Prevention Surpasses Treatment: 5-year Follow-Up, Cost-Utility, and Cost–Benefit of Zeaxanthin Therapy for Neovascular Age-Related Macular Degeneration

**Background:** Neovascular age-related macular degeneration (nAMD) is the leading cause of legal blindness in the US, with 90% of AMD-related blindness attributed to the neovascular form. Intravitreal anti-VEGF monotherapy is standard, but combination therapy (photodynamic therapy, corticosteroid, anti-VEGF) can reduce treatment burden. Retinal carotenoids, particularly zeaxanthin (Zx), are concentrated in the macula and have been shown to prevent AMD in animal models and inhibit VEGF secretion in vitro. A prior 2-year randomized clinical trial demonstrated that oral Zx 20 mg daily reduced fellow-eye nAMD conversion from 23% to 6% (p=0.02). The present study aimed to assess whether this benefit persists at 5 years and to evaluate the cost-effectiveness and societal financial impact of Zx supplementation.

**Methods:** This was a case-control analysis of 227 consecutive patients with unilateral nAMD who received oral Zx 20 mg daily plus triple therapy (photodynamic therapy, intravitreal bevacizumab, intravitreal dexamethasone) for at least 5 years. The primary outcome was 5-year cumulative incidence of fellow-eye conversion to nAMD, calculated using Kaplan-Meier estimates and compared to 5-year data from the CATT trial (n=348 at year 5). Secondary outcomes included vision and cost-utility analyses. An 11-year cost-utility model (reflecting mean life expectancy of 79-year-old patients) was constructed using time trade-off vision utilities from over 1400 ophthalmic patients, 2020 Medicare Fee Schedule costs, and a 3% annual discount rate. Both direct ophthalmic medical and societal cost perspectives were evaluated. Societal costs included direct non-ophthalmic medical costs (depression, injury, nursing home), direct non-medical costs (caregiver), and indirect costs (wage loss). A cost-benefit analysis estimated the 11-year return on investment (ROI) for Zx supplementation in the 2020 US cohort of unilateral nAMD cases.

**Key Results:** Among 227 baseline unilateral nAMD patients, 202 (89%) had 5-year follow-up. The 5-year cumulative incidence of fellow-eye nAMD conversion was 22% (49/227) in the Zx-treated cohort versus 48% (167/348) in the CATT control cohort (p<0.0001), yielding a hazard ratio of 0.46. Mean baseline vision in atrophic fellow eyes was 20/40 and remained 20/40 at 5 years if no conversion occurred. The 11-year model estimated a 0.423 QALY gain per patient (7.7% improvement), including 0.25 years of life saved due to reduced nAMD conversion. Direct ophthalmic medical costs were lower in the Zx cohort (−$242 per patient), resulting in a direct ophthalmic CUR of −$576/QALY. Societal costs saved totaled −$52,530 per patient, yielding a societal CUR of −$125,071/QALY. Both negative CURs indicate that Zx supplementation is dominant (more effective and less costly) versus no supplementation. Sensitivity analyses showed that Zx remained cost-effective at a $100,000/QALY threshold even if the relative conversion rate difference decreased to 2–3%. For the 2020 US cohort of 114,173 new unilateral nAMD cases, Zx supplementation would save society $6.0 billion over 11 years, a 1531% ROI (31.3% annual ROI) on the $391.7 million Zx cost. No serious adverse events from Zx were reported.

**Clinical Implications:** Oral zeaxanthin supplementation at 20 mg daily for patients with unilateral nAMD significantly reduces the long-term risk of fellow-eye conversion to nAMD, with a 54% relative risk reduction at 5 years. This preventive strategy is not only clinically effective but also highly cost-effective and financially beneficial from both direct medical and societal perspectives. The dominant cost-utility ratios and substantial ROI suggest that Zx supplementation should be strongly considered as a standard adjunctive therapy in unilateral nAMD to prevent second-eye involvement. The study highlights that prevention of nAMD in the fellow eye surpasses treatment in value, as it improves quality of life, reduces caregiver burden, and returns significant savings to patients and society. Limitations include the use of historical controls rather than a concurrent randomized control group, and the inability to assess vision benefit directly from Zx beyond its effect on conversion prevention. Nonetheless, the consistency with prior randomized trial data and multiple historical comparators supports the robustness of the findings.