Retina - AMD

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Does age affect retinal drusen, pigmentary abnormalities, and overall macular degeneration? In the Beaver Dam Eye study, 4926 patients from age 43 to 68 were studied using stereoscopic color fundus photography to answer this question.

Key Points:

• Data indicated that individuals 75 years of age or older commonly had signs of AMD
• Identified features included large drusen, soft indistinct drusen, abnormal retinal pigmentation, exudative macular degeneration, and geographic atrophy. 
• 95.5% of the population studied had at least one drusen in the macula of one of their eyes.

Overall, the Beaver Dam Eye study is a landmark trial because it demonstrated the association between AMD and age, and was one of the first large scale prevalence studies for the disease. This association was deemed a “substantial public health problem” that previously had not been realized.

In a world before anti-VEGF, what could we do for wet AMD? Prior to the use of anti-VEGF injections, treatment options for wet AMD were very limited. The TAP study sought to evaluate the efficacy of Verteporfin Photodynamic Therapy (PDT) in reducing vision loss in patients with subfoveal choroidal neovascularization (CNV) caused by AMD. Across two studies, 609 patients were randomized to treatment with verteporfin (n= 402) and placebo (n= 207) followed by laser light at 689 nm delivering 50 J/cm2.

Key Points:

• A greater proportion of verteporfin treated patients lost fewer than 15 letters of visual acuity at 12-month follow-up compared to the placebo group (61% versus 46%, P < 0.001)
• In particular, patients with predominantly classic CNV lesions (>50% of the lesion) had the most notable reduction in vision loss, compared to those with 0-50%

Overall, the TAP trial is a landmark study that showed the efficacy and safety of PDT with verteporfin for treatment of CNV in classic wet AMD. And while this treatment is rarely used today due to the use of anti-VEGF medications that improve vision – not just slow vision loss – the TAP trial provided valuable information that impacted the practice of ophthalmology.

Take your vitamins every day, free of advanced AMD you’ll stay. The Age-Related Eye Diseases Study (AREDS) was designed to study the clinical course of age-related macular degeneration (AMD) and age-related cataract. It included two double-masked, placebo-controlled, randomized clinical trials to test the effect of a vitamin formulation (500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, with or without 80 mg zinc and 2mg copper) on the progression of these two conditions. AREDS enrolled 4,757 people aged 55-80 years to the long-term multicenter study, following them for an average of 6.3 years. 

Key Points:

• Smoking and hypertension were found to be associated with AMD and suggest modifiable factors that could reduce the risk of AMD progression.
• Long-term treatment with AREDS supplements reduced the risk of progression from moderate to advanced AMD by 25%, and reduced odds of severe vision loss by 27%
• Among participants with no AMD or only early-stage AMD, there was no measurable benefit
• AREDS vitamin supplements did not reduce the development of lens opacities 

AREDS was a landmark study because it confirmed the effectiveness of this popular antioxidant formulation in decreasing the progression of severe AMD in the high-risk elderly population. It also left more to follow with AREDS2.

 If at first you don’t “fully” succeed, try, try again. While AREDS1 showed that an oral supplement decreased the risk of developing advanced AMD in 5 years by 25%, observational data suggested that other nutrients may offer an additional protective benefit. AREDS2 aimed to evaluate the safety and efficacy of adding the antioxidant carotenoids lutein and zeaxanthin (L+Z) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) in decreasing the risk of progressing to advanced AMD. The study also sought to determine the effect of reducing the amount of zinc in the AREDS oral supplement and omitting beta-carotene completely. 

Key Points:

• No statistically significant reduction in disease progression was found in the groups assigned to take L+Z and/or omega-3 LCPUFAs in addition to the AREDS supplement
• No statistically significant reduction in disease progression was found with differing doses or zinc or with omission of beta-carotene.
• Significantly more cases of lung cancer occurred in patients who had history of smoking cigarettes and were taking beta-carotene (2%) versus those not taking beta carotene (0.9%); substituting beta-carotene for L+Z is appropriate

Together with AREDS1, which showed a 25% decrease in progression to advanced AMD, AREDS2 fine-tuned the notable vitamin formula by adding lutein and zeaxanthin and removing beta-carotene.

