Topical Dorzolamide-Timolol With Intravitreous Anti–Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration

Abstract

IMPORTANCE There is a subset of eyes with neovascular age-related macular degeneration (AMD) that have persistent exudation despite fixed-interval intravitreous anti-vascular endothelial growth factor (VEGF) injections.OBJECTIVE To evaluate the effect of topical dorzolamide hydrochloride-timolol maleate on anatomic and functional outcomes in eyes with neovascular AMD and incomplete response to anti-VEGF therapy.DESIGN, SETTING, AND PARTICIPANTS An exploratory, prospective single-arm interventional study at a tertiary referral academic private practice. Patients with neovascular AMD and persistent macular edema despite fixed-interval intravitreous anti-VEGF therapy were enrolled. Baseline spectral-domain optical coherence tomography and clinical data, including visual acuity and intraocular pressure, were obtained at enrollment and from one visit before enrollment. The study was performed at the Retina Service of Wills Eye Hospital and the offices of Mid Atlantic Retina from February 1, 2015, through September 30, 2015. Patients were followed up for at least 2 visits after enrollment. Central subfield thickness, maximum subretinal fluid height, and maximum pigment epithelial detachment height from spectral-domain optical coherence tomography were recorded at each visit.INTERVENTIONS Enrolled eyes received a regimen of topical dorzolamide-timolol twice daily and continued to receive the same intravitreous anti-VEGF therapy at the same interval as received before enrollment for the duration of the study. MAIN OUTCOMES AND MEASURESChange in central subfield thickness was the primary outcome measure. Changes in maximum subretinal fluid height, maximum pigment epithelial detachment height, and visual acuity were the secondary outcome measures. RESULTSTen patients (10 eyes) completed the study. The mean age of the patients was 78.2 years (age range, 65-91 years), and 6 were male. Eight eyes received intravitreous aflibercept, and 2 eyes received intravitreous ranibizumab. All study eyes had been receiving long-term anti-VEGF therapy with the same medication before study enrollment for a mean of 21.9injections. The mean central subfield thickness decreased from 419.7 μm at enrollment to 334.1 μm at the final visit (P = .01). The mean maximum subretinal fluid height decreased from 126.6 μm at enrollment to 49.5 μm at the final visit (P = .02). The mean maximum pigment epithelial detachment height decreased from 277.4 μm at enrollment to 239.9 μm at the final visit (P = .12). The mean logMAR visual acuity were 0.54 at enrollment and 0.48 at the final visit (P = .60). CONCLUSIONS AND RELEVANCEThese data suggest that topical dorzolamide-timolol may reduce central subfield thickness and subretinal fluid in eyes with persistent exudation despite consistent, fixed-interval intravitreous anti-VEGF treatment for neovascular AMD.

Systemic Beta-Blockers in Neovascular Age-Related Macular Degeneration

“…They postulated that this discrepancy between human response and animal models may be secondary to higher medication doses and alternate routes of administration in animals 8 . Next, findings in a small prospective interventional study suggested that topical dorzolamide-timolol administered as adjuvant therapy improved treatment response in nAMD subjects with incomplete response to intravitreal anti-VEGF injections 13 . The exact pathophysiology for this response is not clear, but may include its potent aqueous suppressant properties, which would theoretically increase the injected anti-VEGF's half-life, prolonging its length of action in the eye 13 .…”

“…Next, findings in a small prospective interventional study suggested that topical dorzolamide-timolol administered as adjuvant therapy improved treatment response in nAMD subjects with incomplete response to intravitreal anti-VEGF injections 13 . The exact pathophysiology for this response is not clear, but may include its potent aqueous suppressant properties, which would theoretically increase the injected anti-VEGF's half-life, prolonging its length of action in the eye 13 . The effect of the individual drug components also cannot be ignored.…”

“…Although several basic science and animal studies have argued for a role of BBs in CNV response 5-7 , the few existing human studies have displayed contradictory results 8, 9, 13, 14 . First, the findings from the Beaver Dam Eye study 14 and Thomas et al 8 argued against a protective effect of oral BB use in developing CNV.…”

“…The effect of the individual drug components also cannot be ignored. The authors theorize that topical BBs may result in higher intraocular concentrations than oral formulations, improving ocular bioavailability and potentially enhancing its effect 13 .…”

β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

“…16 Recently, in patients with persistent retinal fluid despite maximal anti-VEGF therapy for exudative AMD, topical timolol-dorzolamide treatment in addition to anti-VEGF therapy improved retinal fluid. 17 These studies led us to investigate the role of β-blockers in a laser-induced CNV model. In our prior study, 18 we have found that intraperitoneal propranolol treatment reduces CNV area by 50%, and specific β2-AR blockade decreases VEGF expression in mouse choroidal endothelial and RPE cells in culture.…”