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 commonest 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 can be accompanied by increased intraocular pressure (IOP; i.e. 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.
Glaucoma is the second leading cause of loss of vision in the world (Quigley 2006; Resnikoff 2004), and an increasingly important public health concern due to the aging world population. The World Health Organization (WHO) estimates that 105 million people have glaucoma worldwide and around five million are blind as a consequence (Osborne 2003; Quigley 2006).
Open angle glaucoma is the commonest form of glaucoma in white and African populations, whereas closed angle glaucoma is more common in Asian populations (Bonomi 2002; Tielsch 1991). In the United States, 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 two million individuals in the US, and this number is estimated to increase to more than three million by 2020 because of the rapid aging of the US population (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 considered one of the main risk factors for the development of 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 (near-sightedness) and migraine headaches (Anderson 2003; Armaly 1980; Heijl 2002).
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 if the IOP is within the normal range. This is termed 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 tension glaucoma (HTG) and low tension glaucoma (LTG) is that patients with HTG 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 visualize 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 clinically be detected by specific visual field loss (Schwartz 2000).
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 ever restore it. Most treatment for glaucoma continues to be directed at reducing IOP and slowing the disease progression, although it is also known that 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). Thus, interventions that only focus on reducing IOP may not be beneficial for some glaucoma patients.
Description of the intervention
Treating disease by preventing neuronal death or deterioration has been termed neuroprotection (Levin 1999). Different compounds, 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 B-12 (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 (for example, reducing IOP). This review will consider oral and topical neuroprotective agents for all patients with OAG regardless of IOP.
Neuroprotection occurs in addition to, and as a separate effect from, lowering IOP. If we consider the 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 are consequently targeted by neuroprotective agents, include: (1) the production of external nerve-derived risk factors such as glutamate and nitric oxide (NO); (2) the deprivation of internal trophic (nutritional) factors in the nerve cells; (3) the loss of intracellular self-repair processes; and (4) the 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 lead to preventing 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 what precisely causes 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). This review aims to evaluate the evidence for the effectiveness of neuroprotective agents in treating glaucoma. Consideration of the results of this review may lead health policy planners to improve access to prevention programs for glaucoma.
The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents, either topical or oral, for slowing the progression of OAG in adults.
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) in the review.
Types of participants
We included trials of adults (age 30 years and older) who had OAG with: (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 included:
1. pharmacological antagonists like memantine that inhibit excitotoxicity by binding to NMDA receptors and preventing excitatory activity;
2. alpha 2 adrenergic agonists like brimonidine;
3. calcium channel blocking agents;
4. delivery of brain derived neurotrophic factor (BDNF) to RGC;
5. antioxidant and free radical scavengers;
6. Ginkgo biloba extract;
7. nitric oxide synthetase 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 were compared to one another or different regimens of the same intervention.
Types of outcome measures
The primary outcome for this review was the proportion of participants who developed any progression of visual field loss at follow up five years post intervention. As a result of longer follow up, one is more likely to detect the effect of lowering IOP (AGIS 1994; Nouri-Mahdavi 2004). For this 2012 update of the review, we included a four-year endpoint for visual field loss.
1. Visual acuity: the proportion of participants in each category of visual acuity on the Snellen scale. A 3-line change in visual acuity was considered clinically important. Where visual acuity was measured with a different scale, we planned to convert it to the Snellen scale.
2. Intraocular pressure: differences in mean IOP in the treated group of patients that developed progressive visual field loss and the untreated group of patients that developed progressive visual field loss.
3. Vertical cup-disc ratio: the proportion of participants with asymmetrical vertical cup-disc ratio greater than 0.3.
We reported adverse effects related to the particular treatment reported in the studies included. These included any ocular and systemic side-effects that occurred during the treatment period, tolerability, any abnormal ocular finding or any adverse event. An adverse event is defined as any undesirable event occurring in a participant, whether considered related to the study treatment, or not.
Quality of life measures
We planned to summarize any quality of life data reported in the included studies.
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 include 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.
We included trials with at least five years of follow up to allow for adequate assessment of the effect of neuroprotection on progression of visual field loss. Secondary outcomes were assessed at different follow-up times as available from the included studies. For the 2012 update of the review, we revised the minimum follow-up time to include studies with at least four years of follow up.
