Purpose: Randomized controlled clinical trials are driven by time-given protocols defined by strict exclusion and inclusion criteria. As a result, clinical trials provide the best possible outcomes regarding the efficacy and safety of investigational medical products. Nonetheless, the implementation of protocols suggested by clinical trials has been shown as non-pragmatic into standard treatment care. Not following the protocols recommended by clinical trials in our standard routine treatment care does not provide the benefits of therapy as clinical trials suggest. Therefore, we wanted to investigate whether our proposed treatment protocols with diabetic macular oedema, designed for standard treatment of care, may achieve non-inferior results compared to clinical trials where the non-inferiority was defined by a difference in the vision of up to 10 ETDRS letters. Methods: Manuscripts amalgamated in this doctoral thesis involved patients with fovea-involving macular oedema who were eligible for treatment with intravitreal anti-VEGF injections. All patients applied met the National Institute of Care and Excellence (NICE) criteria for treatment (center-involving diabetic macular oedema ³ 400 microns) and with baseline visual acuity (VA) equal to or less than 80 ETDRS letters. All patients were treated in Moorfields Eye Hospital NHS Foundation Trust, in London, UK. The primary cohort of interest (treatment-naive cohort) involved 89 patients (99 eyes) who were treatment-naive and funded for intravitreal aflibercept injections. We analyzed primary, secondary and tertiary outcomes in short and long terms. In addition, we wanted to see whether those patients who had started treatment on a different anti-VEGF agent (ranibizumab as another licensed anti-VEGF product in the United Kingdom) and didn't respond well to the initiated treatment may benefit from switching to intravitreal aflibercept injections, which may have more potent effect as per available pharmacokinetic data. Therefore, we formed a second cohort that involved 67 switched patients (90 eyes) who had started treatment with intravitreal ranibizumab and were switched to intravitreal aflibercept. In both cohorts, the primary outcomes were visual acuity (VA), central foveal thickness (CFT), and macular volume (MV) 12 months after treatment was commenced/after switching off a drug. The analysis of the same primary outcomes was performed for the treatment-naive cohort 36 months after initiating treatment. Then, we calculated the percentage of eyes that achieved visual acuity gain of ³ 15 ETDRS letters and the percentage of eyes that achieved improvement in CFT for 100 microns or more at the end of year 1 and year 3. As tertiary outcomes, we made a subgroup analysis according to the baseline VA (< 69 ETDRS letters or ³ 69 ETDRS letters). For switched cohorts, we analysed whether the time of switching plays a role in overall results. Results The mixed ANOVA analysis showed no statistically significant difference in baseline variables and 12-month outcomes between short- and long-term followed treatment naïve patients and switched patients. The mean change in vision after three years of initiation of treatment with intravitreal aflibercept injections was +6.89 EDTRS letters, while improvement in CFT and MV during the same time was -140 microns and – 1.38 mm3, respectively. At the end of follow-up of 36 months, 25% of patients improved vision for three or more ETDRS lines (15 letters or more). Just more than 50% of patients had improvement in central foveal thickness for 100 microns or more. Fifty-eight percent of eyes of the primary cohort had baseline visual acuity less than 69 ETDRS letters. The mean change in visual acuity in the subgroup with baseline VA less than 69 letters was +11.27 ETDRS letters (p < 0.0001). Forty-two percent of eyes from the primary cohort had baseline visual acuity ³ 69 ETDRS letters). The mean change in the visual acuity after 36 months in that subgroup was + 0.88 ETDRS letters (p = 0.6041). We sub-divided the switched eyes into two subgroups according to the duration of time between the ranibizumab being discontinued and the aflibercept commencing; 53 eyes were switched with an interval of fewer than three months after the last injection of ranibizumab, and 37 eyes were switched after three months or more had elapsed. There was no statistically significant difference in outcomes ( p > 0.05) between those subgroups. Conclusion Our short and long-term results of visual acuity and anatomical outcomes in patients with sight-impairing, center-involving diabetic macular oedema treated with intravitreal aflibercept showed a significant improvement in vision, comparable with results suggested by landmark clinical trials. Furthermore, our results were non-inferior when compared to landmark clinical trials related to the safety and efficacy of intravitreal aflibercept in the treatment of DMO (VIVID, VISTA, and Protocol T). Our subgroup analysis based on baseline visual acuity proved the importance of starting treatment when visual acuity is initially better. We achieved stable vision over three years of follow-up in those whose baseline visual acuity was 69 ETRDS letters or better (up to 80 ETDRS letters). Those patients kept their good vision which meets driving criteria. Our results are the first published results from the real world, which show the importance of planning the treatment guided by baseline vision, which was first indicated in the Protocol T study. Regarding the results in our switched cohort, we showed that switching from intravitreal ranibizumab to intravitreal aflibercept has a rationale for speeding up the visual recovery and improving the anatomical outcomes in everyday life offer patients sooner improvement and better functioning by using their vision. We proved that time of switching does not play a role in primary outcomes (VA, CFT, MV), which may indicate that indeed the reason for clinical improvement in our switched cohort relies on the mechanism and pharmacokinetics of the aflibercept molecule.