectives

 

  • Identify the current treatment options available for the management of common retinal diseases (neovascular age-related macular degeneration, diabetic eye disease, retinal vein occlusion).
  • Summarize how treatment paradigms have evolved over time and how they relate to current treatment options.
  • Identify the relationships between disease characteristics, drug, treatment frequency, visual and anatomic outcomes.
  • Implement best practices using individualized patient treatment plans to ensure optimal outcomes for patients.

 

Accreditation and Designation Statement

Accreditation Statement

Evolve Medical Education LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

Evolve Medical Education LLC designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This educational activity is provided by Evolve Medical Education

 

Faculty and Disclosures

Faculty 

Aleksandra V. Rachitskaya, MD

Cleveland Clinic

Jorge A. Fortun, MD

Associate Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine
Medical Director, BPEI at Palm Beach Gardens

Mitul Mehta, MD MS

Fellowship Director, Vitreoretinal Surgery
Assistant Clinical Professor
Vitreoretinal Diseases and Surgery
Gavin Herbert Eye Institute
Univ. of California, Irvine

Hemang K. Pandya, MD

Vitreoretinal Specialist
Dallas Retina Center

Veeral Sheth, MD, MBA, FACS

Director of Clinical Research
Board Certified Ophthalmologist and Retinal Surgeon
Clinical Assistant Professor
University of Illinois at Chicago

Lejla Vajzovic, MD

Director, Duke Center for Artificial and Regenerative Vision
Co-Director, Duke Pediatric Retina and Optic Nerve Center
Director, Duke Eye Center Continuing Medical Education
Director, Duke fAVS and AVS Courses
Associate Professor of Ophthalmology
Adult and Pediatric Vitreoretinal Surgery and Diseases
Duke University Eye Center

Jeremy Wolfe, MD

Associated Retinal Consultants

 

Disclosures

It is the policy of Evolve that faculty and other individuals who are in the position to control the content of this activity disclose any real or apparent conflict of interests relating to the topics of this educational activity. Evolve has full policies in place that will identify and resolve all conflicts of interest prior to this educational activity.

The following fellows/faculty members have the following financial relationships with commercial interests:

Aleksandra V. Rachitskaya, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Alcon, Allergan, & Carl Zeiss Meditec.

Jorge A. Fortun, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Allergan, Carl Zeiss, & Novartis; Grant/Research: Allergan, & Novartis.

Mitul Mehta, MD, MS, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Novartis; Speaker: Novartis; Shareholder: Eyedaptic.

Hemang K. Pandya, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Speaker: Novartis.

Veeral S. Sheth, MD, MBA, FACS, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Speaker: Genentech, Alimera, Novartis, EyePoint; Grant/Research: Allergan, Alimera, Genentech, Regeneron, Novartis.

Lejla Vajzovic, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant: Aerie, Alcon, Allergan, Alimera, B&L, DORC, Guidepoint, Orbit Biomedical Inc.; Grant/Research: Heidelberg Engineering, Orbit Biomedical Inc., Second Sight.

Jeremy Wolfe, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Speaker: Allergan, Genentech, Novartis, Regeneron; Grant/Research: Genentech, Novartis.

 

Editorial Support

Erin K. Fletcher, MIT, director of compliance and education, Evolve, has no financial relationships with commercial interests.

Susan Gallagher-Pecha, director of client services and project management, Evolve, has no financial relationships with commercial interests.

Cassandra Richards, director of education development, Evolve, has no financial relationships with commercial interests.

Nisha Mukherjee, MD, peer reviewer, has no financial relationships with commercial interests.

 

Disclaimer

OFF-LABEL STATEMENT
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The opinions expressed in the educational activity are those of the faculty. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER
The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Evolve,  or Regeneron Pharmaceuticals.

Introduction

This activity focuses on age-related macular degeneration (AMD) and retinal vein occlusion (RVO).

The risk of AMD increases with age. The disease is most common among older white Americans, affecting more than 14% of white Americans age 80 and older.

RVO is more likely to occur in people with diabetes, and possibly high blood pressure, high cholesterol levels, or other health problems that affect blood flow.

Retina specialists must be aware of the latest clinical trials and their clinical applications to best treat patients with these conditions.

Retinal Vein Occlusion

There are two types of retinal vein occlusion (RVO): Central retinal vein occlusion (CRVO), the blockage of the main retinal vein, and branch retinal vein occlusion (BRVO), the blockage of one of the smaller branch veins.

