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Neuroprotection for treatment of glaucoma in adults

  1. Dayse F Sena1,*,
  2. Kristina Lindsley2

Editorial Group: Cochrane Eyes and Vision Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 16 OCT 2012

DOI: 10.1002/14651858.CD006539.pub3


How to Cite

Sena DF, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD006539. DOI: 10.1002/14651858.CD006539.pub3.

Author Information

  1. 1

    Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA

  2. 2

    Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, Maryland, USA

*Dayse F Sena, Massachusetts Eye and Ear Infirmary, 243 Charles St, Connecting Building 703, Boston, Massachusetts, 02114, USA. sena.dayse@gmail.com. sena.dayse@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by study ID]
LoGTS 2011

MethodsStudy 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 one year, 36/99 (36%) participants in brimonidine group and 8/79 (10%) participants in timolol group were lost to follow up; at four years, 54/99 (55%) participants in brimonidine group and 23/79 (29%) participants in timolol group were lost to follow up.

Study follow up: planned follow up was four years  .

Sample size calculation: 64 participants for 80% power to detect outcome differences between groups.


ParticipantsCountry: USA (13 clinical centers).

Age (mean ± SD): 64.9 ± 10.7 years.

Gender: women (n = 113; 59.5%) and 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."


InterventionsIntervention 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.


OutcomesPrimary 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).


NotesStudy 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

BiasAuthors' judgementSupport 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 riskDefinition of primary and secondary outcomes differed between baseline paper and results paper. Results for some outcomes measured were not reported (i.e., cup-disc ratio, visual acuity).

Other biasHigh 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"

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alm 2004Not 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 were combined for both types.

Anderson 2003Not the population of interest: RCT to study whether the benefit of lowering IOP varies according to certain traits; was excluded because the outcome measured (the benefit of lowering of IOP and how it varies according to certain traits) was not predefined as an outcome of interest of this review. Also the type of treatment used, topical or oral, was not clear.

Araie 2010Short-term trial: RCT of nipradilol versus timolol in patients with normal-tension glaucoma. Participants were followed for three years.

Araie 2011aNot a randomized trial: review of pressure-independent damaging factors of open angle glaucoma.

Araie 2011bNot a randomized trial: review of calcium channel blockers for glaucoma.

Blumenthal 2001Not a randomized trial: review of methods to assess retinal nerve fiber layers for use in trials.

Cantor 1997Not a randomized trial: review of brimonidine; however, none of the studies reported met the inclusion criteria for this review.

Cellini 1999Not a randomized trial: prospective case series of people with ocular hypertension, treated with omega-3 polyunsaturated fatty acids for three months.

Chader 2012Not a randomized trial: review of neurotrophic agents used in glaucoma.

Changhua 2003Short-term trial: evaluation of the neuroprotection effect of Erigeron breviscapus (vant) Hand. Mazz. (EBHM) on patients with IOP controlled-glaucoma. Participants were followed for six months.

Chen 2006Not a randomized trial: prospective case series of patients switched to Resula after initial treatment with beta-blockers. Patients were followed for one year.

Cho 2010Short-term trial: evaluation of fixed combination of brimonidine 0.2%-timolol 0.5% nipradilol in patients with glaucoma. Participants were followed for up to six months.

CNTGS 1998Not intervention of interest: included any medical and surgical treatment to lower IOP, and was not limited to the agents listed in the protocol.

Cohen 2005Not a randomized trial: review of ocular hypotensive agents for the treatment of glaucoma and ocular hypertension.

Cordeiro 2011Not a randomized trial: editorial discussing clinical trials for neuroprotection in glaucoma.

Danesh-Meyer 2011Not a randomized trial: review of pre-clinical (animal and cellular) studies for neuroprotection in glaucoma.

Drance 1998Short-term trial: randomized, masked study of the effects of betaxolol, timolol, and pilocarpine on visual functions in OAG patients over a 24-month period.

EMGT 2002Not intervention of interest: randomized comparison of the effect of laser trabeculoplasty plus topical betaxolol hydrochloride or no initial treatment; was excluded because laser trabeculoplasty was not a predefined intervention for this review. Also exfoliation glaucoma was not included in this review.

