Medical interventions for primary open angle glaucoma and ocular hypertension

Clemens Vass; Cornelia Hirn; Thomas Sycha; Oliver Findl; Stefan Sacu; Peter Bauer; Leopold Schmetterer

doi:10.1002/14651858.CD003167.pub3

Intervenciones médicas para el glaucoma de ángulo abierto primario y la hipertensión ocular

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Referencias

References to studies included in this review

Ir a:

estudios excluidos
estudios a la espera de valoración
otras referencias

Alexander DW, Berson FG, Epstein DL. A clinical trial of timolol and epinephrine in the treatment of primary open‐angle glaucoma. Ophthalmology 1988;95(2):247‐51.

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Enlace al artículo

The European Glaucoma Prevention Study Group. Results of the European glaucoma prevention study. Ophthalmology 2005;112(3):366‐75.

Enlace al artículo

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References to studies excluded from this review

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estudios incluidos
estudios a la espera de valoración
otras referencias

Araie M, Azuma I, Kitazawa Y. Influence of topical betaxolol and timolol on visual field in Japanese open‐angle glaucoma patients. Japanese Journal of Ophthalmology 2003;47(2):199‐207.

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Hyman LG, Komaroff E, Heijl A, Bengtsson B, Leske MC. Treatment and vision‐related quality of life in early manifest glaucoma trial. Ophthalmology 2005;112(9):1505‐13.

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References to studies awaiting assessment

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estudios incluidos
estudios excluidos
otras referencias

Canadian Glaucoma Study Group. Canadian Glaucoma Study: 1. Study design, baseline characteristics, and preliminary analyses. Canadian Journal of Ophthalmology 2006;41(5):566‐75.

Enlace al artículo

Hommer A, Ganfort Investigators Group I. A double‐masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03% timolol 0.5% with non‐fixed combination use in patients with glaucoma or ocular hypertension. European Journal of Ophthalmology 2007;17(1):53‐62.

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Additional references

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estudios incluidos
estudios excluidos
estudios a la espera de valoración

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Alexander 1988

Methods	RCT. Open label. Active controlled.
Participants	47 participants with newly diagnosed OAG or OHT. 50% of participants included with both eyes (mean of both eyes). 6/24 timolol and 8/23 epinephrine patients were African American. Inclusion criteria: normal Goldmann visual fields and either 1) IOP between 25 and 29 mmHg and wide disc cupping or cupping asymmetry, or 2) IOP between 30 and 35 mmHg with normal optic discs. Exclusion criteria: ocular inflammation, recent ocular surgery or trauma, previous glaucoma therapy.
Interventions	Timolol 0.5% twice daily. Epinephrine 1% twice daily
Outcomes	Incidence of optic cup enlargement or disc haemorrhage (stereophoto). Incidence of reproducible visual field defect. Incidence of failure to achieve an IOP reduction of 20%.
Notes	Mean follow up 33 months. Failures were analysed on patient basis. No drop‐outs, but 18 IOP failures: 7 timolol group, 11 epinephrine group. 5 patients originally assigned to timolol group (1 topical and 4 systemic side effects), and 4 patients of the epinephrine group (local or systemic side effects) switched the group. For failure analysis they were analysed in their original group (intent to treat).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Collignon‐Brach 1992

Methods	RCT. Open label. Active controlled.
Participants	20 people with POAG. Racial constitution is not reported. Inclusion criteria: Untreated IOP of at least 20 mmHg in at least one eye. Exclusion criteria: concomitant ocular or systemic disease.
Interventions	Timolol 0.5% twice daily. Betaxolol 0.5% twice daily.
Outcomes	Change of visual field mean sensitivity, IOP.
Notes	2 years follow up Drop‐out rate is not reported. Authors do not state whether the visual field data are those from one of the eyes, or they did use the mean values of both eyes for analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Collignon‐Brach 1994

Methods	RCT. Open label. Active controlled.
Participants	19 people with OHT or POAG (n=5). Racial constitution is not reported. Inclusion criteria: untreated IOP of at least 20 mmHg in at least one eye. Exclusion criteria: any other significant ocular pathology.
Interventions	Timolol 0.5& twice daily. Betaxolol 0.5% twice daily.
Outcomes	Change of visual field mean sensitivity. IOP.
Notes	4 years follow up. Drop‐out rate was 4 of 19 patients for both groups together, not specified for the groups separately. The authors state that there was no drop‐out due to drug‐related adverse events. Visual field data were averaged for both eyes of each patient.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Drance 1998

Methods	RCT. Partially masked. Active controlled.
Participants	68 people with POAG, proportion of PEX and PDS unknown. 7% African American. inclusion criteria: IOP equal or above 24 mmHg, disc and visual field abnormality, PEX and PG allowed. Exclusion criteria: history of ocular trauma, uveitis, inflammatory disease and recent ocular infection, intraocular surgery within 6 months and laser trabeculoplasty within 3 months, systemic glucocorticoids and medication that may affect IOP.
Interventions	Timolol 0.5% BID. Betaxolol 0.5% BID. Pilocarpine 2% 4 times daily.
Outcomes	Change in visual field mean defect. IOP.
Notes	2 years follow up. Timolol and betaxolol masked, pilocarpine open label. No difference between groups. Drop‐outs due to drug‐related adverse events: 5 timolol, 1 betaxolol, 3 pilocarpine (unspecified whether local or systemic side effects).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