Figure

The prevalence of BRVO increases with age and varies with race and ethnicity.1  CRVO is a common cause of marked or total loss of vision in the middle-aged and elderly population, but no age group is immune to it.2

Multiple factors play a roll in vision loss from RVO: macular ischemia1; neovascular complications including neovascularization of the disc or retina causing vitreous hemorrhage and neovascular glaucoma; and traction retinal detachment. The most common of these is macular edema.3

 

Retinal Vein Occlusion Treatment

Multiple therapies have been evaluated over time:

Corticosteroids4

Anti-VEGF agents5

Macular grid laser6

Vitrectomy with or without removal of internal limiting membrane7

 

The Branch Vein Occlusion Study (BVOS) is one of the historical/gold standard studies.6 This multicenter, randomized, controlled clinical trial was designed to answer several questions regarding the management of complications of BRVO and studied macular grid laser for macular edema versus observation. One hundred thirty-nine eligible eyes were assigned randomly to either a treated or an untreated control group. Comparing treated patients to control patients (mean follow-up 3.1 years for all study eyes), the gain of at least 2 lines of visual acuity (VA) from baseline maintained for two consecutive visits was significantly greater in treated eyes (= .00049, logrank test).6

 

Since then, newer approaches have been looked at with success. For example, the level 1 BRAVO study assessed the efficacy and safety of 0.3 mg or 0.5 mg ranibizumab in 397 patients with macular edema following BRVO.8  The percentage of patients who gained at least 15 letters in BCVA at month 6 was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the sham group (P < .0001 for each ranibizumab group vs sham).8

 

The Central Vein Occlusion Study (CVOS)9 and BVOS studies showed differences in outcomes. The CVOS study evaluated the efficacy of macular grid photocoagulation in preserving or improving central VA in eyes with macular edema due to CRVO and BCVA of 20/50 or poorer. The investigators found that while macular edema was reduced, there was no improvement in VA after grid treatment and no difference in final visual outcome compared to control eyes.

 

The CRUISE study10 assessed the efficacy and safety of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after CRVO and reported that ranibizumab provided rapid improvement in 6-month VA and macular edema following CRVO.

 

More recently, the LEAVO study,11 designed to determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with CRVO-related macular edema, found that mean changes in vision after treatment were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes.

 

In this study, the mean (SD) gain in BCVA letter score among the 463 participants was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat–adjusted mean BCVA difference, 2.23 letters; 95%CI, –2.17 to 6.63 letters; P < .001). Bevacizumab was not noninferior to ranibizumab (intention-to-treat–adjusted mean BCVA difference, –1.73 letters; 95%CI, –6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar. Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, –1.9; 95%CI, –2.9 to –0.8).

 

The SCORE2 study,12 designed to investigate whether bevacizumab is noninferior to aflibercept for the treatment of macular edema secondary to central retinal or hemiretinal vein occlusion, found that in 362 randomized participants with macular edema due to CRVO or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to VA after 6 months of treatment. At month 6, the mean VA letter score was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, -0.14; 97.5% CI, -3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority.

 

AMD Cases Expected to Reach 5 Million

Moving on to AMD, the available data from the National Eye Institute estimate that the prevalence of AMD in the years 2030 and 2050 will be more than 5 million US patients with AMD.  Note:  AMD is a disease of the Caucasian population.13

Figure

Evolution of Treatments in nAMD

Pre-1980 through 1990s

The first treatment developed using a VEGF-neutralizing strategy was bevacizumab, approved by the FDA in 2004 for the treatment of colon cancer in combination with chemotherapy. Not long after, ophthalmologists began injecting bevacizumab directly into the vitreous cavity as an off-label use in the treatment of neovascular AMD because of its efficacy and minimal systemic adverse effects, which led to the first studies to demonstrate an improvement in visual function in patients with neovascular AMD (nAMD).14

 

There has been a rapid revolution of treating nAMD the past few years. Prior to 1980, there wasn’t really an available care and many natural history studies have shown rapid and progressive visual loss.15,16 The majority of patients were legally blind within a 2-year period. Between 1980-1990, benefits of thermal laser were realized, which while destructive did reduce the progression to vision loss in those patients who were studied.17 The Macular Photocoagulation study was the landmark study in this arena that showed a reduction in visual loss, albeit the treatment was thermally destructive and there was no visual improvement for these patients.

