Neuroprotection for treatment of glaucoma in adults

Abstract

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 most common 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 compared with no neuroprotective agent, placebo, or other glaucoma treatment.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 7), Ovid MEDLINE, Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily (January 1946 to August 2016), Embase (January 1980 to August 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (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. We last searched the electronic databases on 16 August 2016.

Selection criteria

We included randomised 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. We obtained full‐text copies of potentially relevant studies and re‐evaluated for inclusion. Two review authors independently extracted data related to study characteristics, risk of bias, and outcomes. We identified one trial for this review, thus we performed no meta‐analysis. Two studies comparing memantine to placebo are currently awaiting classification until study investigators provide additional study details. We documented reasons for excluding studies from the review.

Main results

We included one multicenter RCT of adults with low‐pressure glaucoma (Low‐pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was progression of visual field loss after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, the investigators excluded 12 (6.3%) after randomization; 77 participants (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 progression of visual field loss than participants assigned to timolol (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.14 to 0.86; 101 participants). Because of high risk of attrition bias and potential selective outcome reporting, we graded the certainty of evidence for this outcome as very low. At the four‐year follow‐up, the mean IOP was similar in both groups among those for whom data were available (mean difference 0.20 mmHg, 95% CI ‐0.73 to 1.13; 91 participants; very low‐certainty evidence). The study authors did not report analyzable data for visual acuity or any data related to vertical cup‐disc ratio, quality of life, or economic outcomes. The most frequent adverse event was ocular allergy to the study drug, which affected more participants in the brimonidine group than the timolol group (RR 5.32, 95% CI 1.64 to 17.26; 178 participants; very low‐certainty evidence).

Authors' conclusions

Although the only trial we included in this review found less visual field loss in the brimonidine‐treated group, the evidence was of such low certainty that we can draw no conclusions from this finding. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus on outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. As OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents require a long‐term follow‐up of five years or longer to detect clinically meaningful effects.

Plain language summary

Neuroprotection (medicines to protect nerves involved in sight) for treatment of glaucoma in adults

Review aim 
 The aim of this Cochrane review was to find out if neuroprotective medications (which aim to protect the nerves and cells in the eye) are effective for treating glaucoma in adults. We searched for all relevant studies to answer this question and found one study.

Key messages 
 Neuroprotective glaucoma medications aim to prevent vision loss in eyes with glaucoma. However, at present there is not enough evidence to show if these medicines are effective treatments for glaucoma or protect nerves and cells in the eyes directly.

What was studied in this review? 
 Glaucoma is a leading cause of blindness worldwide. The disease leads to damage of the optic nerve that worsens over time. Furthermore, cells in the retina that send messages to the optic nerve (retinal ganglion cells) become damaged and die off. This affects normal sight in the areas of the middle, sides, or top and bottom of a person’s view (loss of visual field).

Medicines exist that might protect the optic nerve from damage and prevent the death of retinal ganglion cells in people with glaucoma. Neuroprotective medication(s) are prescribed for glaucoma with the goal of preventing or slowing vision loss by protecting the optic nerve.

Key results 
 We searched multiple electronic databases for studies and found one study that compared two different eyedrop treatments, given to two groups of adults with low‐pressure glaucoma. One group received brimonidine, a neuroprotective drug. The other group received timolol, a drug that lowers fluid pressure in the eyes. The study investigators followed these two groups of people for four years to see if either treatment protected the optic nerve and prevented vision loss.

The study began with 99 people in the brimonidine group and 79 people in the timolol group. After four years, many of the people had dropped out of the study: only 45 people (45%) remained in the brimonidine group and 56 (70%) people in the timolol group. As so many people dropped out, and more people who left the study were taking brimonidine than were taking timolol, it was difficult to interpret the results of the study. Bearing this in mind, after four years of treatment, people in the brimonidine group had kept more of their vision (40/45 or 88%) than those in the timolol group (38/56 or 67%). We do not know the results for the people who dropped out of the study.

Neither group showed any important change in eye pressure (intraocular pressure). Information about visual sharpness (visual acuity) was reported sufficiently for analysis. No information about vertical cup‐disc ratio (a measure of potential optic nerve damage), quality of life or economic outcome was reported. The most common side effect was an allergic reaction to the medicines in the eye, which affected 20/99 (20%) people in the brimonidine group and 3/79 (4%) people in the timolol group.

How up‐to‐date is this review? 
 We searched for studies published up to 16 August 2016.

Summary of findings

Summary of findings for the main comparison. Neuroprotection compared with control for glaucoma.

Neuroprotection compared with control for glaucoma
Population: adults with open angle glaucoma Settings: ophthalmology clinics Intervention: brimonidine 0.2% Comparison: timolol 0.5%
Outcomes*	Illustrative comparative risks** (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control (timolol)	Neuroprotection (brimonidine)
Visual field: the proportion of participants with progression of visual field loss at 4 years' follow‐up	321 per 1000	113 per 1000 (45 to 276)	RR 0.35 (0.14 to 0.86)	101 (1 study)	⊕⊝⊝⊝ very low1,2
Visual acuity: the proportion of participants with loss of visual acuity at 4 years' follow‐up	Not reported	Not reported	‐	‐	‐	Trial investigators reported visual acuity changes within treatment groups; no between‐group data reported.
Intraocular pressure: mean IOP at 4 years' follow‐up	The mean IOP was 14.0 mmHg in the timolol group.	The mean IOP in the brimonidine group was 0.20 mmHg higher (0.73 mmHg lower to 1.13 mmHg higher).	MD 0.20 (‐0.73 to 1.13)	91 (1 study)	⊕⊝⊝⊝ very low1,2	Among participants with visual field loss at 4 years, the RR for IOP reduction of 20% or greater was 1.15 (95% CI 0.49 to 2.70) when comparing 9 brimonidine participants with 31 timolol participants (very low certainty).
Vertical cup‐disc ratio: the proportion of participants with asymmetrical vertical cup‐disc ratio greater than 0.3 at 4 years' follow‐up	Not reported	Not reported	‐	‐	‐	No vertical cup‐disc ratio outcome was reported by the study.
Adverse effects: ocular allergy to the study medication requiring discontinuation up to 4 years' follow‐up	38 per 1000	202 per 1000 (62 to 655)	RR 5.32 (1.64 to 17.26)	178 (1 study)	⊕⊝⊝⊝ very low1,2	6 participants, 5 in the brimonidine group and 1 in the timolol group, died during the study due to causes unrelated to the study treatments.
Quality of life measures	Not reported	Not reported	‐	‐	‐	No quality of life outcome was reported by the study.
Economic data	Not reported	Not reported	‐	‐	‐	No economic outcome was reported by the study.
*The primary follow‐up time point for this review was 5 years, however data were only available at 4 years. **The basis for the assumed risk is risk in the control group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the control group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; IOP: intraocular pressure; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

¹Downgraded for attrition bias (‐2): data missing for 55% of participants in brimonidine group versus 29% of participants in timolol group.
 ²Downgraded for selective outcome reporting (‐1): definitions of primary and secondary outcomes differed between baseline paper and results paper; results for some outcomes that were measured were not reported (i.e. cup‐disc ratio, visual acuity).

Background

Description of the condition

Glaucoma is part of a heterogeneous group of conditions with multiple etiologies (causes). It is characterized by optic neuropathies that involve structural damage of the optic nerve, death of retinal ganglion cells (RGCs), and defects of the visual field. The optic nerve, formed by the clustering of axons from RGCs located in the ganglion cell layer of the retina, carries visual impulses from the eye to the brain (Gupta 1997). When optic nerve damage or deterioration causes the transfer of information to be disrupted, vision loss occurs.

There are two main categories of primary glaucoma: open angle glaucoma and closed angle glaucoma. Open angle glaucoma (OAG), the most common form of glaucoma, is a chronic and progressive optic nerve disease that is likely to be affected by multiple genetic and environmental factors (Fan 2010; Hauser 2006a; Hauser 2006b). Open angle glaucoma may be accompanied by increased intraocular pressure (IOP) (pressure inside the eye), as with primary open angle glaucoma (POAG), or normal IOP, as with normal‐tension glaucoma. Closed angle glaucoma tends to occur suddenly and is beyond the scope of this review.

Epidemiology

Glaucoma is the second‐leading cause of vision loss in the world (Quigley 2006; Resnikoff 2004), and an increasingly important public health concern due to the aging world population. The World Health Organization estimates that 105 million people have glaucoma worldwide, and around 5 million are blind as a consequence (Osborne 2003; Quigley 2006).

Open angle glaucoma is the most common form of glaucoma in white and African populations, whereas closed angle glaucoma is more common in Asian populations (Bonomi 2002; Tielsch 1991). In the USA, rates of POAG are reported to be four to five times greater in African‐American populations compared to European‐derived populations, with the rates for Mexican‐Americans in between (Quigley 2001; Tielsch 1991). The prevalence of POAG in Chinese populations is reported to be similar to European‐derived populations, but is greater in populations from southern India compared to European‐derived populations (Foster 2000; Ramakrishnan 2003). According to a 2004 meta‐analysis of population‐based studies, OAG affects more than 2 million individuals in the USA, and due to the rapid aging of the US population, this number is estimated to increase to more than 3 million by 2020 (Friedman 2004).