Search methods for identification of studies
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 9, part of The Cochrane Library. www.thecochranelibrary.com (accessed 16 October 2012), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2012), EMBASE (January 1980 to October 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 16 October 2012.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (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 through studies that cited the included study to identify additional trials.
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 stated above. We classified the abstracts as 'definitely exclude', 'unsure' or 'definitely include'. We obtained full text copies of those in the 'definitely include' or 'unsure' categories and re-assessed for inclusion. We resolved any disagreements through discussion. When necessary, we contacted the authors of studies labeled as 'unsure' for further clarification. 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 the Cochrane Eyes and Vision Group and adapted for this review. We extracted the following data: country of clinical trial; age and sex 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. It was anticipated that certain parameters, such as visual field, would be measured by various methods in different trials. We resolved any discrepancies between the two review authors by discussion. One review author (KL) entered data into RevMan 5 (RevMan 2011), 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). Methods employed to address the following systematic biases were considered to determine the methodological quality of each study:
a. Selection bias (sequence generation and allocation concealment): any method of allocation concealment such as centralized randomization or use of sequential opaque envelopes, which provide reasonable confidence that the allocation sequence was concealed from participating physicians and patients, was considered to be 'low risk of bias'. If the allocation was based on unconcealed lists or envelopes, or there was no qualifying statement describing allocation, we assessed it as 'unclear risk of bias'.
b. Masking of participants and care providers with regard to treatment allocation to assess for performance bias.
c. Masking of outcome assessors to assess for detection bias.
d. Rates of follow up, reasons for loss to follow up and analysis by the principle of intention-to-treat to assess for attrition bias. We considered a trial to have been analyzed by the principle of intention-to-treat if it analyzed patients as randomized, and included patients for whom no outcome measurements were made, and those who received only part or none of the intended treatment.
e. Selective outcome reporting was examined to assess for reporting bias.
We resolved any disagreement between the review authors through discussion. We did not need to contact the authors of the included study for additional information related to assessing risk of bias.
Measures of treatment effect
As only one study was included in this review, we performed no meta-analysis. If additional studies are included in the future and meta-analysis is 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 will summarize the dichotomous outcomes using risk ratios. We will summarize continuous outcomes as weighted mean differences. We will use the standardized mean difference to summarize outcomes measured on different scales.
Unit of analysis issues
The unit of analysis was the individual.
Dealing with missing data
We did not contact primary investigators from the included study as data were provided in the published reports. If in the future, additional information is needed we will contact primary investigators of trials for missing data.
Assessment of heterogeneity
As only one study was included in this review, we did not assess for heterogeneity across studies. If additional studies are included in the future, we will assess clinical heterogeneity qualitatively before performing statistical tests. If the participants in the included trials differed in any major or obvious way, we will take note and a decision will be made whether or not to perform meta-analysis. We will examine study characteristics and symmetry of the forest plots. We will interpret a poor degree of overlap in the confidence intervals of the studies as the presence of statistical heterogeneity. The effect estimates across studies will be formally tested for inconsistency using the Chi
Assessment of reporting biases
We will use a funnel plot to identify publication bias if ten or more studies are included.
If additional studies are included in the future, and meta-analysis is warranted, we will synthesize data. If the I
We will examine the impact of excluding studies of lower methodological quality, unpublished data and industry-funded studies through sensitivity analyses. We will conduct sensitivity analysis to examine whether the summary effect estimate is influenced by any assumptions that have been made during the review.
Description of studies
Results of the search
The original electronic searches run in 2010 revealed 1500 records of articles, abstracts and reviews. We obtained full text copies of 24 potentially relevant records and re-evaluated for inclusion. We also reviewed 11 additional articles identified from screening the reference lists of full text articles.
Of the 35 full text articles that we reviewed, which reported 29 total studies, none met the inclusion criteria for this review. From 29 studies excluded at this stage: six were not randomized trials; six did not involve patients with OAG or did not limit the study to patients with OAG; two did not compare the interventions of interest for this review; 15 were short-term trials, between two hours and four years, and thus did not meet the five year follow-up period required for this review.
Through a search of the ClinicalTrials.gov database, we identified two phase III trials investigating the effects of memantine in patients 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 were reported to show potential beneficial effects by two review papers (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 patients receiving high-dose memantine compared to patients receiving low-dose memantine, but that there was no significant effect compared to patients receiving placebo. These trials are awaiting classification for inclusion in this review because the follow-up times for outcome measurements are unclear.