 

Early 2000s

In 2000, submacular surgery studies began to show a stability or preservation of vision, but not really an improvement of vision in those patients, especially in those with subfoveal neovascularization from AMD. Therefore, those results were less than ideal.16

 

Several studies during the 1990s showed that photodynamic therapy (PDT) slowed the progression of the disease and when combined with Kenalog actually showed some additional benefits in reducing the progression, but did not have a significant proportion of patients who had a gain in vision.17,18

 

Mid-2000s to Present Day

From 2005 and onward, anti-VEGF treatments have been the mainstay of treatment for AMD. At this point, trials were showing had significant improvements in vision from baseline, including a gain of 10 letters in some studies.17,18,19,20,21,22

Figure

Comparison of Current and Emerging Anti-VEGF Agents

This image show the current and emerging anti-VEGF agents, their format, molecular structure, molecular weight, and clinical dose used for treating wet AMD. Note the large size of bevacizumab and aflibercept. It was once hypothesized that large molecules, if delivered intravitreally, would not be able to penetrate the retina to treat choroidal neovascularization (CNV). Clearly that theory has been disproven and both bevacizumab and aflibercept are effective agents in treating wet AMD. Also, note, the small molecular weight of brolucizumab. This allows a high dose to be delivered. Finally, abicipar is a DARPin platform that is distinct from the other agents.  DARPin molecules are a novel class of binding proteins with the potential to overcome some limitations of antibody-based therapeutics. DARPin molecules are small, highly stable proteins that contain engineered ankyrin repeat domain(s) and can be selected to bind any given target protein with high specificity and affinity.23,24,25,26,27,28,29,30,31

Figure

Dosing Approaches in Clinical Trials

The studies listed in this image highlight all of the anti-VEGF dosing paradigms investigated in large, randomized clinical trials.  It is important to note that monthly dosing is still the best AMD treatment32,19,20 and all other treatments are compared to this standard of care. Furthermore, no subsequent dosing paradigm has been found to be superior to monthly dosing. All paradigms have been tested in clinical trials with a primary endpoint of noninferiority.

 

While monthly dosing is believed to produce the best VA results in wet AMD patients over 1 and 2 years in large clinical trials, it has been felt that monthly dosing is not realistically possible to execute for patients in the real world.33,34 Thus, the various dosing approaches have been aimed at reducing the treatment burden while maintaining VA gains: bimonthly with aflibercept, PRN, and treat and extend with all currently available anti-VEGF agents.

Figure

The newest anti-VEGF to receive FDA approval is brolucizumab. According to the package insert, the recommended dose for brolucizumab is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection monthly (approximately every 25-31 days) for the first three doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8 to 12 weeks.35 may help stretch the treatment interval. In two head-to-head clinical trials, brolucizumab was noninferior to aflibercept in visual function at week 48, and more than 50% of brolucizumab 6 mg-treated eyes were maintained on an every-12-week dosing interval through week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682NCT02434328).36

 

Optimizing Visual Benefits for Patients With Neovascular AMD

Outlined by Lanzetta and Lowenstein, the pillars of optimal treatment include early diagnosis; initiation of treatment using the loading dose; titrating treatment intervals; and sustained therapy. All of these have been validated in other studies where they’ve shown that early diagnosis leads to the better visual outcomes.37 Patients who present with better vision at earlier times have better outcomes than those who have worse vision at the first visit. The LUMINOUS study showed that loading doses matter because it has a 4 or 5 letter VA benefit over those patients who did not have a loading dose.38 Next is to titrate to the patient’s needs. The personalization of anti-VEGF has been important because we see a wide variety of treatment intervals for patients. And lastly that sustained proactive approaches have led to long-term visual outcome.37

Figure

CASE 1: A 71-YEAR-OLD WOMAN WITH HISTORY OF nAMD

This woman presented in 2017 with a history of nAMD in both eyes. She had a typical past medical history of someone her age. Her anterior segment examination was essentially normal except for cataract surgery and slightly diminished vision.

She had been receiving injections approximately every 8 weeks of aflibercept in each eye during the past 2 years on an as-needed (PRN) protocol with fairly good preservation of vision in the left eye (OS) and mild decrease in the right eye (OD).

Figure

Next steps for this would include imaging. In this chronically treated patient, OCT, FA and/or ICGA would be helpful.  While fluorescein angiography (FA) is the gold standard for diagnosing neovascularization, an ICG can be helpful, especially in cases of polypoidal choriovasculopathy (PCV).  SD-OCT has largely replaced FA and ICGA in the monitoring of chronic nAMD.39,40,41

The terms “classic” and “occult” are to describe CNVM are angiographic terms, but these categories can often be determined by OCT. From a clinic flow standpoint, OCT is faster, less invasive and easier to perform on all AMD patients than FA and does not require trained ophthalmic photographers to get an excellent image.