Primary open angle glaucoma is inherited as a complex trait, although environmental factors may also contribute to the disease (Hunter 2005). Ocular hypertension, or high IOP, is one of the main risk factors for glaucoma, but is neither necessary nor sufficient to induce the neuropathy. Other risk factors for glaucoma include aging, positive family history of glaucoma in a first‐degree relative, central corneal thickness less than 555 microns, high myopia (nearsightedness), and migraine headaches (Anderson 2003; Armaly 1980; Heijl 2002), none of which is modifiable in an effort to reduce risk.

Presentation and diagnosis

Open angle glaucoma is usually asymptomatic in the early stages. In some cases the disease may go unnoticed until unrecoverable damage to the optic nerve causes peripheral visual field defects. Without treatment there is a gradual loss of vision over time, ultimately leading to irreversible blindness.

In some patients the degeneration of the optic nerve occurs even while the IOP remains within the normal range. Glaucoma of this type is known as normal‐ or low‐tension glaucoma, and is thought to represent a subtype of adult‐onset OAG. The clinical appearance of the optic nerve in normal‐tension glaucoma and in primary optic neuropathies is very similar. The distinction between high‐ and low‐tension glaucoma is that people with high‐tension glaucoma present with an IOP of 21 mmHg or more (Kamal 1998).

In addition to measuring IOP when testing for glaucoma, it is equally important to perform a visual field test and to examine the optic nerve to establish the diagnosis of glaucoma. Measurements of the vertical cup‐disc ratio, especially in relation to the optic disc size, may be useful in identifying potential cases of glaucoma (Garway‐Heath 1998). In some patients, RGC death can be detected clinically by specific visual field loss (Schwartz 2000).

Treatment options

Early detection and treatment of glaucoma is critical as progression of the disease will result in permanent blindness (Shields 1996). Once peripheral or central vision is lost due to glaucoma, no form of treatment can restore it. Most treatments for glaucoma continue to be directed at reducing IOP and slowing the disease progression, although for many patients the reduction of IOP by itself does not prevent optic nerve damage or visual field loss. Furthermore, studies have shown that the loss of RGCs continues despite lowering IOP (Brubaker 1996; Cockburn 1983). Interventions that only focus on reducing IOP thus may not be beneficial for some glaucoma patients.

Description of the intervention

Treating disease by preventing neuronal death or deterioration is known as neuroprotection (Levin 1999). Different compounds, both natural and synthetic, have been reported to have neuroprotective activity. These include antioxidants, N‐methyl‐D‐aspartate (NMDA) receptor antagonists, inhibitors of glutamate release, calcium channel blockers, polyamine antagonists and nitric synthase inhibitors, as well as cannabinoids, aspirin, melatonin, and vitamin B₁₂ (Neacsu 2003; Neufeld 1998; Weinreb 1999).

Neuroprotection for glaucoma refers to any intervention intended to protect the optic nerve or prevent the death of RGCs. The intervention can operate by affecting cellular factors derived from the optic nerve itself, or by eliminating risk factors external to the nerve (e.g. reducing IOP). In this review we considered oral and topical neuroprotective agents for all people with OAG regardless of IOP.

Neuroprotection occurs in addition to, and as a separate effect from, lowering IOP. If we consider lowering of IOP as an indirect approach for neuroprotection, and therefore a treatment for glaucoma, it may be necessary to supplement additional neuroprotective agents (Schwartz 2000; Weinreb 1999). Other neuroprotective interventions include neutralization of the toxicity of risk factors, for example the use of glutamate receptor antagonists or inhibitors of nitric oxide synthase can be considered as different approaches to neuroprotection (Neufeld 1997).

How the intervention might work

Glaucoma is now recognized as a neurodegenerative disease associated with long‐term progressive RGC death (Bathija 1998; Quigley 1999; Schwartz 1996). Some of the cellular processes that result in the death of RGCs and that are consequently targeted by neuroprotective agents, include the:

1. production of external nerve‐derived risk factors such as glutamate and nitric oxide;

2. deprivation of internal trophic (nutritional) factors in the nerve cells;

3. loss of intracellular self repair processes; and

4. generation of intracellular destructive processes (Schwartz 2000).

The rationale for treatment is that by acting as pharmacological antagonists, neuroprotective agents can correct the imbalance between cellular death and survival signals, thus preventing RGC death and optic nerve damage. Also, self repair via neuroprotection may prevent the loss of RGC function by targeting the various processes involved in causing the death of RGCs. Since the loss of RGCs is the terminal process in the pathophysiology of glaucoma, neuroprotection may be helpful in preserving visual function (Chader 2012). However, there is still no consensus on the precise cause of glaucomatous optic neuropathy.

Why it is important to do this review

Glaucoma is a leading cause of permanent blindness worldwide. As a chronic and progressive condition, glaucoma is amenable to treatment in the early stages of disease. As such, many types of interventions have been proposed for the treatment of glaucoma. There is a published Cochrane review of topical treatments for the prevention of progression or onset of glaucomatous optic neuropathy (Vass 2007). In this review, we updated our evaluation of the evidence regarding the effects of neuroprotective agents when used to treat glaucoma. Consideration of the results of this review may lead health policy planners to improve access to prevention programs for glaucoma, encourage early detection and treatment of glaucoma, and stimulate development of new neuroprotective agents.

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 compared with no neuroprotective agent, placebo, or other glaucoma treatment.

Methods

Criteria for considering studies for this review

Types of studies

We included only randomised controlled trials in the review.

Types of participants

We included trials of adults (age 30 years and older) who had OAG documented by:

1. at least two reliable visual fields demonstrating visual field loss compatible with glaucomatous damage (on the basis of mean deviation and corrected pattern standard deviation or corrected loss variance of Humphrey or Octopus perimetry); and

2. glaucomatous optic nerve changes.

Types of interventions

We included trials that used topical and oral treatments to prevent RGC death. Such agents include:

• pharmacological antagonists like memantine that inhibit excitotoxicity by binding to NMDA receptors and preventing excitatory activity;

• alpha 2 adrenergic agonists like brimonidine;

• calcium channel blocking agents;

• delivery of brain‐derived neurotrophic factor (BDNF) to RGC;

• antioxidant and free radical scavengers;

• Ginkgo biloba extract;

• nitric oxide synthase inhibitor.

We included trials that compared any of the above interventions with placebo or no intervention. We also included trials in which any of the above interventions had been compared to another or in which different regimens of the same intervention had been compared.

Types of outcome measures

Primary outcomes

The primary outcome for this review was the proportion of participants who developed any progression of visual field loss at a follow‐up of five years' postintervention. The effect of lowering IOP is better measured during longer follow‐up (AGIS 1994; Nouri‐Mahdavi 2004). As of the 2013 update of the review (Sena 2013), we have included visual field loss after four years.

Secondary outcomes

1. Visual acuity: the proportion of participants with loss of two or more lines of visual acuity measured by LogMAR chart. As a subgroup, we also compared differences between the treated group of participants who experienced progressive visual field loss and the untreated group of participants who experienced progressive visual field loss.

2. Intraocular pressure: differences in mean change in IOP in the treated group compared with the untreated group. As a subgroup, we also compared differences in mean IOP in the treated group of participants who experienced progressive visual field loss and the untreated group of participants who experienced progressive visual field loss.

3. Vertical cup‐disc ratio: the proportion of participants with asymmetrical vertical cup‐disc ratio greater than 0.3.

Adverse effects

We reported adverse effects related to the particular treatment reported in the included studies. These included any ocular and systemic side effects that occurred during the treatment period, tolerability, any abnormal ocular finding, or any adverse event. We defined an adverse event as any undesirable event occurring in a participant, whether or not considered to be related to the study treatment.

Quality of life measures

We planned to summarize any quality of life data reported in the included studies.

Economic data

We planned to summarize any economic data including, but not limited to, cost‐effectiveness and cost‐benefit analyses reported in the included studies. Economic data included direct costs associated with the treatment follow‐up, estimated and calculated per participant, and indirect costs such as transportation and expenses necessary to the medical follow‐up.

Follow‐up

We aimed to include trials with at least five years of follow‐up to allow for adequate assessment of the effect of neuroprotection on prevention of visual field loss. For the 2013 update of the review, we revised the minimum follow‐up time to include studies with at least four years of follow‐up because the editorial reviewers indicated that four years may be a sufficient amount of time to detect differences between treatment groups (Sena 2013).

Search methods for identification of studies

Electronic searches

We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 7), Ovid MEDLINE, Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily (January 1946 to August 2016), Embase (January 1980 to August 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (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. We last searched the electronic databases on 16 August 2016.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), Embase (Appendix 3), LILACS (Appendix 4), the ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6), and the ICTRP (Appendix 7).

