Treatment of Severe Diabetic Macular Oedema With Anti-vascular Endothelial Growth Factor (Anti-VEGF) Monotherapy vs Anti-VEGF Followed by Subthreshold Micropulse Laser When the Thickness of the Central Retina Goes Below 400 Microns: Pragmatic Randomised Equivalence Trial

Background DMO is a leading cause of sight loss in people living with diabetes (PLWD). Considering the prevalence of DMO (7%) and diabetes (~4.8 million), around 336,000 PLWD have DMO in the UK. With its increasing incidence, DMO will continue to be a burden to society. In DMO, fluid collects at the macula, the area that gives central vision, leading to sight loss. As fluid accumulates, the macula thickens. This is measured in microns (μm) with optical coherence tomography (OCT) scans. A measure of central retinal subfield thickness (CRT) is obtained with OCT scans when DMO is diagnosed, guiding treatment selection. National Institute for Health and Care Excellence (NICE) guidance advises intraocular injections of anti-VEGF for PLWD presenting with severe (CRT ≥400μm) centre involved DMO. For PLWD presenting with milder forms of centre involved DMO (CRT <400μm), NICE advises macular laser because it is as effective as anti-VEGFs but costs less.

Most patients presenting to UK Hospital Eye Services (HES) have DMO with CRT ≥400μm and are treated with anti-VEGFs. Currently, as per standard practice, anti-VEGFs are given monthly initially (loading dose) and then typically every 1-3 months until the macula dries, even if CRT falls to below 400μm. In 72% of people on anti-VEGFs, the fluid remains until at least the second year of treatment. Trials have shown that after 5 years, 38-48% of participants still require anti-VEGFs either because DMO remains or because it recurs after clearing once anti-VEGFs are stopped. Most patients on anti-VEGFs need follow-up for life. Anti-VEGFs are expensive and carry potential harms including increased intraocular pressure, retinal detachment, cataract, and infection (endophthalmitis). The latter, although rare, can lead to total blindness. Furthermore, intraocular injections cause discomfort to many patients during administration and for hours thereafter and elicit anticipatory stress responses. Research has shown that a significant proportion of patients (25%) experience high levels of preprocedural anxiety, and nearly 10% report high levels of pain. Other experiences of treatment burden, not commonly assessed in previous studies, have been found to be important including time and functional disruption associated with intravitreal injections. Moreover, HES are unable to cope with the demand and injections are not being given in a timely manner, which has a negative impact on outcomes and the cost-effectiveness of the treatment. Finding ways to reduce the number of injections to optimise patient experience and maximise adherence is a goal pursued worldwide.

Trials comparing anti-VEGFs with standard macular laser have shown superior efficacy of anti-VEGFs against laser in severe DMO. These trials included predominantly eyes with very thickened retinas (e.g. >460μm in RISE and RIDE and >479μm in VIVID and VISTA. When anti-VEGFs were used in combination with macular laser in some of these trials, combined treatment (anti-VEGFs and macular laser) did not appear to be superior to anti-VEGFs alone. However, macular laser was not necessarily applied when CRT had gone below 400μm following anti-VEGFs. It would be at this stage that macular laser would have more chance to be effective, as its penetration through the neurosensory retina and areas of macular oedema, and subsequently, its uptake by the retinal pigment epithelium (RPE) would be more adequate when compared with its likely reduced penetration and effect on the RPE when the macula is very thickened by marked DMO.

Rationale DAME will be a pragmatic trial comparing clinical- and cost-effectiveness, side effects and participant experience and acceptability of combined treatment with anti-VEGFs + Subthreshold Macular Laser (SML) for participants who present with severe DMO and are treated initially with anti-VEGF, with the SML applied after CRT falls to <400μm (when laser has more chance to succeed), versus the current standard of care of continuing with anti-VEGF monotherapy even when the CRT falls below 400μm if DMO is present.

DAME follows from the DIAMONDS trial, which showed that SML, which does not damage the macula, is as effective to treat DMO of <400μm as standard laser, which produces a burn. Although DIAMONDS participants had poor glycaemic control (mean HbA1c 8.5%), most maintained excellent sight and fulfilled driving standards throughout their 2-year follow-up. Those treated with SML needed, on average, only two sessions of laser, with clinic visits every 3-4 months and only 18% received rescue treatment with anti-VEGFs, with an average total cost of care of £898 per participant (similar to the cost of the drug in a single anti-VEGF injection).