Neuroprotection for treatment of glaucoma in adults

Background Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the commonest form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death. Objectives The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to October 2012), EMBASE (January 1980 to October 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 16 October 2012. Selection criteria We included randomized controlled trials (RCTs) in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow up time was four years. Data collection and analysis Two review authors independently reviewed titles and abstracts from the literature searches. Full-text copies of potentially relevant studies were obtained and re-evaluated for inclusion. Two review authors independently extracted data related study characteristics, risk of bias, and outcome data. One trial was identified for this review, thus we performed no meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until additional study details are provided. We documented reasons for excluding studies from the review. Main results We included one multi-center RCT of adults with low-pressure glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was visual field progression after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, 12 (6.3%) were excluded after randomization and 77 (40.5%) did not complete four years of follow up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%). Of those remaining in the study at four years, participants assigned to brimonidine showed less visual field progression than participants assigned to timolol (5/45 participants in the brimonidine group compared with 18/56 participants in the timolol group). Since no information was available for the 12 participants excluded from the study, or the 77 participants who dropped out of the study, we cannot draw any conclusions from these results as the participants for whom data are missing may or may not have progressed. The mean IOP was similar in both groups at the four-year follow up among those for whom data were available: 14.2 mmHg (standard deviation (SD) = 1.9) among the 43 participants in the brimonidine group and 14.0 mmHg (SD = 2.6) among the 48 participants in the timolol group. Among the participants who developed progressive visual field loss, IOP reduction of 20% or greater was not significantly different between groups: 4/9 participants in the brimonidine group and 12/31 participants in the timolol group. The study authors did not report data for visual acuity or vertical cup-disc ratio. The most frequent adverse event was ocular allergy to study drug, which occurred more frequently in the brimonidine group (20/99 participants) than the timolol group (3/79 participants). Authors' conclusions Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, this trial did not provide evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in people with OAG. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. Since OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents would require long-term follow up (more than four years) in order to detect clinically meaningful effects.