Searching other resources

We manually searched the reference lists of publications from the included study to identify additional trials. We also used the Science Citation Index to screen studies that cited any included study to identify additional trials (last searched 30 November 2016).

Data collection and analysis

Selection of studies

Two review authors (DS and KL) independently reviewed titles and abstracts resulting from the literature searches according to the inclusion criteria described above. We classified the abstracts as 'relevant,' 'potentially relevant,' or 'definitely not relevant.' We obtained the full‐text report of those in the 'relevant' or 'potentially relevant' categories and assessed the studies they reported for inclusion. We resolved any disagreements through discussion. When necessary, we contacted the authors of studies for clarification of eligibility. For all studies excluded after review of the full text, we documented the reasons for exclusion.

Data extraction and management

Two review authors (DS and KL) independently extracted data from the reports of the one included study using data extraction forms developed by Cochrane Eyes and Vision and adapted for this review. We extracted the following data: country of clinical trial; age and gender of participants; trial design; details of the interventions including doses, route of administration, and duration of treatment; follow‐up schedule and timing of outcome measurements; participant flow charts and the associated numbers. We also recorded details of the methods used to ascertain outcomes. We anticipated that certain parameters, such as visual field, would be measured by differently in different trials; we thus extracted any reported outcome related to visual field from the included trial. Any discrepancies between the two review authors were resolved by discussion. One review author (KL) entered data into Review Manager 5 (RevMan 2014), and a second review author (DS) verified the data.

Assessment of risk of bias in included studies

Two review authors (DS and KL) independently assessed the included studies for risk of bias according to guidelines set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We considered methods employed to address the following systematic biases to determine the methodological quality of each study.

• Selection bias (sequence generation and allocation concealment before randomization): We considered any method of allocation concealment such as centralized randomization or use of sequential, opaque envelopes, which provides reasonable confidence that the allocation sequence was concealed from physicians and participants, to confer 'low risk of bias.' When the allocation was based on unconcealed lists or envelopes, or there was no qualifying statement describing allocation method or timing, we assessed the study as having 'unclear risk of bias.'

• Masking of participants and care providers with regard to treatment allocation to assess for performance bias.

• Masking of outcome assessors to assess detection bias.

• Rates of follow‐up, reasons for loss to follow‐up, and analysis by the intention‐to‐treat principle to assess for attrition bias. We considered a trial to have been analyzed by the intention‐to‐treat principle that analyzed participants as randomized, and included participants for whom no outcome measurements were made and those who received only part or none of the intended treatment.

• Selective outcome reporting was examined to assess reporting bias.

Any disagreements between the review authors were resolved through discussion. We did not need to contact the authors of any included study for additional information related to risk of bias.

Measures of treatment effect

As this review included only one study, we performed no meta‐analysis. If in the future additional studies are included and meta‐analysis is deemed appropriate, we will perform data analysis according to the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We reported dichotomous outcomes using risk ratios and continuous outcomes using mean differences. We planned to use the standardized mean difference to summarize outcomes measured on different scales.

Unit of analysis issues

The unit of analysis was the individual participant.

Dealing with missing data

We did not contact primary investigators from the only included study, as the desired data were provided in the published reports. In the future when additional information is needed, we will contact primary investigators of trials for unreported outcome data. We did not impute outcome data for the purposes of this review.

Assessment of heterogeneity

As this review included only one study, we did not assess heterogeneity across studies. When additional studies are included in future updates, we will assess clinical heterogeneity qualitatively before performing statistical analysis. When the participants in the included trials differ in any substantial way, we will take note and decide whether to perform meta‐analysis. We will examine study characteristics and symmetry of the forest plots. We will interpret a poor degree of overlap of the confidence intervals on the effect estimates from the studies included in a meta‐analysis as indicative of statistical heterogeneity. The effect estimates across studies will be tested for inconsistency using the Chi² test and quantified using the I² statistic. An I² statistic greater than 50% will indicate the presence of substantial statistical heterogeneity.

Assessment of reporting biases

We will use a funnel plot to identify publication bias whenever 10 or more studies are included in a meta‐analysis. We also assessed selective outcome reporting as part of our 'Risk of bias' assessment.

Data synthesis

We aimed to synthesize data both qualitatively and quantitatively. We planned to combine the effect estimates in a meta‐analysis using a random‐effects model whenever appropriate. We planned to use a fixed‐effect model when the number of included trials was fewer than three. If there was significant clinical heterogeneity, or the I² statistic was greater than 50%, we planned not to present a meta‐analysis in such cases; instead, we would present a tabulated summary, narrative summary, or both.

Subgroup analysis and investigation of heterogeneity

As a subgroup, we compared differences between the treated group of participants that developed progressive visual field loss and the untreated group of participants that developed progressive visual field loss for visual acuity and IOP outcomes.

Sensitivity analysis

When data were sufficient, we planned to examine the impact of excluding studies at high risk of bias, unpublished data, and industry‐funded studies through sensitivity analyses.

Summary of findings

We have presented a 'Summary of findings' table with the estimated effects for the outcomes assessed in this review. We used the GRADE approach to assess the certainty of evidence for each outcome (GRADEpro 2014). Two review authors (DS and KL) independently graded the certainty of each outcome estimate as very low, low, moderate, or high according to five criteria: risk of bias within individual studies, indirectness of comparisons, heterogeneity among studies, imprecision of estimate (wide confidence intervals), and publication bias. Any discrepancies were resolved by discussion.

Results

Description of studies

Results of the search

The original electronic searches run in 2010 yielded 1500 records of articles, abstracts, and reviews. We obtained full‐text copies of 24 potentially relevant records and evaluated the studies for inclusion. We also reviewed 11 additional articles identified by screening the reference lists of full‐text articles. Of the 35 full‐text reports we reviewed, which reported 29 studies, none met all the inclusion criteria for this review. Of the 29 studies excluded at this stage, six were not randomized trials; six did not involve people with OAG or did not limit the study to people with OAG; two did not compare the interventions of interest for this review; and 15 were short‐term trials, between two hours and four years, and thus did not meet the five‐year follow‐up period specified for the review in 2010.

Through a search of the ClinicalTrials.gov database, we identified two phase III trials investigating the effects of memantine in people with chronic glaucoma (NCT00141882; NCT00168350). Both studies were conducted by Allergan Inc. and are described as randomized, double‐masked, placebo‐controlled, parallel‐assignment studies. Data for the first trial were not published, but two review papers reported them to show potential beneficial effects (Cheung 2008; McKinnon 2008). The results of the second trial failed to corroborate the results of the first trial. Reports of the second trial publicly released by Allergan Inc. indicated that progression of glaucoma was significantly lower in participants receiving high‐dose memantine compared with participants receiving low‐dose memantine, but that there was no significant effect compared with participants receiving placebo. These trials are awaiting classification for inclusion in this review because the follow‐up times for outcome measurements are unclear.

We updated the electronic search on 16 October 2012 and identified 655 new records. At this time, we modified the eligibility criteria for this review to include studies with four or more years of follow‐up based on feedback from external content experts. One of the studies identified by the original electronic searches in 2010 became eligible based on this change (LoGTS 2011). Of the 655 new records identified, we excluded 638 by screening titles and abstracts, and reviewed full‐text documents for 17 records. Of the 17 full‐text reports reviewed, we excluded 14 and included three in the review. These three records were reports from one study, LoGTS 2011.

We updated the electronic searches on 16 August 2016 (Figure 1). Of 1294 new records identified, we excluded 1283 by screening titles and abstracts and 11 after reviewing the full‐text reports. The 11 excluded full‐text reports were from eight studies. We identified no other potentially relevant records from searching other sources.

1.

Study flow diagram.

Included studies

We included one study in this review (LoGTS 2011). LoGTS 2011 was a multicenter randomized controlled trial of people with low‐pressure glaucoma conducted in the USA. Brimonidine, an alpha 2 adrenergic agonist and neuroprotective agent, was compared with timolol, a beta‐adrenergic receptor blocker and IOP‐lowering agent, over a four‐year treatment period. Participants and study investigators were masked to treatment groups. All study participants discontinued topical ocular hypotensive medications, and there was a washout period prior to beginning study interventions.

The 190 study participants included men and women 30 years of age or older with untreated glaucoma and IOP of 21 mmHg or less. After randomization, 12/190 (6%) of the study participants were excluded due to the exclusion of a study site (10 participants), withdrawal of consent (one participant), or because the participant did not meet study eligibility criteria (one participant). Of the 178 participants who remained in the study, 99 had been randomized to receive brimonidine tartrate 0.2% monotherapy (Alphagan; Allergan Inc., Irvine, California, USA) and 79 had been randomized to receive timolol maleate 0.5% monotherapy (Timoptic; Merck & Co., West Point, Pennsylvania, USA). Both treatment solutions contained benzalkonium chloride (0.005% (50 ppm) in brimonidine, and 0.01% (100 ppm) in timolol) and were instilled in both eyes twice a day. The primary outcome of the study was progression of visual field loss. After one year of follow‐up, 36/99 (36%) participants in the brimonidine group and 8/79 (10%) participants in the timolol group had missing outcome data, and after four years of follow‐up, 54/99 (55%) participants in the brimonidine group and 23/79 (29%) participants in the timolol group had missing outcome data.