 

OCT Images

The red arrow points to subretinal fluid which indicates active leakage and the yellow arrow points to a fibrovascular PED which indicates the presence of a Type I or Occult choroidal neovascular membrane (CNVM).

Figure

Figure

Notice the difference between the left and right eye.

Red arrow again showing subretinal fluid; and blue arrow showing fibrovascular PED, but this one has more hyperreflectivity which implies more fibrous material in the subRPE space and less subRPE fluid.

 

OCT Angiography

The red arrows point to the choroidal neovascular membranes (CNVM) in both eyes. The ability to see them on OCTA means there is blood flow in the CNVMs. You will notice that the right eye membrane is less well defined on OCTA. This is a limitation of OCTA to image occult membranes, which are slower flowing. But the lack of leakage obscuring the details of the CNVM compared to FA can be an advantage as well.42,43,44,45

Figure

Despite the large well defined CNVM on OCTA of both eyes, there is no subretinal fluid in the right eye. In this case the BCVA in the right eye improved to 20/25 but dropped to 20/40 in the left eye.

Figure

Take-Home Point

Make sure to look at all of the cuts. There was a hint of SRF and the patient was symptomatic.

This patient has been getting injections for 4 years, so when she says that things are not right, it is a pretty good indicator that there is disease activity. It is debatable if this is really subretinal fluid, but we treated her with aflibercept and she called me 2 days later saying her vision was better.

Figure

A Proactive T&E Regimen

A proactive treat-and-extend (T&E) regimen aims to personalize treatment by finding the optimum treatment interval for each patient. Proactive treatment regimen begins with three loading doses. If the OCT shows stability or there is no fluid on the OCT, the interval between the injections is gradually extended and then the idea is to reach a steady interval of time by which you can not extend the injections further. Therefore you keep the patient at extended T&E intervals for that period of treatment.46,37

Figure

CAN-TREAT Study

To compare the efficacy of ranibizumab using a T&E regimen with monthly dosing in treatment-naive patients with neovascular nAMD, Kertes et al conducted a prospective, randomized, open-label, multicenter, noninferiority, postauthorization study. The primary outcome measure was mean change in VA from baseline to month 12. Patients with nAMD were randomized 1:1 to receive intravitreal ranibizumab at a dose of 0.5 mg in either a T&E or monthly dosing regimen. The noninferiority of T&E compared with the monthly dosing regimen was to be shown using a margin of 5 letters in best-corrected visual acuity (BCVA) improvement.

Baseline and 12-month VA data are available for 526 patients (T&E, n = 268; monthly, n = 258). The primary outcome of noninferiority regarding VA was met with mean BCVA improvement of 8.4 letters (SD, 11.9 letters) and 6.0 letters (SD, 11.9 letters; P = 0.017) in the T&E and monthly regimens, respectively, with a between-group mean difference of 2.38 letters (95% CI, 0.32-4.45 letters). Per protocol, a secondary analysis was performed to test for superiority of number of injections received up to month 12. This analysis demonstrated significantly fewer injections with T&E versus monthly dosing (9.4 and 11.8 injections, respectively), with a mean difference of -2.46 injections (95% CI-2.68 to -2.23 injections).

Figure

Patients in the T&E group were treated monthly until disease stability (defined as a gain in VA of ≤3 ETDRS letters from the prior month; no clinical evidence of lesion growth, fluid or blood; and no SRF or IRF on OCT) was reached; treatment intervals were extended thereafter by 2 weeks at a time to a maximum interval of 12 weeks if no signs of disease instability were detected.

The 12-month results of this 2-year study demonstrated that regarding visual outcomes, the T&E regimen was noninferior to a monthly dosing regimen. Similar visual outcomes in the T&E group as in the monthly dosing group were achieved with significantly fewer injections. 47,48

 

LUCAS Study

The LUCAS study was a multicentre, randomized phase 4 clinical trial in Norway to compare ranibizumab and bevacizumab T&E (N=441) in patients with nAMD. Patients were treated monthly until there were no signs of active neovascular disease (defined as signs of active neovascular disease were defined as any fluid on OCT, new or persistent haemorrhage or dye leakage, or increased lesion size on fluorescein angiography) treatment intervals were extended thereafter by 2 weeks at a time to a maximum interval of 12 weeks if no signs of active neovascular disease were detected.

