Hsu J, Patel SN, Wolfe JD, et al. Effect of Adjuvant Topical Dorzolamide-Timolol vs Placebo in Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2020 Apr 2. doi: 10.1001/jamaophthalmol.2020.0724. [Epub ahead of print]
Anti-vascular endothelial growth factor (VEGF) therapy is the gold standard for neovascular age-related macular degeneration (nvAMD). Despite monthly injections, some patients are resistant to treatment and have persistent intraretinal and/or subretinal fluid. Prior studies have hypothesized that topical dorzolamide-timolol treatment, in addition to monthly anti-VEGF therapy, could reduce persistent fluid by decreasing flow through the trabecular meshwork, thus prolonging the duration and effects of anti-VEGF medications. Although these prior prospective reports showed improved retinal fluid in patients with nvAMD and retinal vein occlusions undergoing adjuvant dorzolamide-timolol therapy, they were uncontrolled, suggesting that the improved retinal fluid could represent regression to the mean rather than treatment effect.
This prospective, randomized, multicenter clinical trial investigated the effects of topical dorzolamide-timolol therapy vs placebo, in addition to continued anti-VEGF therapy, for patients with treatment resistant nvAMD. Inclusion criteria included patients >45 years old with nvAMD, 4 prior injections (ranibizumab or aflibercept) in the last 6 months, persistent retinal fluid at each visit with central subfield thickness (CST) >270 microns, treatment interval of 4-6 weeks for the last 2 injections, and the same anti-VEGF agent for the last 2 injections. Exclusion criteria were prior intraocular inflammation, epiretinal membrane, macular hole, vitreous hemorrhage, prior glaucoma or vitrectomy surgery, prior ophthalmic surgery in the last 6 months, current use of eye drops (intraocular pressure [IOP] lowering, steroid, or non-steroidal anti-inflammatory), sulfonamide allergy, or contraindication to beta-blocker. Participants were randomized 1:1 to topical dorzolamide-timolol twice daily vs placebo twice daily. Participants were evaluated at baseline, month 1, month 2, and month 3 with visual acuity, IOP, and optical coherence tomography (OCT). At each visit, participants were given the same anti-VEGF agent prior to enrollment at the same treatment interval.
This study enrolled 25 patients (with 23 completing the study) into the placebo arm and 27 patients (27 completed) into the dorzolamide-timolol group. The groups were well matched in terms of persistent fluid and prior injections (mean = 21.1 placebo, 20.0 dorzolamide-timolol). The primary outcome was mean change in CST, which showed a +1.7 micron change in placebo vs -36.6 micron change in dorzolamide-timolol group at 3 months (p = 0.04). Secondary outcome measured include visual acuity, IOP, mean change in subretinal fluid (SRF) height, and mean change in pigment epithelial detachment (PED) height. No differences were detected in visual acuity, IOP, or mean SRF height. Alternatively, mean PED height change was -39.1 microns in dorzolamide-timolol group vs +1.1 in the placebo group (p = 0.01). No adverse events were reported.
The major conclusion of this study was that adjuvant topical dorzolamide-timolol reduced persistent retinal fluid in nvAMD patients receiving monthly anti-VEGF therapy with no adverse events. This report confirms prior uncontrolled studies, which demonstrate improved retinal fluid in patients receiving monthly anti-VEGF therapy, suggesting a real treatment benefit over placebo. The mechanism by which dorzolamide-timolol reduces retinal fluid is still unknown and could be prolonged anti-VEGF medication effect due to reduced trabecular meshwork outflow, intrinsic effects of dorzolamide on intraretinal fluid (similar to inherited retinal dystrophies), or the anti-angiogenic effects of beta-blockers. Because dorzolamide-timolol had no effect on visual acuity, this treatment will likely not be widely adopted into clinical practice. However, since most retinal practitioners use a treat-and-extend approach, if adjuvant dorzolamide-timolol drops can extend treatment interval, then dorzolamide-timolol could be an important tool in our nvAMD armamentarium. Future studies will be needed to investigate this approach.
Jeremy Lavine, MD, PhD