“I ran” to the MARINA to fight the wet AMD. The MARINA trial to sought to determine the treatability of neovascular age-related macular degeneration (nAMD) with ranibizumab, an anti-VEGF antibody. This trial selected 716 nAMD patients with minimally classic or occult choroidal neovascularization. Patients were randomized to three groups: sham injection (n= 238), intravitreal injection of 0.3 mg ranibizumab (n=238), and intravitreal injection of 0.5 mg ranibizumab (n=240); Verteporfin photodynamic therapy was allowed if the choroidal neovascularization in the study eye became predominantly classic.

Key Points:  

• At 12 months, 94.5% of patients receiving 0.3mg of ranibizumab and 94.6% of patients receiving 0.5mg of ranibizumab lost fewer than 15 letters from baseline VA compared to the 62.2% that received sham injections (P<0.001)
• Roughly ¼ of patients receiving 0.3 mg and 1/3 of patients receiving 0.5mg injections gained 15 or more letter in VA compared with 5% or less of those in the sham-injection group (P<0.001)
• At 12 months, mean increase in VA was 6.5 letters in the 0.3 mg group and 7.2 letters in the 0.5 mg group compared to a 10.4 letter decrease in the sham-injection group (P<0.001)

Overall, the MARINA trial was a landmark study because it identified a biologic, ranibizumab, that could prevent vision loss and improve visual acuity for NAMD. In the larger context, the MARINA trial in conjunction with the ANCHOR trial were landmark studies which showed ranibizumab to be effective for different types of neovascularization in AMD. Not only did this trial prove efficacious treatment for nAMD, which had not previously had very successful options, but it also jumpstarted the potential use of anti-VEGF treatment for many other disorders.

Anchors aweigh! Say farewell to verteporfin and ahoy to ranibizumab. In this double-masked phase III clinical trial, ranibizumab, an anti-VEGF antibody, was compared with the standard of care of the time - verteporfin photodynamic therapy (PDT). 423 patients with age-related macular degeneration (AMD) with predominantly classic neovascularization (CNV) were randomized to receive either verteporfin PDT, or monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) for 2 years. 

Key Points:

• Ranibizumab was superior in preserving and improving visual acuity: ~90% lost fewer than 15 letters, and 34-41% gained >15 letters compared to ~65% and 6.3% in the PDT group
• Ranibizumab treatment significantly improved the size and severity of angiographic lesions, stabilizing the total lesion area and decreasing area of classic CNV
• Ranibizumab did not increase risk of ocular or systemic adverse events

Results of the ANCHOR trial confirmed the clinical benefit of ranibizumab found in the landmark MARINA study, and demonstrated that ranibizumab outperformed verteporfin PDT in all measures evaluated in AMD patients with predominantly classical CNV lesions. Together they were instrumental in altering clinical practice and providing new hope in patients with numerous retinal conditions.

Is the Ranibizumab monthly tax needed? The PIER (2008) and EXCITE (2011) studies sought to evaluate the efficacy and safety of extended quarterly ranibizumab treatment regimens in the setting of subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The PIER study compared the efficacy of quarterly dosing of ranibizumab (0.3 mg or 0.5 mg) with that of sham treatment. The EXCITE study built upon findings from PIER and compared the efficacy of quarterly dosing of ranibizumab (0.3 or 0.5 mg) to monthly dosing (0.3 mg). The total trial period for both studies was 12 months and included an initial 3-month loading phase of monthly treatments. 

Key Points:  

• The PIER study showed quarterly treatment after month 3 was superior to sham treatment, where 12-month BCVA declined by a mean of 1.6 letters (0.3 mg group) and 0.2 letters (0.5 mg group) in the treated eyes compared to a 16.3 letter decline in the sham group
• The EXCITE study showed that quarterly treatment was inferior to monthly treatment: between months 3 and 12, the patients in the quarterly treatment groups lost 1.8 (0.3 mg group) and 2.8 (0.5 mg group) letters, while patients in the monthly treatment group gained 0.8 letters on average

The PIER and EXCITE studies showed that both monthly and quarterly ranibizumab treatments provide vision benefit for patients wet AMD. However, the primary importance of these studies was in showing that monthly ranibizumab treatment provided better outcomes than quarterly injections.