A total of 339 patients (79%) completed the 2-year visit. According to per-protocol analysis at 2 years, bevacizumab was equivalent to ranibizumab, with 7.4 and 6.6 letters gained, respectively (95% CI of mean difference, -4.1 to 2.5; P =.634). Intention-to-treat analysis was concordant, with a gain of 7.8 letters for bevacizumab and 7.5 letters for ranibizumab (95% CI of mean difference, -3.2 to 2.7; P = .873).

Figure

There was a statistically significant difference between the drugs regarding the number of treatments given, with 18.2 injections for bevacizumab and 16.0 injections for ranibizumab.

At 2 years, bevacizumab and ranibizumab had an equivalent effect on VA and reduction of central retinal thickness when administered according to a T&E protocol for nAMD. There was no significant difference in the number of serious adverse events between the treatment groups.49

VIEW 1 / 2 Studies

VIEW 1 and VIEW 2 were double-masked, multicenter, parallel-group, active-controlled, randomized trials that enrolled patients (n = 2419) with active, subfoveal, CNV lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4).

All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the two studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures.

The authors concluded that intravitreal aflibercept dosed monthly or every 2 months after three initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring.50

Figure

During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.21 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group.

The 96-week results from VIEW 1 / 2 revealed that all aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing.21

Richard et al analyzed VA outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52, and found there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom week 52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at week 52 is a plausible explanation.51

 

ALTAIR Study

This phase 4 trial that enrolled Japanese patients with symptomatic nAMD was another T&E-focused study. The ALTAIR study, in conjunction with other previous clinical trials, suggests that T&E protocol with aflibercept is an effective anti-VEGF dosing regimen for patients with nAMD, as it produces good visual gains and minimizes cost and burden for the patient.52,53

A total of 255 patients were included in the study. Inclusion criteria included age older than 50 with treatment-naive nAMD, active subfoveal CNV lesions seen on fluorescein angiography, and BCVA of 25 to 73 ETDRS letters (approximately 20/40-20/320 Snellen equivalent) in the study eye. Study patients received three monthly intravitreal aflibercept injections and patients were then randomized to either 2-week or 4-week treatment intervals for injections. Main outcome measured was mean change in BCVA from baseline to week 52. One hundred twenty-four patients were in the 2-week adjustment group and 123 patients were in the 4-week adjustment group.52,53,54,55

The ALTAIR study showed that both the 2- and 4-week extension protocols for T&E regimens improved visual and anatomical outcomes through week 52. Most patients in both the 2- and 4-week extension groups of the study achieved greater than 12 week extension intervals for their anti-VEGF injections. None of the patients in the 2-week extension group were extended to 16 weeks.56

Figure

ALTAIR Study: Treatment Intervals

According to a review article by Wai and Singh, it is important to recognize that patients in the 2-week extension arm, in comparison to the 4-week extension arm, were unable to be fully extended to a 16-week treatment interval within the 52-week period due to the protocol guidelines of extending only 2-week periods at a time. “Overall, these findings demonstrate the efficacy of T&E regimens with both 2- and 4-week adjustment periods, though perhaps a 4-week extension interval is more preferable as it requires less injection and clinic burden to the patient. ALTAIR is the first large prospective randomized controlled study for nAMD to evaluate two separate T&E regimens using aflibercept,” the authors wrote.52,53,55,56

Figure

ALTAIR Study: Vision Gains

The 2-week extension group has a mean gain of 9.0 letters, and the 4-week extension group had a mean gain of 8.4 letters at 52 weeks. 32.5% of patients in the 2-week adjustment group and 30.9% of patients in the 4-week adjustment group gained ≥ 15 ETDRS letters by 52 weeks. The last interval before the week 52 was an average of 10.7 weeks for the 2-week extension group and 11.8 weeks for the 4-week extension group. In the 2-week extension group, the last interval was more than 8 weeks for 72 patients (58.5%), more than 12 weeks for 52 patients (42.3%), and 16 weeks for zero patients. In the 4-week extension group, the last interval was >8 weeks for 74 patients (60.2%), more than 12 weeks for 61 patients (49.6%), and 16 weeks for 50 patients (40.7%).52,53,54,55,56

Figure

ALTAIR Study: 12-week Intervals

The ALTAIR study showed that both the 2- and 4-week extension protocols for T&E regimens improved visual and anatomical outcomes through week 52. At week 96, 57 to 60% of patients in both the 2- and 4-week extension groups of the study achieved greater than 12-week extension intervals for their anti-VEGF injections.52,53,55,56

This is the first time this extension period of 16 weeks or more was seen in a significant proportion of patients.