Excluded studies

We excluded 49 studies from the review following the full‐text assessment of reports. Thirteen were not randomized trials; six did not enroll participants with OAG, or did not limit the study to participants with OAG; four did not compare the interventions of interest for this review; and 26, with between two hours' and three years' follow‐up, did not meet the fours years' follow‐up requirement for inclusion in this review.

See: Characteristics of excluded studies for further details.

Risk of bias in included studies

Allocation

LoGTS 2011 was a randomized controlled trial. The randomization list was computer generated and maintained during the study by supplying coded study medications to the clinical centers. For these reasons, we assessed the risk of selection bias related to sequence generation and allocation concealment to be low.

Masking (performance bias and detection bias)  

"Full masking of patients, physicians, technicians, and the reading center for visual fields and optic disc photographs" was reported in LoGTS 2011. Furthermore, analysis of visual fields, the primary outcome of the trial, was masked. For these reasons, we judged the study to be at low risk of performance and detection bias.

Incomplete outcome data

To assess risk of attrition bias, we considered:

1. exclusion of participants after randomization;

2. rates of loss to follow‐up;

3. handling of missing data.

The total number of participants stated as enrolled in the study differed between trial reports (LoGTS 2011). The authors of the design and baseline paper, published in 2005, reported that 190 participants were randomized (number assigned to each treatment group was not specified). In the results paper, published in 2011, the study investigators reported that 178 participants were randomized. We considered 12/190 (6%) participants to have been excluded from the study based on the difference between the 2005 and 2011 study reports.

There were differential losses to follow‐up between the brimonidine and timolol groups at one and four years of follow‐up. At one year, 36/99 (36%) participants in the brimonidine group were lost to follow‐up, compared with 8/79 (10%) participants in timolol group (P < 0.001). Allergy to the study medication was the most common reason for participants dropping out of the study and was greater in the brimonidine group (20/99 participants in brimonidine group compared with 3/79 participants in timolol group). At four years' follow‐up, 54/99 (55%) participants in brimonidine group and 23/79 (29%) participants in timolol group were lost to follow‐up (P < 0.001).

With reference to the study design of LoGTS 2011, a participant was withdrawn from the study whenever: the IOP increased to more than 21 mmHg; visual field loss progressed; allergy or intolerance to a study medication developed; or the treating ophthalmologist decided that the participant should be discontinued from the study. The proportions of participants analyzed at the four‐year follow‐up time for the primary visual field outcome were 45/99 (45%) in the brimonidine group and 56/79 (71%) in the timolol group. Data were thus missing for 89/190 (47%) participants at the four‐year follow‐up time, so that no conclusions can be drawn from this study with regard to neuroprotective effects for the participants with missing data or overall.

Due to the exclusion of participants after randomization, the differential rates of loss to follow‐up between the study groups, and inadequate handling of missing data, we assessed the study to have a high risk of attrition bias.

Selective reporting

The authors of LoGTS 2011 specified primary and secondary outcomes related to progression of visual field loss, but the ranking of the outcomes differed between the design and baseline paper published in 2005 and the results paper published in 2011. In the 2005 design report, the primary outcome was defined as "significant progression of the same two or more points, on the Humphrey glaucoma change probability maps or by Progressor linear regression analysis, in 3 consecutive (over an 8‐month period) Humphrey 24‐2 full threshold fields." In the 2011 results paper, the outcome for visual field was separated into a primary outcome ("the primary outcome measure was visual field progression in either eye as determined by pointwise linear regression analysis of all study visual fields with Progressor software (Medisoft Inc., Leeds, UK)" and a secondary outcome ("a secondary outcome was visual field progression in either eye evaluated by Humphrey glaucoma change probability maps (GCPM)").

Although not specified as outcomes for the study, other measures relevant to glaucoma and targeted for this review were recorded at follow‐up visits: IOP, visual acuity, changes to optic nerve structure, and cup‐disc ratio. Due to the variation in outcome definitions between the published reports, and failure to report other outcomes that were measured and that are commonly reported in glaucoma trials, we judged the study to have a high risk of reporting bias.

Other potential sources of bias

Inclusion criteria for this study allowed for the inclusion of one or both eyes of participants, and non‐independence of eyes was taken into account when both eyes were included. Although the study was "patient‐based," progression of visual field loss was based on the first eye with progression when both eyes were included. The authors did not report progression findings in the second eye after one eye progressed.

The study was partially funded by Allergan Inc. through an unrestricted grant and the provision of study medications. Additional funding support included an unrestricted grant from Research to Prevent Blindness Inc. (New York, New York, USA).

Due to issues related to the unit of analysis and industry source of funding, we assessed the study as having other potential sources of bias.

Effects of interventions

See: Table 1

Brimonidine 0.2% versus timolol 0.5%

A summary of the effects of interventions is provided in Table 1.

Progression of visual field loss

Progression of visual field loss was the primary outcome of LoGTS 2011. Three methods were used to measure visual fields:

1. Progressor pointwise linear regression analysis;

2. Humphrey glaucoma change probability maps using pattern deviation; and

3. the 3‐omitting method for pointwise linear regression analysis.

Agreement among the three methods for detecting progression of visual field loss was good (overall kappa of 0.628, standard error (SE) = 0.051), with the highest agreement between the Progressor pointwise linear regression and 3‐omitting method (kappa of 0.719, SE = 0.068) and the lowest agreement between glaucoma change probability maps and 3‐omitting method (kappa of 0.554, SE = 0.079).

At the four‐year follow‐up examination, 5/45 participants in the brimonidine group and 18/56 participants in the timolol group had progression of visual field loss detected by all three methods (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.14 to 0.86). However, these results do not take into account the higher rate of missing data in the brimonidine group compared with the timolol group (data missing for 55% of participants in brimonidine group versus 29% of participants in timolol group). Due to the amount of missing data and the imbalance between groups in participants followed up and selective reporting bias, we graded the certainty of evidence for this outcome as very low.

Visual acuity

The study authors reported that linear regression slopes of the Snellen decimal visual acuity fraction was not statistically different between treatment groups among participants with progression of visual field loss, participants completing the four‐year follow‐up without progression of visual field loss, or participants who did not complete the one‐year follow‐up. However, no data were available to compare visual acuity outcomes between treatment groups.

Intraocular pressure

At the four‐year follow‐up examination, mean IOP was similar in the two treatment groups. Mean IOP was 14.2 mmHg (standard deviation (SD) = 1.9) among the 43 participants with data available in the brimonidine group and 14.0 mmHg (SD = 2.6) among the 48 participants with data available in the timolol group (mean difference 0.20 mmHg, 95% CI ‐0.73 to 1.13). Among the participants who experienced progressive visual field loss, IOP reduction of 20% or greater did not differ significantly between groups: 4/9 participants in the brimonidine group and 12/31 participants in the timolol group with visual field loss, as determined by Progressor pointwise linear regression analysis, had IOP reduction of 20% or greater at time of further visual field loss (RR 1.15, 95% CI 0.49 to 2.70). Due to the amount of missing data and the imbalance between treatment groups in the number of participants followed up and selective reporting bias, we graded the certainty of evidence for IOP outcomes as very low.

Vertical cup‐disc ratio

Vertical cup‐disc ratio outcomes were not reported in LoGTS 2011.

Adverse effects

The most common adverse effect was ocular allergy to the study medication that required discontinuation. Allergic reactions occurred among more brimonidine participants (20/99 discontinued the study for this reason) compared with timolol participants (3/79 discontinued the study for this reason) (RR 5.32, 95% CI 1.64 to 17.26). Six participants, five in the brimonidine group and one in the timolol group, died during the study due to causes unrelated to the study treatments (trauma, myocardial infarction, pulmonary embolism, or complications from bowel surgery).

We graded the certainty of evidence for adverse effects as very low due to the amount of missing data and the imbalance between groups in numbers of participants followed up and selective reporting bias.

Discussion

Glaucoma is understood to be a progressive neurodegenerative disease, therefore medical therapies that focus directly on protecting the optic nerve and preventing the death of RGCs should play a role in the future of glaucoma treatment. Furthermore, studies have shown that interventions intended to only lower IOP, the most common risk factor for glaucoma progression, are not always effective in preventing visual field loss (Brubaker 1996; Cockburn 1983). Considered by some to be a complementary or alternative therapy (NICE Guidelines), neuroprotective treatment for glaucoma endeavors to preserve vision by preventing, slowing, or reversing the death of RGCs. For the purpose of examining the evidence according to this definition of neuroprotection, the scope of this review was limited by the inclusion criteria to identify studies with long‐term outcomes directly related to visual field defects or to the optic nerve itself.