Two heads may be better than one, but are two injections really needed each month?  In 2012, the VIEW1 & VIEW2 trials aimed to compare the efficacy and safety of monthly and every two month aflibercept to monthly ranibizumab for the treatment of wet age-related macular degeneration (AMD). These large studies (total n=2419) were conducted in the wake of the prior studies, which revealed the safety shortcomings of both monthly bevacizumab and ‘as needed’ ranibizumab. The VIEW studies demonstrated the statistical non-inferiority (margin of 10%) and clinical equivalence (margin of 5%) of three treatment regimens of aflibercept to monthly ranibizumab measured by preservation of vision and reduction in central retinal thickness. 

Key Points:   

• All 3 monthly aflibercept treatment regimens were non-inferior and clinically equivalent to monthly ranibizumab in preventing moderate visual acuity loss at 52 weeks
• The sustained durability of intravitreal aflibercept demonstrated by the every-2-month regimen is consistent with prior evidence of higher binding affinity to VEGF than ranibizumab.

Overall, VIEW1 & VIEW2 are landmarks studies by providing evidence of the clinical efficacy for less frequent anti-VEGF injections with aflibercept. These studies came at a time when prior studies highlighted the need for monthly rather than as-needed injections, raising concerns of the large treatment burden of monthly visits. However, the VIEW studies revived the hope for extended treatment regimens, which have become part of today’s clinical practice.

An anti-VEGF a month keeps the ophthalmologist away, but which one? The CATT trials looked assess the relative safety and efficacy of two treatments for subfoveal neovascular Age-Related Macular Degeneration (AMD). Most AMD-related blindness is attributable to choroidal neovascularization and therefore anti-VEGF therapy treatment was a crucial development in the fight to improve visual outcomes. In the CATT trial, patients with AMD (n=1185) were randomized to receive either intraocular injections of ranibizumab or bevacizumab (a cheaper, off-label alternative) at either a monthly or as needed regimen. Those patients in the monthly arm of the trial were equally divided again after 1 year to either remain monthly or switch to as needed. 

Key Points:  

• Ranibizumab and bevacizumab had similar effects on visual acuity (mean increase in letters of visual acuity from baseline was 8.8 in the ranibizumab-monthly group, 7.8 in the bevacizumab-monthly group, 6.7 in the ranibizumab-as-needed group, and 5.0 in the bevacizumab-as-needed group)
• Switching to as-needed treatment after one year of monthly treatment yielded outcomes nearly equal to those obtained with as-needed treatment for the full two years, with the mean number of injections was 5.0 for ranibizumab-treated patients and 5.8 for bevacizumab-treated patients
• There were no differences between the two drugs in rates of death or arteriothrombotic events, which are sometimes associated with systemic anti-VEGF treatment for cancer

The CATT was the first multicenter and largest trial to compare bevacizumab to ranibizumab (the more expensive, yet standard of the time). This study was crucial to establish the differences and similarities of the two drugs, primarily the non-inferiority of bevacizumab on similar treatment frequencies.

 Might perfect be the enemy of good…when it comes to subretinal fluid retention. In the 2019 FLUID Study, visual acuity was assessed in patients with neovascular age-related macular degeneration (nAMD) previously randomized to treatment with monthly ranibizumab 0.5mg until resolution of intraretinal fluid (IRF) only (tolerating 200 microns of SRF) (n=175) versus complete resolution of both IRF and subretinal fluid (SRF) (n=174) before extending treatment intervals.

Key Points:  

•  Of the 279 (79.9%) patients completing 24-month follow-up, there was no statistical difference in visual acuity outcomes between the two groups (P=0.99)
• Participants in group that allowed residual SRF received fewer ranibizumab injections over 24 months (P = 0.001) and significantly more participants with residual SRF extended to and maintained 12-week treatment intervals (P = 0.005)

 Overall, the FLUID study is a landmark study because it showed that incomplete subretinal fluid resolution did not create significant differences in long-term visual acuity in patients with nAMD and demonstrated the need for fewer injections with longer maintenance intervals in its treatment.