**Background:** Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of blindness worldwide. Aspirin and omega-3 fatty acids (FAs) have potential disease-modifying roles through anti-thrombotic, anti-inflammatory, and anti-angiogenic mechanisms, but randomized evidence is limited. The ASCEND trial (n=15,480) provided an opportunity to evaluate these effects in a large, well-characterized population with diabetes.
**Methods:** ASCEND-Eye is a sub-study of the double-blind, 2×2 factorial, placebo-controlled ASCEND trial, which randomized 15,480 UK adults aged ≥40 years with diabetes (94% type 2) and no prior cardiovascular disease to 100 mg aspirin daily vs. placebo and, separately, 1 g omega-3 FAs daily (containing 0.41 g eicosapentaenoic acid and 0.34 g docosahexaenoic acid) vs. placebo. Eye outcomes were derived from three sources: (1) participant-reported events from six-monthly ASCEND follow-up questionnaires (adjudicated) and a Visual Function Questionnaire (VFQ) sent after the main trial; (2) electronic linkage to NHS Diabetic Eye Screening Programme (DESP) data in England and Wales; and (3) the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25). The primary efficacy outcome is time to first referable diabetic eye disease (composite of referable retinopathy [R2 or R3a/s] or referable maculopathy [M1]) in the DESP-linked cohort (n=7360). Secondary outcomes include incident AMD (participant-reported, n=15,480), progression in retinopathy grade, and NEI-VFQ-25 composite scores (n=8839). The primary safety outcome is sight-threatening eye bleeding. Statistical analyses will use intention-to-treat logrank methods, with a two-sided P<0.05 considered significant for primary outcomes.
**Key Results:** Baseline characteristics of the full ASCEND population (n=15,480) included mean age 63.3 years (SD 9.2), 63% male, median diabetes duration 7 years, 94% type 2 diabetes, 82% overweight/obese, and 62% on hypertension treatment. The DESP-linked cohort (n=7360) had mean age 63.5 years (SD 8.9), 62% male, median diabetes duration 6 years, 95% type 2, 85% overweight/obese, and 62% on hypertension treatment. The VFQ cohort (n=8846) had mean age 62.5 years (SD 8.3), 63% male, median diabetes duration 7 years, 94% type 2, 85% overweight/obese, and 61% on hypertension treatment. Baseline characteristics were well-balanced between treatment arms in all cohorts. Blinded analyses identified 1061 primary efficacy outcomes, providing 81% power to detect a 15% proportional reduction in referable diabetic eye disease at 2P<0.05. For AMD, 260 events were identified, providing 62% power to detect a 25% proportional difference at 2P<0.05.
**Clinical Implications:** ASCEND-Eye will provide the largest randomized assessment of aspirin and the first prospective randomized test of omega-3 FAs on DR, and will contribute reliable data on AMD. Given the widespread use of aspirin and omega-3 supplements in populations at risk for DR and AMD, the results will inform the balance of risks and benefits for eye health. Limitations include reliance on participant-reported AMD outcomes without imaging, underpowered analyses for AMD, and limited ethnic diversity. Results are anticipated by late 2023.