On October 16, 2012, the electronic search was updated, and 655 new records were identified. At this time, we modified the eligibility criteria for this review to include studies with four or more years of follow up. Previously, only studies with a minimum of five years follow up were eligible for this review. One of the studies identified from the original electronic searches in 2010 became eligible based on the change to four years follow up (LoGTS 2011). Of the 655 new records identified, we excluded 638 by screening titles and abstracts and 17 were further reviewed by the full text. Of the 17 full text articles reviewed, we excluded 14 and included three in the review. These three records included in the review all reported one study, LoGTS 2011.
Ultimately, one study was included in this review (LoGTS 2011). LoGTS 2011 was a multi-center, randomized controlled trial (RCT) 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 LoGTS 2011 study participants included men and women 30 years of age or older with untreated glaucoma of 21 mmHg or less IOP. 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 were randomized to receive brimonidine tartrate 0.2% monotherapy (Alphagan; Allergan, Inc, Irvine, California, USA) and 79 were 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 applied bilaterally twice a day. 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 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 data. The primary outcome of the study was visual field progression.
Forty-one studies were excluded from the review following full text assessment. The reasons for exclusion included: 12 were not randomized trials; six did not involve patients with OAG, or did not limit the study to patients with OAG; two did not compare the interventions of interest for this review; and 21 were short-term trials, between two hours and three years, and thus did not meet the four year follow-up period required for inclusion in the update of this review.
See: 'Characteristics of excluded studies' for further details.
Risk of bias in included studies
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 study to have low risk of selection bias related to sequence generation and allocation concealment.
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. Further, analysis of visual fields, the primary outcome of the trial, was masked. For these reasons we assessed the study to have low risks of performance bias and detection bias.
Incomplete outcome data
To assess for risk of attrition bias, we considered:
- exclusion of participants after randomization;
- rates of loss to follow up;
- handling of missing data.
The total number of participants stated as enrolled in the study differs 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. Ideally, participants should not be excluded from the study after randomization.
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 value < 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 than the timolol group (20/99 participants in brimonidine group compared with 3/79 participants in timolol group). At four years of follow up, 54/99 (55%) participants in brimonidine group and 23/79 (29%) participants in timolol group were lost to follow up (P value < 0.001).
In reference to the study design of LoGTS 2011, participants were withdrawn from the study if: their IOP increased to more than 21 mmHg; they had visual field progression; developed allergy or intolerance to a study medication; or the treating ophthalmologist decided that the participants should be discontinued from the study. In order to prevent biased study results, participants should not be excluded from clinical trials by the study investigators and should remain in the study, even if discontinuing study interventions, as part of the intent-to-treat population. The proportion of participants analyzed at the four-year endpoint for the primary visual field outcome was 45/99 (45%) in the brimonidine group and 56/79 (71%) in the timolol group. Thus, data were missing for 89/190 (47%) participants at the four-year follow up and no conclusions can be drawn from this study with regard to neuroprotective effects for the participants with missing data.
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 high risk of attrition bias.
The authors of LoGTS 2011 only specified primary and secondary outcomes related to visual field progression and these 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 were recorded at follow-up visits such as IOP, visual acuity, changes to optic nerve structure, and cup-disc ratio. Due to the variation in outcome definitions between the published reports, and the non-reporting of other outcomes that were measured and are common for glaucoma trials, we assessed the study to have a high risk of reporting bias.
Other potential sources of bias
Inclusion criteria allowed one eye or both eyes of participants to be included in this study and non-independence of eyes were taken into account when both eyes were included. Although the study was "patient-based", visual field progression was based on the first eye with progression when both eyes were included. The authors did not report results for progression in the second eye if one eye progressed.
The study was partially funded by Allergan, Inc (Irvine, California) by an unrestricted grant and by providing study medications. Additional funding support included an unrestricted grant from Research to Prevent Blindness, Inc (New York, New York).
Due to issues related to the unit of analysis and sources of funding, we assessed the study to have other potential sources of bias.