Summary of main results

After failure to identify any eligible study with five or more years of follow‐up, we examined findings from one randomized controlled trial that had compared brimonidine 0.2% with timolol 0.5% and aimed to follow participants for four years (LoGTS 2011). Outcome data were derived from 99 participants randomized to the brimonidine monotherapy group and 79 participants randomized to the timolol monotherapy group. Although results from the four‐year follow‐up examination suggested that brimonidine may slow or prevent visual field loss compared with timolol, these estimates ignore the higher number of participants with missing data in the brimonidine group compared with the timolol group (55% versus 29%, respectively). Subgroup analyses of participants who experienced progression of visual field loss, participants who completed the study without progression, and participants who did not complete the study did not show any statistical differences between treatment groups in terms of the rate of change of Snellen decimal visual acuity fraction during follow‐up. At the four‐year follow‐up, mean IOP was similar in the two treatment groups. The study investigators did not report vertical cup‐disc ratios during follow‐up or changes over time. More participants in the brimonidine group experienced adverse events compared with the timolol group, with ocular allergy to the study medication that required discontinuation being the most common adverse event (5.32 times more participants affected in the brimonidine group compared with the timolol group, 95% CI 1.64 to 17.26).

Overall completeness and applicability of evidence

The outcomes targeted in this review were specific to OAG. The population of interest was restricted to people with OAG and did not include people with ocular hypertension, thus prevention of glaucoma by neuroprotection was not addressed in this review. Furthermore, 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 (AAO Preferred Practice Pattern). Although the study authors of LoGTS 2011 reported visual field outcomes and noted that annual optic nerve photographs were taken, they have not reported the correlation between visual field function and optic nerve structure changes in their results paper. Comparisons of optic nerve or retinal nerve fiber layer changes, or both, with the visual field changes would be of interest.

We defined the primary outcome for this review as the proportion of participants who had experienced any progression of visual field loss at four years' postintervention. This outcome is consistent with current recommendations for visual function endpoints for ophthalmic studies (Csaky 2008). Although the reduction of IOP has been the outcome of interest in previous research (Danesh‐Meyer 2009), it was not the primary focus of this review since lowering IOP alone is not always effective in preventing visual field loss from glaucoma. We included mean change in IOP as a secondary outcome, as it is currently the most common risk factor for glaucoma disease progression, and reduction may be beneficial for some patients (Seong 2009). Furthermore, the Collaborative Normal Tension Glaucoma Study showed that a 30% reduction in IOP yielded significant benefit; since that report was published, a 30% reduction in IOP has become the standard of glaucoma care because it is a strong predictor of glaucomatous damage (CNTGS 1998). The study design of LoGTS 2011 allowed participants with any pressure below 21 mmHg to enroll; IOP data were reported only for those participants with 20% reduction in IOP and progressive visual field loss.

After one year, 36/99 (36%) participants in the brimonidine group and 8/79 (10%) participants in the timolol group had been lost to follow‐up; by four years, 54/99 (55%) participants in the brimonidine group and 23/79 (29%) participants in the timolol group had been lost to follow‐up. Due to excessive attrition, we cannot conclude that brimonidine is more effective than timolol, as those participants not followed up may have had better or worse outcomes; the outcome estimates may therefore not be generalizable to the clinical setting.

Quality of the evidence

As noted above, there was a differential amount of missing data between treatment groups in LoGTS 2011. The high attrition rate and the difference in attrition between groups suggest a high risk of attrition bias in estimates of outcomes. Four‐year outcome data were missing for the majority of participants in the brimonidine group, thus results from this study are inconclusive. We therefore judged the certainty of evidence for the outcomes in this review to be very low.

The study criteria allowed for the inclusion of one or both eyes of participants. Although outcomes in the two eyes could be correlated, the study investigators did not account for non‐independence of the two eyes. Participants were withdrawn from the study once further visual field loss was detected in the first eye.

With regard to reporting bias, the definition of primary and secondary outcomes differed between the published baseline paper and the results paper. The study investigators did not explain the change when they reported four‐year outcomes. Also, some outcomes that were measured were not reported (i.e. cup‐disc ratio, visual acuity for all participants, changes to optic nerve structure).

Potential biases in the review process

We attempted to minimize bias in the review process by conducting an extensive, highly sensitive search of the literature. Two review authors independently executed all steps in screening references, extracting data, and assessing studies. We consulted with glaucoma specialists and methodologists during the review process.

Agreements and disagreements with other studies or reviews

The endpoint for the primary outcome of this review was set at four years' postintervention to assess the long‐term effects of neuroprotection. As such, we excluded 21 potentially relevant trials with a follow‐up ranging from two hours to three years. Five of these studies reported results for visual outcomes at follow‐up times of two years or greater (Araie 2010; Drance 1998; Garcia‐Medina 2015; Koseki 1999; Sawada 1996).

The excluded study with the longest follow‐up time, three years, was conducted in Japan and included participants with normal‐tension glaucoma (NTG) and mild to moderate damage (Araie 2010). The aim of the study was to determine the rates of visual field loss among participants given nipradilol 0.25% versus timolol 0.5%. Of the 158 randomized participants, 146 met the study eligibility criteria and were included in the analyses (72 participants received nipradilol and 74 received timolol). During the study, 13/72 (18%) participants in the nipradilol group and 11/74 (15%) participants in the timolol group were withdrawn due to adverse events; loss to follow‐up; use of restricted drugs; complications not related to study treatment; and change of address. At three years, the study authors concluded that there was no significant difference between treatments in terms of overall visual field loss (mean deviation ± SE: −0.03 ± 0.06 decibels/year in nipradilol group and −0.05 ± 0.06 decibels/year in timolol group), but the superior‐central subfield and the corrected pattern standard deviation measures were significantly changed within treatment groups compared with baseline (P ≤ 0.001). Among subgroups of participants with early visual field loss or younger participants, nipradilol showed some benefit in slowing visual field deterioration compared with timolol (mean deviation 0.29 in nipradilol group versus ‐0.20 in timolol group, P = 0.005 for participants with stage 1 classification; mean deviation 0.15 in nipradilol group versus ‐0.23 in timolol group, P = 0.039 for participants 40 years of age or younger).

The study with the second‐longest follow‐up time, of two and a half years, was also conducted in Japan, by Sawada and colleagues (Sawada 1996). The study was a randomized, prospective investigation of the effect of oral brovincamine fumarate (Sabromin; 20 mg three times daily) compared to placebo (three times daily) in participants with NTG. Brovincamine fumarate is a calcium channel blocker. In Sawada's study, 28 participants were allocated to receive either brovincamine or placebo. Visual fields were tested every four months using a Humphrey Field Analyzer, with mean follow‐ups of 39.1 ± 8.7 months for the treatment group and 37.9 ± 10.1 months for the placebo group. With reference to visual fields analysis, 6/14 eyes in the treatment group had visual field improvement and 8/14 had no visual field improvement. In the control group, 12/14 had no visual field changes and 2/14 had an increased visual field loss. This study reported a beneficial effect of brovincamine on visual field in some participants with NTG, however the study was unable to provide a definitive conclusion due to the small number of participants included in the trial (14 in the brovincamine‐treated group and 14 in the placebo‐treated group). We contacted the lead author of this study and he informed us that data for longer follow‐up times were not collected as brovincamine had become unavailable in Japan. 

Koseki 1999 investigated the effect of oral brovincamine on further deterioration of the visual field in participants with NTG. Participants with IOP less than 15 mmHg were randomly assigned to a group receiving oral brovincamine (20 mg three times daily) or an untreated control group for two years. This study reported that oral brovincamine may retard further visual field deterioration in participants with NTG who have low to normal IOP, however the study enrolled only a small group of participants (22 in the brovincamine group and 26 in the control group). The authors commented that the slightly better visual field performance during the study period in the brovincamine group may have been attributed to an improvement in cerebral function caused by cerebral vasodilatation rather than a reflection of protection from further glaucomatous damage.

Drance 1998 investigated the effects of betaxolol, timolol, and pilocarpine on visual functions in people with OAG. A total of 68 participants were randomized to receive one of the three treatments, and visual outcomes were measured after two years. No significant difference was reported for visual field effects between the treatment groups. The author did note that although all three treatments were effective in reducing IOP, there was dissociation between reduction of IOP and protection of visual function.

The fifth excluded study with visual outcomes at follow‐up times of two years or greater was Garcia‐Medina 2015. Participants with primary open angle glaucoma were randomly assigned to one of three groups: oral antioxidant supplementation with omega‐3 fatty acids; oral antioxidant supplementation without omega‐3 fatty acids; and control. The authors reported no difference in visual field global indices between the treatment groups after two years. This study was presented as a conference abstract; the full report has yet to be published.