Evans 2003Short-term trial: RCT of timolol versus brimonidine in POAG. Measurements taken at baseline and three months.

Frolov 2011Short-term trial: RCT of 1000 mg/day vs 500 mg/day intravenous citicoline for 10 days.

Gandolfi 2004Short-term trial: RCT of brimonidine 0.2% twice daily vs argon laser trabeculoplasty. Follow up was 18 months after randomization.

Garcia-Medina 2011Short-term trial: placebo-controlled RCT of oral antioxidant supplementation for POAG. follow up was 2 years.

Ge 2008Not a randomized trial: review of pre-clinical (animal and cellular) studies for neuroprotection in glaucoma.

Harris 1995Short-term trial: RCT comparing the effect of selective (betaxolol) and nonselective (timolol) beta-adrenergic blocking drugs on flow velocities in orbital vessels in 13 patients 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 1999Short-term trial: RCT to determine how dorzolamide alters visual function and ocular blood flow in patients with NTG. Trial period was 4 weeks.

Hoyng 2002Not a randomized trial: review of medical treatment for NTG.

Iester 2004Short-term trial: RCT on short-term effects after switching or adding bimatoprost in POAG patients. Measurements taken at baseline, 1 h, 2 h, 1 week, 1 month and 3 months.

Inan 2003Short-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 1989Not 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 1995Short-term trial: RCT of latanoprost versus placebo given topically twice a day for 14 days in 20 patients with normal pressure glaucoma.

Koseki 1999Short-term trial: RCT to study the effect of oral brovincamine on further deterioration of visual field in patients with NTG over a 2-year period.

Liu 2002Short-term trial: RCT of latanoprost versus brimonidine in patients with NTG. Trial period was 4 weeks.

Mastropasqua 1998Short-term trial: RCT on the effect of acute administration of 1% apraclonidine on visual field parameters. Measurements taken at baseline and 2 h after administration of drops.

McCarty 2003Not the population of interest: RCT evaluating the acute neuroprotective qualities of brimonidine during LASIK, glaucoma patients were excluded.

O'Donoghue 2000Not the population of interest: RCT of latanoprost versus dorzolamide; excluded because the participants included in the study had either POAG or ocular hypertension. Trial period was 3 months.

Park 2011Short-term trial: RCT of Ginkgo biloba extract on ocular blood flow in patients with NTG. Follow up was 2 years.

Pfeiffer 2002Not the population of interest: RCT of latanoprost and timolol; excluded because the participants included in the study had either POAG or ocular hypertension. Trial period was 6 months.

Robin 1993Short-term trial: RCT of 1% topical apraclonidine in reducing IOP following combined cataract surgery in POAG patients. Measurements taken at baseline, 24 h, 1 week, 2 weeks and 4 weeks after surgery.

Rulo 1996Short-term trial: RCT evaluating the IOP-reducing potential and side effects of latanoprost in patients with normal pressure glaucoma. Trial period was 3 weeks for each treatment (50 μg/ml latanoprost once daily, 15 μg/ml latanoprost twice daily, and placebo).

Sawada 1996Short-term trial: RCT of brovincamine fumarate versus placebo for NTG. Patients were followed for 2.5 years.

Wang 2010Short-term trial: RCT evaluating the protective effect of yiyanming on the optic nerve of POAG patients with controlled IOP. Participants were followed for 12 weeks.

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT00141882

MethodsRandomized, double-blind, placebo-controlled, parallel assignment study (phase III trial).

Enrollment: 1100 participants.

ParticipantsAdults (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).

Interventions3 arms: high-dose memantine; low-dose memantine; and placebo.

OutcomesPrimary outcome: progression of glaucoma.

NotesStudy 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

MethodsRandomized, double-blind, placebo-controlled, parallel assignment study (phase III trial).

Enrollment: 1100 participants.

ParticipantsAdults (18-80 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).

Interventions3 arms: high-dose memantine; low-dose memantine; and placebo.

OutcomesPrimary outcome: progression of glaucoma.

NotesStudy sponsored by Allergan, Inc.

Study was completed as of 18 December 2007.

Study information collected from trial registration and press release by Allergan, Inc.