Effects of interventions
Brimonodine 0.2% versus timolol 0.5%
Visual field progression
Visual field progression was the primary outcome of LoGTS 2011. Three methods were used to measure visual field progression:
- Progressor pointwise linear regression analysis;
- Humphrey glaucoma change probability maps (GCPM) using pattern deviation; and
- the 3-omitting method for pointwise linear regression analysis.
Agreement among the three methods for detecting visual field progression 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 GCPM and 3-omitting method (kappa of 0.554, SE = 0.079).
At the four-year follow up, 5/45 participants in the brimonidine group and 18/56 participants in the timolol group had visual field progression detected by all three methods (risk ratio (RR) 0.35; 95% confidence interval (CI) 0.14 to 0.86). These results, however, 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).
Based on visual field progression detected by the Progressor pointwise linear regression analysis method, there were nine participants in the brimonidine group and 31 participants in the timolol group with visual field progression at four years. The Snellen decimal fraction acuity did not significantly change from baseline among the nine brimonidine participants with visual field progression (mean acuity ± standard deviation (SD) = 0.92 ± 0.21 at baseline and 0.89 ± 0.21 at time of progression, P value > 0.05), whereas the 31 timolol participants with visual field progression had decreased Snellen decimal acuity compared with baseline (mean acuity ± SD = 0.92 ± 0.21 at baseline and 0.82 ± 0.19 at time of progression, P value 0.008).
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 visual field progression, participants completing the four-year follow up without visual field progression, or participants who did not complete the one-year follow up.
At the four-year follow up, mean IOP was similar in both groups. Mean IOP was 14.2 mmHg (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 (MD) 0.20 mmHg; 95% CI -0.73 to 1.13). 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 with visual field loss, as determined by Progressor pointwise linear regression analysis, had IOP reduction of 20% or greater at time of progression (RR 1.15; 95% CI 0.49 to 2.70).
Vertical cup-disc ratio
Vertical cup-disc ratio outcomes were not reported by LoGTS 2011.
The most common adverse effect was ocular allergy to the study medication requiring discontinuation. This adverse effect occurred more with brimonidine (20/99 participants in the brimonidine group discontinued the study for this reason) compared with timolol (3/79 participants in the timolol group 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).
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 only to 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 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 modifying the eligibility criteria of the review to include studies with four or more years of follow up (previously minimum follow-up period was five years), we identified and included one randomized controlled trial comparing brimonidine 0.2% with timolol 0.5% (LoGTS 2011). There were 99 participants randomized to the brimonidine monotherapy group and 79 participants randomized to the timolol monotherapy group. Although results at the four-year follow up suggested brimonidine may slow or prevent visual field progression over timolol (65% decreased risk of visual field progression in the brimonidine group compared with the timolol group; 95% CI 14% to 86%), 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). Subgroup analyses of participants with visual field progression, participants who completed the study without visual field progression, and participants not completing the study did not show any statistical differences between treatment groups in terms of linear regression slopes of the Snellen decimal visual acuity fraction. At the four-year follow up, mean IOP was similar in both groups. The study did not report vertical cup-disc ratio outcomes. Adverse events occurred more often in the brimonidine group compared with the timolol group, with ocular allergy to the study medication requiring discontinuation being the most common adverse event (5.32 times more in the brimonidine group compared with the timolol group; 95% CI 1.64 to 17.26).
Overall completeness and applicability of evidence
The conditions covered by this 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, 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 did not report the correlation between visual field function and optic nerve structure changes in their results paper. It would be interesting to compare optic nerve or retinal nerve fiber layer (RNFL) changes, or both, with the visual field changes.
We defined the primary outcome for this review as the proportion of patients who developed any progression of visual field loss at follow up four years post intervention. 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. Mean change in IOP, however, was included 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 (CNTGS 1998) showed that a 30% reduction in IOP had significant benefit and, since that time a 30% reduction in IOP has become the standard of glaucoma care because it is a strong predictor of glaucomatous damage. The study design of LoGTS 2011 allowed participants with any pressure below 21 mmHg to be eligible and IOP data are reported only for those with 20% reduction in IOP and visual field progression.
After one year, 36/99 (36%) participants in the brimonidine group and 8/79 (10%) participants in the timolol group were lost to follow up, and by four years, 54/99 (55%) participants in the brimonidine group and 23/79 (29%) participants in the timolol group were lost to follow up. Due to the great amount of attrition, we cannot conclude that brimonidine is more effective than timolol, since there could have been more progressors in those lost to follow up; therefore, the study results may not apply to individuals in a clinical setting.