We identified two potentially relevant phase III trials assessing the effects of memantine in people with chronic glaucoma (NCT00141882; NCT00168350). Memantine has been theorized as a promising neuroprotective agent for the treatment of glaucoma that may work by blocking N‐methyl‐D‐aspartate glutamate receptors, which may play a role in RGC death (Levin 2008; Lipton 2003). Positive results from preclinical data suggesting a possible clinical benefit of memantine led to clinical trials being done in humans (Hare 2009; Ju 2009; Zhong 2007). Both of the phase III memantine trials were randomized, placebo‐controlled trials conducted by Allergan Inc. To date, Allergan has not published the results of either trial, but has reported via press releases that potential beneficial effects of memantine observed in the first trial were not supported by the second trial (Cheung 2008; McKinnon 2008).

The aim of our systematic review was to summarize the evidence related to the effectiveness of different topical and oral neuroprotective agents for treating OAG in adults. Thus far, we have not identified any randomized trial providing convincing evidence for neuroprotective benefit regarding preventing or slowing visual field loss in OAG.

Authors' conclusions

Implications for practice.

Recently there has been a growing interest in using neuroprotective drugs for the treatment of glaucoma. Neuroprotective agents such as pharmacological antagonists that inhibit excitotoxicity by activation, and N‐methyl D‐aspartate receptors like memantine; alpha 2 adrenergic agonists like brimonidine; calcium channel blocking agents; deliverers of brain‐derived neurotrophic factor to retinal ganglion cells (RGCs); antioxidants and free radical scavengers; Ginkgo biloba extract; and nitric oxide synthase inhibitors have shown promise in preventing or slowing RGC death in preclinical studies. However, the current evidence has not shown topical or oral neuroprotective agents to be effective in preventing RGC death or in preserving the visual field in people with open angle glaucoma (OAG).

Implications for research.

Although a fair amount of cellular and animal research has been completed, the effectiveness of neuroprotective oral and topical medical therapy for treating OAG in adults remains inconclusive. Further research is needed in this area, however there are certain research challenges (commitment of researchers and participants to long‐term follow‐up for study outcomes, even if treatment is modified or halted; selection of patient‐important outcomes; accounting for variability of disease manifestations, etc.). Future studies should be designed to measure clinically meaningful outcomes, such as progression of visual field loss, in order to inform clinical practice (Osborne 2009). Further efforts should be directed towards investigating long‐term visual field preservation with neuroprotective drugs, since OAG is a chronic, progressive disease.

Another complication in studying the clinical efficacy of neuroprotective agents for glaucoma is that current methodologies used to detect RGC death may not be sufficiently sensitive to show the effect of neuroprotection. Perhaps the ability to prove the efficacy of a neuroprotective drug will depend on the ability to develop and validate new endpoints related to quantitative morphological methods of assessing the retinal ganglion cell layer. The use of sophisticated optical instrumentation and new methodologies to detect cellular events early in the disease process, such as real‐time in vivo imaging of an apoptotic event (known as detection of apoptosing retinal cell, or DARC), may be useful quantitative measurements to assess neuroprotection in people with glaucoma.

As intraocular pressure (IOP) remains a standard measure in glaucoma research, the reasons for and considerations of the variation of IOP should be investigated. For example, one study showed that brimonidine may increase retinal blood flow while reclining, which could affect retinal blood flow autoregulation in OAG (Feke 2008). Evaluating the systemic effects of neuroprotective agents and the role they may play in clinical efficacy and basic mechanisms of action would allow us to determine whether neuroprotection is independent of IOP.

Additionally, in light of the non‐significant findings reported from an expensive and time‐consuming phase III trial of memantine, it is doubtful whether another long‐term randomized controlled trial on neuroprotection will be undertaken in the absence of promising results from other sources. Futility trials, which are designed to eliminate ineffective interventions from development rather than determine whether interventions work, have been proposed for neuroprotection research in people with glaucoma (Quigley 2012). Compared with the costs of large‐scale (sample size of thousands), long‐term (three to five years) randomized controlled trials, futility trials could be done with fewer participants and shorter follow‐up periods. Quigley estimated that a futility trial for a neuroprotective agent for glaucoma could be done with fewer than 100 participants followed for two years (Quigley 2012). Any neuroprotective agent found not to be futile could then be tested in a phase III randomized controlled trial.

What's new

Date	Event	Description
17 January 2017	New citation required but conclusions have not changed	Issue 1, 2017: No new trials identified
17 January 2017	New search has been performed	Issue 1, 2017: Updated searches conducted

History

Protocol first published: Issue 2, 2007
 Review first published: Issue 2, 2010

Date	Event	Description
30 January 2013	New search has been performed	Issue 2, 2013: Updated searches conducted; one new trial met the inclusion criteria and has been added (LoGTS 2011).
30 January 2013	New citation required but conclusions have not changed	Issue 2, 2013: The Abstract, Plain Language Summary, Results, Discussion, and Authors' Conclusions have all been updated accordingly.
23 May 2008	Amended	Converted to new review format.

Notes

As of Issue 2, 2010 of the Cochrane Library:

• this review replaced the published review: Sycha T, Vass C, Findl O, Bauer P, Groke I, Schmetterer L, et al. Interventions for normal tension glaucoma. Cochrane Database of Systematic Reviews 2003, Issue 1;

• the review by Sycha and colleagues was withdrawn from publication in the Cochrane Database of Systematic Reviews.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Glaucoma
 #2 glaucoma*
 #3 (#1 OR #2)
 #4 MeSH descriptor Neuroprotective Agents
 #5 neuroprotect*
 #6 MeSH descriptor Retinal Ganglion Cells
 #7 ganglion near cell*
 #8 retina* near cell*
 #9 RGC
 #10 MeSH descriptor Optic Nerve Diseases
 #11 optic near neuropath*
 #12 MeSH descriptor Memantine 
 #13 memantine
 #14 (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
 #15 (#3 AND #14)

Appendix 2. MEDLINE Ovid search strategy

1. randomized controlled trial.pt.
 2. (randomized or randomised).ab,ti.
 3. placebo.ab,ti.
 4. dt.fs.
 5. randomly.ab,ti.
 6. trial.ab,ti.
 7. groups.ab,ti.
 8. or/1‐7
 9. exp animals/
 10. exp humans/
 11. 9 not (9 and 10)
 12. 8 not 11
 13. exp glaucoma/
 14. glaucoma$.tw.
 15. or/13‐14
 16. exp neuroprotective agents/
 17. neuroprotect$.tw.
 18. exp retinal ganglion cells/
 19. (ganglion adj2 cell$).tw.
 20. (retina$ adj2 cell$).tw.
 21. RGC.tw.
 22. exp optic nerve disease/
 23. (optic adj2 neuropath$).tw.
 24. Memantine/
 25. memantine.tw.
 26. or/16‐25
 27. 15 and 26
 28. 12 and 27

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.

Appendix 3. Embase Ovid search strategy

1. exp randomized controlled trial/
 2. exp randomization/
 3. exp double blind procedure/
 4. exp single blind procedure/
 5. random$.tw.
 6. or/1‐5
 7. (animal or animal experiment).sh.
 8. human.sh.
 9. 7 and 8
 10. 7 not 9
 11. 6 not 10
 12. exp clinical trial/
 13. (clin$ adj3 trial$).tw.
 14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
 15. exp placebo/
 16. placebo$.tw.
 17. random$.tw.
 18. exp experimental design/
 19. exp crossover procedure/
 20. exp control group/
 21. exp latin square design/
 22. or/12‐21
 23. 22 not 10
 24. 23 not 11
 25. exp comparative study/
 26. exp evaluation/
 27. exp prospective study/
 28. (control$ or prospectiv$ or volunteer$).tw.
 29. or/25‐28
 30. 29 not 10
 31. 30 not (11 or 23)
 32. 11 or 24 or 31
 33. exp glaucoma/
 34. glaucoma$.tw.
 35. or/33‐34
 36. exp neuroprotective agent/
 37. neuroprotect$.tw.
 38. exp retinal ganglion cell/
 39. (ganglion adj2 cell$).tw.
 40. (retina$ adj2 cell$).tw.
 41. RGC.tw.
 42. exp optic nerve disease/
 43. (optic adj2 neuropath$).tw.
 44. Memantine/
 45. memantine.tw.
 46. or/36‐45
 47. 35 and 46
 48. 32 and 47

Appendix 4. LILACS search strategy

glaucoma$ and neuroprotect$ or memantine

Appendix 5. ISRCTN search strategy

glaucoma AND (neuroprotection OR memantine)

Appendix 6. ClinicalTrials.gov search strategy

glaucoma AND (neuroprotection OR memantine)

Appendix 7. ICTRP search strategy

glaucoma = Condition AND neuroprotection or memantine = Intervention

Characteristics of studies

Characteristics of included studies [ordered by study ID]

LoGTS 2011.

