4D-150

Age-related macular degeneration is a spectrum of macular disorders with atrophic and neovascular late stages. About 80% of people with AMD have the non-neovascular form, but the neovascular form accounts for nearly 90% of the severe visual acuity loss (20/200 or worse) caused by AMD, and AMD accounts for an estimated 46% of severe visual loss in people older than 40 years in the United States. In 2019, an estimated 1.49 million people aged 40 years or older in the United States had late-stage AMD (crude prevalence 0.94%) and 18.34 million had early-stage AMD (11.64%). An earlier estimate for 2000 put the prevalence of neovascular AMD or geographic atrophy at 1.47% of the US population aged 40 years or older, or 1.75 million people. Globally, pooled prevalence mapped to ages 45 to 85 years was 0.37% for late AMD and 8.69% for any AMD, corresponding to 196 million people with AMD in 2020 and a projected 288 million in 2040. In the United States, annual incidence of late AMD in White Americans aged 50 years or older was estimated at 3.5 per 1,000 (about 293,000 new cases per year), of which neovascular AMD accounted for 1.8 per 1,000, and incidence was 38% higher in women than men; among Medicare beneficiaries aged 65 years or older, 3-year incidence of exudative AMD was 9.4 to 11.4 per 1,000. In Europe, pooled annual incidence of any late AMD was 1.4 per 1,000, with incident cases projected to rise from about 400,000 to about 700,000 per year by 2050. In untreated unilateral disease, neovascular AMD developed in the fellow eye in 12.2% of patients by 12 months and 26.8% by 4 years.

Untreated neovascular AMD progresses to severe central vision loss. In a synthesis of untreated cohorts, mean visual acuity fell by 2.7 lines at 12 months and 4 lines at 24 months, the proportion of patients losing more than 6 lines rose from 21.3% at 6 months to 41.9% at 3 years, and the proportion with acuity worse than 20/200 rose from 19.7% at baseline to 75.7% at 3 years. Macular atrophy developed after untreated neovascular AMD in 9.6% of eyes at 2 years, 31.4% at 5 years, 43.1% at 7 years, and 61.5% at 10 years, a linear risk of about 6.5% per year. Globally in 2020, an estimated 1.85 million people were blind and 6.23 million had moderate or severe vision impairment because of AMD, and the number with AMD-related vision impairment rose from 3.64 million in 1990 to 8.06 million in 2021, with a projection of about 21.34 million in 2050; disability-adjusted life-years attributable to AMD rose by 91%, from 0.30 million to 0.58 million. After anti-VEGF therapy became available, the incidence of legal blindness attributable to AMD in people aged 50 years or older fell by 50%, from 52.2 to 25.7 cases per 100,000 per year between 2000 and 2010. Late AMD is associated with higher mortality: meta-analyses report hazard ratios of 1.20 (95% CI 1.02 to 1.41) and 1.23 (1.11 to 1.36) for all-cause mortality and 1.46 (1.13 to 1.98) and 1.28 (1.04 to 1.57) for cardiovascular mortality, whereas early AMD is not associated with either outcome.

Treatment changes but does not normalize the long-term course. At 5 years in the CATT cohort, 50% of eyes had acuity of 20/40 or better and 20% had 20/200 or worse, with mean change of -3 letters from baseline and -11 letters from the 2-year value; geographic atrophy was present in 213 of 515 gradable eyes (41%). Cumulative incidence of geographic atrophy among 1,011 participants without it at baseline was 12% at 1 year, 17% at 2 years, and 38% at 5 years, and the cumulative proportion of eyes with a fibrotic scar was 32%, 46%, and 56% at years 1, 2, and 5. At a mean of 7.3 years after entry into the pivotal ranibizumab trials, 37% of study eyes had acuity of 20/70 or better and 37% had 20/200 or worse, and macular atrophy was detected in 98% of eyes. Routine care produces smaller gains than trials: among 49,485 treatment-naive eyes in a United States database, a mean of 7.3 injections in the first year produced a mean gain of 0.95 letter, and in an 8-country study mean injections fell from 5.0 in year 1 to 2.2 in year 2 with mean gains of +2.4 and +0.6 letters. Of 162,902 eyes in United States practice, 34.3% presented with acuity of 20/40 or better at diagnosis.

The humanistic burden tracks vision in the better-seeing eye. Time trade-off utility values fell from 0.89 in patients with 20/20 to 20/25 vision to 0.40 in those with 20/800 to no light perception, and patients in the worst group were willing to trade 60% of their remaining lifetime for perfect vision, compared with 11% in the best group. Depressive symptoms have been reported in 15.7% to 44% of people with AMD and anxiety symptoms in 9.6% to 30.1%; in one anti-VEGF clinic cohort, 56% of 132 patients reported treatment-related anxiety, 17% had clinical levels of anxiety, and 12% had clinical levels of depression. Charles Bonnet syndrome was found in 15.8% of patients overall and 7.2% of consecutively recruited clinic patients with neovascular AMD. Impairment of basic, instrumental, and total activities of daily living was reported in 37.76%, 67.82%, and 39.59% of participants in one cohort, and AMD was associated with an increased risk of falls (hazard ratio 1.25, 95% CI 1.23 to 1.27) and fractures (1.18, 1.15 to 1.21).

Direct and societal costs are substantial and rise as vision worsens. In a commercially insured United States population, mean annual all-cause cost was $24,520 for prevalent and $18,943 for incident patients, with neovascular AMD-related outpatient costs accounting for 28% of the total; patients had a mean of 6.6 disease-related outpatient visits and 3.9 anti-VEGF-related visits per year. Mean annual societal cost was $39,910 in patients with neovascular AMD versus $6,116 in controls, ranging from $20,339 in the best-vision subcohort to $82,984 in the worst, and direct nonmedical costs, primarily caregiving, made up 67.1% of societal ophthalmic costs. Medicare spent an average of $9,719 and $9,934 per year on each beneficiary receiving ranibizumab and aflibercept injections, and the two agents accounted for 12% of the annual Medicare Part B budget. The total economic burden of vision loss in the United States was estimated at $134.2 billion, $98.7 billion direct and $35.5 billion indirect, or $16,838 per affected person per year. Caregivers carry part of this burden: an average clinic visit takes 90 minutes, but patients report almost 12 hours per visit including 66 minutes of travel and 9 hours of recovery, and caregivers took time away from work (22%) and personal activities (28%) to provide transportation. Caregivers provided support a mean of 4.2 days per week and 6.0 hours per day, 45.6% reported impairment in daily activities, and 70.5% of 44 working caregivers reported work absenteeism because of treatment and monitoring appointments. Most caregivers were a child or grandchild (47%) or partner (23%) and only 7% were professional caregivers, and 16% of patients missed a clinic visit; mean caregiver burden on the Caregiver Reaction Assessment was 3.2.