Quality of the evidence
As noted above, there was a differential amount of missing data between treatment groups during the study, specifically 55% of participants in the brimonidine group and 29% of participants in the timolol group at four years. The high attrition rate and the difference in attrition between groups introduce a high risk of attrition bias to the study results. In the case of the brimonidine group, data are missing for the majority of participants, making results from this study inconclusive.
The study criteria allowed one eye or both eyes of participants to be included in this study. Although eyes could be interconnected, there was no accounting for non-independence between eyes. Participants were dropped from the study once visual field progression 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 results paper. Results for some outcomes measured were not reported (i.e., cup-disc ratio, visual acuity). The primary outcome as defined in the baseline paper was "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." The primary outcome as defined in the results paper 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)", with the secondary outcome specified as "visual field progression in either eye evaluated by Humphrey glaucoma change probability maps (GCPM)." It was not explained why the outcome definitions were changed. Also results for some outcomes 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 biases in the review process by conducting an extensive, highly sensitive search of the literature. All steps in screening references, extracting data, and assessing studies were done in duplicate by two review authors independently. Along with including content experts and methodologists in the review team, we consulted with glaucoma specialists 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 post intervention in order to assess the long-term effects of neuroprotection. As such we excluded 21 potentially relevant trials, ranging from two hours to three years follow up. Five of these studies reported results for visual outcomes at follow up times two years or greater (Araie 2010; Drance 1998; Garcia-Medina 2011; Koseki 1999; Sawada 1996).
The excluded study with the longest follow up time, of 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 rates of visual field loss among participants given nipradilol 0.25% versus timolol 0.5%. Of the 158 participants randomized, 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 form the study 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 dB/year in nipradilol group and −0.05 ± 0.06 dB/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 value ≤ 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 value 0.005 for participants with stage 1 classification; mean deviation 0.15 in nipradilol group versus -0.23 in timolol group, P value 0.039 for participants 40 years or younger).
The study with the second longest follow up time, of two and half years, also was conducted in Japan by Sawada and colleagues (Sawada 1996). It 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. In reference to visual fields analysis, 6/14 eyes had visual field improvement and 8/14 had no improvement at all. In the control group, 12/14 had no visual fields changes and 2/14 had an increased visual field loss. This study reported a beneficial effect of brovincamine on visual field in some patients with NTG; however, the study was not able 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, since brovincamine became 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 to 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.
The effects of betaxolol, timolol and pilocarpine on visual functions in patients with OAG were examined in Drance 1998. In total, 68 patients 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 two years or greater was Garcia-Medina 2011. Participants with POAG 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. After two years, the authors reported no difference in visual field global indices between the treatment groups. This study was presented as a conference abstract, and the full report has yet to be published.
Two potentially relevant phase III trials assessing the effects of memantine in patients with chronic glaucoma were identified during this review (NCT00141882; NCT00168350). Memantine has been theorized to be a promising neuroprotective agent for the treatment of glaucoma that may work by blocking N-methyl-D-aspartate (NMDA) glutamate receptors that 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, our review did not identify any clinical trials that establish evidence for neuroprotective benefits on visual field loss progression in OAG.
Implications for practice
Recently, there has been a growing interest in using neuroprotective drugs for the treatment of glaucoma. Neuroprotective agents such as: (1) pharmacological-antagonists that inhibit excitotoxicity by activation, and N-methyl D-aspartate (NMDA) receptors like memantine; (2) alpha 2 adrenergic agonists like brimonidine; (3) calcium channel blocking agents; (4) deliverers of brain derived neurotrophic (BDNF) factor to retinal ganglion cells (RGCs); (5) antioxidants and free radical scavengers; (6) Ginkgo biloba extract and (7) nitric oxide synthetase inhibitors have shown promise in preventing or slowing RGC death in preclinical studies. At this time, however, it has not been shown that topical or oral neuroprotective agents are effective in preventing RGC death or in preserving the visual field in patients 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 barriers for research to overcome (e.g., long-term follow up of participants; selecting patient-important outcomes; variability of disease symptoms, etc.). Potential studies in this area should be designed to measure clinically meaningful outcomes, such as progression of visual field loss, in order to guide 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 (termed detection of apoptosing retinal cell or DARC), may be useful quantitative measurements to assess neuroprotection in glaucoma patients.