Methods	Study design: parallel‐group randomized controlled trial Number randomized (total and per group): 190 total participants randomized; number per group not reported Number analyzed (total and per group): Exclusions: 12 total participants randomized; number per group not reported Loss to follow‐up: at 1 year, 36/99 (36%) participants in brimonidine group and 8/79 (10%) participants in timolol group were lost to follow‐up; at 4 years, 54/99 (55%) participants in brimonidine group and 23/79 (29%) participants in timolol group were lost to follow‐up Study planned follow‐up was 4 years Sample size calculation: 64 participants for 80% power to detect outcome differences between groups
Participants	Country: USA (13 clinical centers) Age (mean ± standard deviation): 64.9 ± 10.7 years Gender: women (n = 113; 59.5%); men (n = 77; 40.5%) Inclusion criteria: "Men and women, ≥ 30 years of age, with previously diagnosed LPG. Untreated LPG with Goldmann applanation IOP ≤ 21 mmHg on a diurnal (8 AM, 10 AM, 12 PM, 4 PM) curve before medication randomization." Exclusion criteria: "History of untreated IOP > 21 mmHg, or a > 4 mmHg difference in IOP between the eyes. Advanced visual field loss (mean deviation, > 15 dB) or threat to fixation. Corrected visual acuity < 20/40 in either eye. Pigmentary or exfoliative glaucoma. History of angle‐closure or an occludable angle by gonioscopy. Prior filtration surgery or laser iridotomy. Cataract surgery with posterior chamber lens implant performed less than 1 year before enrollment. Argon laser trabeculoplasty performed less than 6 months previously or for an untreated IOP > 21 mmHg. History or signs of inflammatory eye disease, ocular trauma, or potentially progressive retinal disease. History of allergy or intolerance to topical timolol, brimonidine, or to any components of these medications. Resting pulse rate < 50 beats/minute. Severe, unstable, or uncontrolled cardiovascular, renal, or pulmonary disease. Women pregnant, nursing, or contemplating pregnancy."
Interventions	Intervention 1: bilateral treatment with topical brimonidine 0.2% twice daily Intervention 2: bilateral treatment with topical timolol 0.5% twice daily General procedures for all participants: topical ocular hypotensive medications were discontinued prior to study with appropriate washout periods; no other IOP‐lowering agents were allowed during study period
Outcomes	Primary outcome, as defined in baseline paper: "Significant progression of the same two or more points, on the Humphrey glaucoma change probability maps or by Progressor linear regression analysis, in 3 consecutive (over an 8‐month period) Humphrey 24‐2 full threshold fields." Primary outcome, as defined in results paper: "The primary outcome measure was visual field progression in either eye as determined by pointwise linear regression analysis of all study visual fields with Progressor software (Medisoft Inc., Leeds, UK)." Secondary outcome, as defined in results paper: "A secondary outcome was visual field progression in either eye evaluated by Humphrey glaucoma change probability maps (GCPM)." Other measurements taken at baseline and follow‐up visits: "patient reported ocular and systemic events; measurement of blood pressure, pulse, best‐corrected visual acuity, and IOP; slit‐lamp examination; and optic disc evaluation for cup‐to‐disc ratio and the presence or the absence of disc hemorrhage. Gonioscopy and stereoscopic optic disc photographs are performed at yearly intervals. Humphrey achromatic visual fields (full‐threshold 24‐2 program) are performed according to protocol guidelines at 4‐month intervals after randomization." Measurements taken "every 4 months with visual fields and yearly optic disc photographs for a minimum of 4 years." Unit of analysis: individual (patient‐based)
Notes	Study dates: enrollment from June 1998 to August 2000 Funding source(s): Allergan Inc. (Irvine, CA); Chicago Center for Vision Research (Chicago, IL) Conflicts of interest: none reported Publication language: English
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Participants were assigned to 1 of 2 treatment groups, brimonidine tartrate 0.2% or timolol maleate 0.5% (both medications used throughout the study), according to a computer‐generated randomization list stratified by center."
Allocation concealment (selection bias)	Low risk	"The randomization assignment list is maintained and masked study medications are provided directly to the clinical centers by Fountain Valley Pharmacy (Fountain Valley, CA). Optic disc, visual field, and coordinating centers are masked from each other. Data on treatment effects and the randomization code are not provided during the course of the study."
Masking of participants and personnel (performance bias)	Low risk	"Full masking of patients, physicians, technicians, and the reading center for visual fields and optic disc photographs."
Masking of outcome assessment (detection bias)	Low risk	"Full masking of patients, physicians, technicians, and the reading center for visual fields and optic disc photographs." "Data Center for masked computer analysis of the visual fields."
Incomplete outcome data (attrition bias) Exclusion of participants	High risk	"12 randomized patients were subsequently excluded (10 from withdraw of a study site, 1 withdrew consent, and 1 did not meet entry criteria)." "End points requiring withdrawal from the study include the following: (1) treated IOP of more than 21 mmHg that is repeatable within 1 month; (2) visual field progression; (3) development of allergy or intolerance to the study medication; (4) clinical decision by the treating ophthalmologist that it is unsafe for the patient to continue in the study."
Incomplete outcome data (attrition bias) Rates of loss to follow‐up	High risk	"Statistically more subjects assigned to brimonidine (36/99, 36.4%) dropped out prior to the year‐1 examination than assigned to timolol (8/79, 10.1%) (P < .001). The most common reason for discontinuation before the year‐1 examination was localized ocular allergy that necessitated discontinuing the study medication in 20 of the 99 (20.2%) brimonidine and 3 of the 79 (3.8%) timolol subjects (P < .001)."
Incomplete outcome data (attrition bias) Handling of missing data	High risk	"Collection of data from discontinued patients ceased at their final study visit. Data up to this point were included in the analysis, but discontinued patients were no longer followed as part of the study."
Selective reporting (reporting bias)	High risk	Definitions of primary and secondary outcomes differed between baseline paper and results paper. Results that were measured for some outcomes were not reported (i.e. cup‐disc ratio, visual acuity).
Other bias	High risk	"Publication of this article was supported by an unrestricted grant to the Low‐Pressure Glaucoma Study Group from Allergan, Inc, Irvine, California; the Chicago Center for Vision Research, Chicago, Illinois; and an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York (Northwestern University). Study medications were provided by Allergan, Inc. Funding organizations had no role in the design and conduct of the study"

