Methodological quality of the review: High confidence

Author: Sena DF, Lindsley K

Geographical coverage: United States of America (USA)

Sector: Glaucoma

Sub-sector: See above

Equity focus: None specified

Review type: Effectiveness review

Quantitative synthesis method: Narrative synthesis

Qualitative synthesis method: Not applicable

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 intra-ocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death.

Objectives: To systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults.

Main findings: Of the 35 full-text articles reviewed by the authors for inclusion, only one met the inclusion criteria. Through the search of the ClinicalTrial.gov database, the authors identified two phase III trials investigating the effects of memantine in patients with chronic glaucoma. Data on one of the trials was not published, and results of the second trial failed to show potential beneficial effects by two review papers. As such, one trial was included in the review.

The included trial consisted of a multi-centre randomised controlled trial (RCT) of adults with low-pressure glaucoma 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 randomisation 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 mm Hg (standard deviation (SD) = 1.9) among the 43 participants in the brimonidine group and 14.0 mm Hg (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 noted that there was a high attrition rate and the difference in the attrition between groups introduced high risk of attrition bias to the study results. In terms of reporting bias, authors stated that the definition of primary and secondary outcomes differed between the published baseline paper and results paper.

The authors concluded that 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.

Authors note that further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG.

Methodology: The authors 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). The authors did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on October 16 2012. In addition, the authors reviewed references of included studies for potentially relevant studies.

The authors included RCTs in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow-up time was four years.

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 authors independently extracted data related study characteristics, risk of bias, and outcome data.

The authors used a narrative synthesis approach, as only one trial was identified.

Applicability/external validity: Review authors note that conditions covered by the review were specific to OAG. The population of interest was narrowed to patients with OAG and did not include patients with only ocular hypertension; thus, the prevention of glaucoma by neuroprotection was not studied by this review. Furthermore, the authors stated that although the treatment of ocular hypertension is a method commonly used to prevent glaucoma and delay vision loss, it should be considered as a separate or adjunct focus for prevention since glaucoma can occur in the absence of increased IOP.

Geographic focus: The authors did not identify trials conducted in low- and middle-income settings which met the inclusion criteria. The included study was conducted in the USA.

Summary of quality assessment: Overall, there is high confidence in the conclusions about the effects of this study. The authors conducted comprehensive searches of the literature without using any search restrictions. Appropriate methods were used to conduct the review in terms of data extraction, appraising the quality of included studies and synthesising evidence from included studies.