As intraocular pressure (IOP) remains a standard measure in glaucoma research, consideration should be paid to assessing the variation of IOP. 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 RCT 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) RCTs, 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 RCT.
We thank Dr Roberta Scherer, Dr Jayter Silva de Paula and Dr Maria de Lourdes Veronesse Rodrigues for their comments on this review. We also acknowledge Swaroop Vedula, Xue Wang, and Anupa Shah for their assistance with the preparation of this review. We thank Iris Gordon for creating and executing the search strategies and Nancy Fitton for editing the Plain Language Summary.
We acknowledge Kanchan Ramchand for contributions to the first publication of this review (Sena 2010).
Data and analyses
This review has no analyses.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor Glaucoma
#3 (#1 OR #2)
#4 MeSH descriptor Neuroprotective Agents
#6 MeSH descriptor Retinal Ganglion Cells
#7 ganglion near cell*
#8 retina* near cell*
#10 MeSH descriptor Optic Nerve Diseases
#11 optic near neuropath*
#12 MeSH descriptor 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 (OvidSP) search strategy
1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp glaucoma/
16. exp neuroprotective agents/
18. exp retinal ganglion cells/
19. (ganglion adj2 cell$).tw.
20. (retina$ adj2 cell$).tw.
22. exp optic nerve disease/
23. (optic adj2 neuropath$).tw.
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 et al (Glanville 2006).
Appendix 3. EMBASE (OvidSP) search strategy
1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
7. (animal or animal experiment).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$)).tw.
15. exp placebo/
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp glaucoma/
36. exp neuroprotective agent/
38. exp retinal ganglion cell/
39. (ganglion adj2 cell$).tw.
40. (retina$ adj2 cell$).tw.
42. exp optic nerve disease/
43. (optic adj2 neuropath$).tw.
47. 35 and 46
48. 32 and 47
Appendix 4. LILACS search strategy
glaucoma$ and neuroprotect$ or memantine
Appendix 5. metaRegister of Controlled Trials search strategy
(neuroprotection or memantine) and glaucoma
Appendix 6. ClinicalTrials.gov search strategy
glaucoma and neuroprotection
glaucoma and memantine
Appendix 7. ICTRP search strategy
glaucoma = Condition AND neuroprotection or memantine = Intervention
Last assessed as up-to-date: 16 October 2012.
Protocol first published: Issue 2, 2007
Review first published: Issue 2, 2010
Contributions of authors
First publication of review (2010)
Conceiving the review: DS
Designing the review: DS, KR
Coordinating the review: DS
Data collection for the review
- Designing and undertaking electronic search strategies: Cochrane Eyes and Vision Group
- Screening search results: DS, KR
- Organizing retrieval of papers: DS, KL
- Screening retrieved papers against inclusion criteria: DS, KR, 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 (2012)
Data collection for the review
- Designing and undertaking electronic search strategies: Cochrane Eyes and Vision Group
- 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
Declarations of interest
Sources of support
- No sources of support supplied
- Contract N-01-EY-2-1003, National Eye Institute, National Institutes of Health, USA.2010 first publication of review
- Grant 1 U01 EY020522-01, National Eye Institute, National Institutes of Health, USA.2012 update of review
Differences between protocol and review
We stated the minimum follow-up period to be five years for eligible studies in the protocol (Issue 2, 2007) and first published version (Issue 2, 2010) of this review. In updating the review in 2012, we modified the minimum follow-up period to four years.
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, Eichler HG. Interventions for normal tension glaucoma. Cochrane Database of Systematic Reviews 2003, Issue 1.
- The review by Sycha et al. was withdrawn from publication in the Database of Systematic Reviews.
Medical Subject Headings (MeSH)
Antihypertensive Agents [*therapeutic use]; Disease Progression; Glaucoma, Open-Angle [*drug therapy]; Neuroprotective Agents [*administration & dosage]; Optic Nerve; Optic Nerve Diseases [etiology; prevention & control]; Quinoxalines [therapeutic use]; Randomized Controlled Trials as Topic; Retinal Ganglion Cells [physiology]; Timolol [therapeutic use]
MeSH check words
* Indicates the major publication for the study