Abbreviations

IOP: intraocular pressure
 LPG: low‐pressure glaucoma

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Alm 2004	Not the population of interest: 5‐year, multicenter, open‐label safety study of adjunctive latanoprost therapy for glaucoma; was excluded because the people included in the study had either POAG or exfoliation glaucoma, and the results for both types were combined.
Anderson 2003	Not the population of interest: RCT evaluating whether the benefit of lowering IOP varies according to certain traits; was excluded because the outcome measured (the benefit of lowering IOP and how it varies according to certain traits) was not predefined as an outcome of interest of this review. Also, it was unclear whether the treatment was topical or oral.
Araie 2010	Short‐term trial: RCT of nipradilol versus timolol in people with NTG. Participants were followed for 3 years.
Araie 2011a	Not a randomized trial: review of pressure‐independent damaging factors of open angle glaucoma
Araie 2011b	Not a randomized trial: review of calcium channel blockers for glaucoma
Blumenthal 2001	Not a randomized trial: review of methods to assess retinal nerve fiber layers for use in trials
Cantor 1997	Not a randomized trial: review of brimonidine, however none of the studies reported met the inclusion criteria for this review.
Cellini 1999	Not a randomized trial: prospective case series of people with ocular hypertension treated with omega‐3 polyunsaturated fatty acids for 3 months
Chader 2012	Not a randomized trial: review of neurotrophic agents used in glaucoma
Changhua 2003	Short‐term trial: evaluation of the neuroprotective effect of Erigeron breviscapus (vant.) Hand. Mazz. (EBHM) on people with IOP‐controlled glaucoma. Participants were followed for 6 months.
Chen 2006	Not a randomized trial: prospective case series of patients switched to unoprostone isopropyl ophthalmic solution (Rescula) after initial treatment with beta‐blockers. Participants were followed for 1 year.
Cho 2010	Short‐term trial: evaluation of fixed combination of brimonidine 0.2%‐timolol 0.5% in people with glaucoma. Participants were followed for up to 6 months.
CNTGS 1998	Not intervention of interest: included any medical and surgical treatment to lower IOP, and was not limited to the agents listed in the protocol.
Cohen 2005	Not a randomized trial: review of ocular hypotensive agents for the treatment of glaucoma and ocular hypertension
Cordeiro 2011	Not a randomized trial: editorial discussing clinical trials for neuroprotection in glaucoma
Costagliola 2014	Short‐term trial: RCT of palmitoylethanolamide versus no palmitoylethanolamide in people with NTG. Participants were followed for 6 months.
Danesh‐Meyer 2011	Not a randomized trial: review of preclinical (animal and cellular) studies for neuroprotection in glaucoma
Drance 1998	Short‐term trial: randomized, masked study of the effects of betaxolol, timolol, and pilocarpine on visual functions in people with OAG over a 24‐month period
EMGT 2002	Not intervention of interest: randomized comparison of the effect of laser trabeculoplasty plus topical betaxolol hydrochloride versus no initial treatment; was excluded because laser trabeculoplasty was not a predefined intervention for this review. Also, this review did not include exfoliation glaucoma.
Eren 2012	Not intervention of interest: cross‐over RCT of dorzolamide/timolol fixed combination compared with latanoprost/timolol fixed combination in people with OAG. Each treatment phase was 6 weeks, with a 6‐week washout period.
Erichev 2016	Short‐term trial: cross‐over RCT of intravenous choline alphoscerate versus oral choline alphoscerate in participants with progressive glaucomatous optic neuropathy. Each treatment phase was 4 months.
Evans 2003	Short‐term trial: RCT of timolol versus brimonidine in POAG. Measurements taken at baseline and 3 months.
Frolov 2011	Short‐term trial: RCT of 1000 mg/day vs 500 mg/day intravenous citicoline for 10 days
Gandolfi 2004	Short‐term trial: RCT of brimonidine 0.2% twice daily vs argon laser trabeculoplasty. Follow‐up was 18 months after randomization.
Garcia‐Medina 2015	Short‐term trial: placebo‐controlled RCT of oral antioxidant supplementation for POAG. Follow‐up was 2 years.
Ge 2008	Not a randomized trial: review of preclinical (animal and cellular) studies for neuroprotection in glaucoma
Guo 2014	Short‐term trial: cross‐over RCT of Ginkgo biloba extract compared with placebo in people with NTG. Each treatment phase was 4 weeks, with an 8‐week washout period.
Harris 1995	Short‐term trial: RCT comparing the effect of selective (betaxolol) and non‐selective (timolol) beta‐adrenergic blocking drugs on flow velocities in orbital vessels in 13 people with NTG. Trial period consisted of a 1‐month drug treatment double‐masked cross‐over design, with a 3‐week washout before each drug was used.
Harris 1999	Short‐term trial: RCT to determine how dorzolamide alters visual function and ocular blood flow in people with NTG. Trial period was 4 weeks.
Hoyng 2002	Not a randomized trial: review of medical treatment for NTG
Iester 2004	Short‐term trial: RCT on short‐term effects after switching or adding bimatoprost in people with POAG. Measurements taken at baseline, 1 h, 2 h, 1 week, 1 month, and 3 months.
Inan 2003	Short‐term trial: randomized, open‐label, parallel study on the effects of latanoprost and brimonidine on blood flow velocity of retrobulbar vessels. Measurements taken at baseline and 3 months.
Kass 1989	Not the population of interest: 5‐year, randomized, double‐masked study on whether treatment with topical timolol maleate was effective in preventing or delaying the onset of glaucomatous visual field loss in participants with ocular hypertension
Kjellgren 1995	Short‐term trial: RCT of latanoprost versus placebo given topically twice a day for 14 days in 20 people with NTG
Koseki 1999	Short‐term trial: RCT to study the effect of oral brovincamine on further deterioration of visual field in people with NTG over a 2‐year period
Liu 2002	Short‐term trial: RCT of latanoprost versus brimonidine in people with NTG. Trial period was 4 weeks.
Ma 2012	Not intervention of interest: RCT of pneumatic trabeculoplasty compared with latanoprost in people with POAG. Measurements were taken up to 6 months after treatment.
Mastropasqua 1998	Short‐term trial: RCT on the effect of acute administration of 1% apraclonidine on visual field parameters. Measurements were taken at baseline and 2 h after administration of drops.
McCarty 2003	Not the population of interest: RCT evaluating the acute neuroprotective qualities of brimonidine during LASIK; people with glaucoma were excluded.
O'Donoghue 2000	Not the population of interest: RCT of latanoprost versus dorzolamide; excluded because the included participants had either POAG or ocular hypertension. Trial period was 3 months.
Park 2011	Short‐term trial: RCT of Ginkgo biloba extract on ocular blood flow in people with NTG. Follow‐up was 2 years.
Pfeiffer 2002	Not the population of interest: RCT of latanoprost and timolol; excluded because the included participants had either POAG or ocular hypertension. Trial period was 6 months.
Roberti 2014	Short‐term trial: RCT of topical citicoline plus hypotensive therapy compared with hypotensive therapy alone in people with OAG. Trial period was 3 months.
Robin 1993	Short‐term trial: RCT of 1% topical apraclonidine in reducing IOP following combined cataract surgery in people with POAG. Measurements were taken at baseline, 24 h, 1 week, 2 weeks, and 4 weeks after surgery.
Rulo 1996	Short‐term trial: RCT evaluating the IOP‐reducing potential and side effects of latanoprost in people with NTG. Trial period was 3 weeks for each treatment (50 μg/mL latanoprost once daily, 15 μg/mL latanoprost twice daily, and placebo).
Sari 2016	Short‐term trial: RCT of Ginkgo biloba extract compared with placebo in people with POAG. Trial period was 6 months.
Sawada 1996	Short‐term trial: RCT of brovincamine fumarate versus placebo for NTG. Participants were followed for 2.5 years.
Wang 2010	Short‐term trial: RCT evaluating the protective effect of yiyanming on the optic nerve of people with POAG and controlled IOP. Participants were followed for 12 weeks.
Wu 2015	Not a randomized trial: cohort of patients with acute angle‐closure glaucoma given nerve growth factor gel or saline after trabeculectomy

Abbreviations

IOP: intraocular pressure
 LASIK: laser‐assisted in‐situ keratomileusis
 NTG: normal‐tension glaucoma
 OAG: open angle glaucoma
 POAG: primary open angle glaucoma
 RCT: randomized controlled trial

Characteristics of studies awaiting assessment [ordered by study ID]

NCT00141882.

Methods	Randomized, double‐blind, placebo‐controlled, parallel‐assignment study (phase III trial). Enrollment: 1100 participants
Participants	Adults (18 to 80 years) with open angle glaucoma Inclusion criteria: glaucoma damage on examination of the visual field and optic disc; good visual acuity (with glasses if needed)
Interventions	3 arms: high‐dose memantine; low‐dose memantine; placebo
Outcomes	Primary outcome: progression of glaucoma
Notes	Study sponsored by Allergan Inc. Study was completed as of 18 December 2007. Study information collected from trial registration and press release by Allergan Inc.

NCT00168350.

Methods	Randomized, double‐blind, placebo‐controlled, parallel‐assignment study (phase III trial). Enrollment: 1100 participants
Participants	Adults (18 to 80 years) with open angle glaucoma Inclusion criteria: glaucoma damage on examination of the visual field and optic disc; good visual acuity (with glasses if needed)
Interventions	3 arms: high‐dose memantine; low‐dose memantine; placebo
Outcomes	Primary outcome: progression of glaucoma
Notes	Study sponsored by Allergan Inc. Study was completed as of 18 December 2007. Study information collected from trial registration and press release by Allergan Inc.

It is not clear which trial numbers correspond to the first study completed and which correspond to the second study completed. Press release only mentions that the results of the second phase III trial differed from the first phase III trial.

Differences between protocol and review

In the protocol and first published version of this review (Sena 2007; Sena 2010), we stated the minimum follow‐up period for eligible studies to be five years. When updating the review in 2012, we modified the minimum follow‐up period to be four years (Sena 2013).

For this update, we included a 'Summary of findings' table and GRADE assessments in accordance with Cochrane standards. We also modified the outcomes to better represent current methods for visual acuity measurements and comparative effective research. Specifically, we changed the visual acuity outcome from the proportion of participants in each Snellen category to the proportion of participants with loss of two or more lines of visual acuity measured by LogMAR chart. We also considered differences between the treated group of participants that developed progressive visual field loss and the untreated group of participants that developed progressive visual field loss as a subgroup rather than as part of the main analyses.

Contributions of authors

First publication of review (2010)

Conceiving the review: DS
 Designing the review: DS, Kanchan Ramchand
 Co‐ordinating the review: DS

Data collection for the review

• Designing and undertaking electronic search strategies: Cochrane Eyes and Vision Group

• Screening search results: DS, Kanchan Ramchand

• Organizing retrieval of papers: DS, KL

• Screening retrieved papers against inclusion criteria: DS, Kanchan Ramchand, KL

• Providing additional data about papers: DS

• Obtaining and screening data on unpublished studies: DS, KL

Data management for the review: DS, KL
 Analysis of data: DS, KL
 Writing the review: DS, KL

Update of review (2017)

Data collection for the review

• Designing and undertaking electronic search strategies: Iris Gordon, Cochrane Eyes and Vision Information Specialist

• Screening search results: DS, KL

• Organizing retrieval of papers: KL

• Screening retrieved papers against inclusion criteria: DS, KL

• Providing additional data about papers: DS

Data management for the review: DS, KL
 Analysis of data: DS, KL
 Writing the review: DS, KL

Sources of support

Internal sources

• No sources of support supplied

External sources

• Grant 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA.

• National Institute for Health Research (NIHR), UK.

  • Richard Wormald, Co‐ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
  • The NIHR also funds the CEV Editorial Base in London.

  The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the Department of Health.

Declarations of interest

DS: none known.
 KL: none known.

New search for studies and content updated (no change to conclusions)