Figure

ARIES Study

ARIES, a multicentre, randomized, open-label, active-controlled, parallel-group, phase 4/3b study in treatment-naïve patients with nAMD across eight countries, looked at whether a proactive treatment approach in year 1 versus a proactive treatment approach in year 2 would result in differential outcomes. For example, in previous studies like VIEW patients had a period in the first year when there was a mandated treatment approach, but this study aimed to determine at effect, if any, did that have on the final visual outcome in comparison to those patients who were T&E early in the study.

Mean change in BCVA (ETDRS letter score) from randomization to week 104 was the primary endpoint.57,58

Figure

Over the 2-year period of the study, 47 to 52% of patients had a final injection interval of 12 weeks or beyond; 52% of patients were in the late-start T&E and 47% in the early-start T&E, with 30% of patients achieving almost a 16-week interval treatment.59

Figure

CASE 2: A 77-YEAR-OLD MAN WITH BLURRED VISION

A 77-year-old white man male presents with 3 days of blurred vision in the right eye.

Case – History
  • 77-year-old white man presents with blurred vision in the right eye
  • Medical History: Hypertension, hypercholesterolemia
  • Social History: former smoker (50 years, quit 5 years ago); social alcohol; denies illicit drug use
  • Family history: sister – breast cancer, denies blindness
  • Allergies: NKDA
  • Medications: Lisinopril, atorvastatin, clopidogrel
  • Surgical History: Coronary stents, coronary artery bypass graft (CABG), carotid endarterectomy
  • Ocular history: cataract surgery – both eyes

 

Exam Results

Technician’s Exam Results

  • Visual Acuity: 20/20 OU
  • IOP: 15 OD, 13 OS
  • Pupils: Equally round and reactive OU
  • Confrontational Visual Fields: Full OU
  • Extraocular Movements: unrestricted OU

 

Anterior Segment Exam

  • Eyelids: unremarkable OU
  • Conjunctiva: unremarkable OU
  • Cornea: mild guttata OU
  • Anterior Chamber: unremarkable OU
  • Iris: unremarkable OU
  • Lens: well centered intraocular lens OU

 

What are the baseline imaging tests that should be obtained in the evaluation of a new patient with exudative AMD?

 

At baseline, I like to have an OCT.

I previously would order fluorescein angiography (FA), but now reserve this for borderline cases, ie, AMD masquerades like macular telangiectasia. Select colleagues have baseline orders for fundus photos, OCT, FA, and Indocyanine Green (ICG) for all new macular degeneration patients. Even fewer have access to optical coherence tomography angiography (OCTA).

Right Eye:

Optic nerve cup-to-disc ratio is 0.1 and appears healthy.

Left image (right eye) shows the macula has confluent small, intermediate, and large soft drusen and subretinal hemorrhage (superior perifoveal macula).

 

Left Eye:

Optic nerve cup-to-disc ratio is 0.1 and appears healthy.

Right image (left eye) shows the macula has confluent small and intermediate soft drusen, and RPE atrophy.

Figure

OCTs of the right eye and left eye show drusen, but no evidence of subretinal or intraretinal fluid.

Figure

In the image on the right, there is subretinal hemorrhage blocking the choroidal vessel filling, and there is staining of drusen.

 

Figure

In the image on the left (right eye), there is subretinal hemorrhage blocking the choroidal vessel filling, and there is staining of drusen.

In the image on the right (left eye), there is staining of drusen.

The patient was treated with aflibercept monthly in the right eye for 6 months, then every 6 weeks for another 6 months.

 

Figure

Conclusion

This program highlighted some of the most significant clinical trials in the treatment of nAMD, with the most recent data indicating extended T&E dosing is efficacious in some patients.

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    Identify the current treatment options available for the management of common retinal diseases (neovascular age-related macular degeneration, diabetic eye disease, retinal vein occlusion).
    Summarize how treatment paradigms have evolved over time and how they relate to current treatment options.
    Identify the relationships between disease characteristics, drug, treatment frequency, visual and anatomic outcomes.
    Implement best practices using individualized patient treatment plans to ensure optimal outcomes for patients.
    Recognize the growing importance of imaging for use in disease management.
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