EGPS 2005

Methods	RCT. Double‐masked. Placebo controlled. Multicenter (18).
Participants	1081 people with OHT. 99.9% caucasian. Inclusion criteria: IOP between 22 and 29 mmHg, 2 normal and reliable visual fields, normal optic discs (stereophoto), PEX allowed (below 2%), normal optic discs in both eyes (stereophoto), open angle, PEX and PDS allowed. Exclusion criteria: visual acuity below 20/40, previous intraocular surgery, previous laser trabeculoplasty within 3 months, secondary causes of elevated IOP.
Interventions	Dorzolamide 2% 3 times daily. Placebo.
Outcomes	Incidence of reproducible visual field defects. Incidence of reproducible optic disc changes (stereophoto).
Notes	Median follow up 55.3 months. 338 drop‐outs: 192 dorzolamide group (116 adverse events), 146 placebo group (51 adverse events). PEX and pigment dispersion in both groups 1 to 2 percent.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Epstein 1989

Methods	RCT. Open label.
Participants	107 participants with OHT. 16/107 patients had only 1 eye included. Analysis was always based on patient not eye, if both eyes were included. 6/53 patients in timolol group and 15/54 untreated were African American. Inclusion criteria: IOP between 22 and 28 mmHg, normal Goldmann visual fields, normal optic disc. Exclusion criteria: previous ocular surgery, progressive retinopathy.
Interventions	Timolol 0.5% twice daily. No treatment.
Outcomes	Incidence of IOP above 32 mmHg on two separate occasions. Incidence of optic cup enlargement (masked stereophoto). Incidence of reproducible visual field progression on Goldmann perimeter or of progressive damage on computerized static perimetry.
Notes	Mean follow up was 56 months in timolol group and 51 months in untreated group. 23 drop‐outs: 11 timolol group and 12 untreated group (timolol: 1 local and 9 systemic adverse events). Additionally 5 patients failed the IOP criterion (all untreated) and 5 patients were "escape hatched" (3 timolol and 2 untreated) because the examiner believed that the patient's vision was at risk. During the trial period computerized static perimetry was introduced and additionally used. Some of the patients might have had early POAG instead of OHT when analysed with computer perimetry. 2/4 timolol treated patients who developed visual field defects did so after discontinuation of treatment for adverse reaction or pregnancy.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Fama 1996

Methods	RCT. Active controlled.
Participants	36 people with OAG. Racial constitution is not reported. Inclusion criteria: unknown whether PEX or PDS were included, IOP above 23 mmHg without therapy, initial glaucomatous visual field defects, clinical signs of glaucomatous optic nerve damage. Exclusion criteria: active ocular infection or inflammation, acute or progressive retinal disorder, current use of systemic beta‐blocker.
Interventions	Timolol 0.5% twice daily. Betaxolol 0.5% twice daily. Carteolol 2% twice daily.
Outcomes	Change of visual field mean sensitivity. IOP. Corneal sensitivity. Tear production.
Notes	12 months follow up. No drop‐outs occurred. The authors do not state whether they analysed the mean sensitivities of both eyes of each patient.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Flammer 1992

Methods	RCT. Double‐masked. Active controlled.
Participants	120 patients with OAG (72 were evaluated). Both eyes of all patients included, analysis based on patient. Racial constitution is not reported. Inclusion criteria: IOP greater than 21 mmHg, visual field damage (MD greater 2 dB or CLV greater 7 dB). Exclusion criteria: visual acuity below 0.8, pupil diameter below 2.5 mm, any other type of ocular disease, diabetes mellitus, systemic hypotension, systemic drugs that might influence the IOP.
Interventions	Timolol 0.5% twice daily. Carteolol 2% twice daily.
Outcomes	Change of visual field mean sensitivity. Incidence of glaucomatous progression. IOP.
Notes	12 months follow up. Of the originally included 120 patients, 21 did not complete it (1 patient in carteolol group systemic adverse event). Additionally a further 27 patients were excluded after the end of follow up, because they did not match the protocol or had unreliable visual field exams.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Geyer 1988

Methods	RCT. Double‐masked. Active controlled.
Participants	51 participants with OAG or OHT (1 patient). Racial constitution is not reported. Inclusion criteria: IOP 23 mmHg or higher. Exclusion criteria: secondary glaucoma, angle closure glaucoma, c/d ratio of more than 0.7 in either eye, aphakia, chronic ocular inflammation, systemic beta‐blockers.
Interventions	Timolol 0.5% twice daily. Levobunolol 0.5% twice daily. Levobunolol 1% twice daily.
Outcomes	IOP control. Cup/disc‐ratio (direct ophthalmoscopy). Incidence of glaucomatous visual field defect (Goldmann).
Notes	Allocation concealment deemed likely, based on double‐masked design. 4 years follow up. 14 drop‐outs: 6 levobunolol 0.5% (3 drug‐related adverse events), 6 levobunolol 1% (1 drug‐related adverse effect), 2 timolol (not drug‐related). Between 41% and 53% of the participants terminated their participation due to inadequate IOP control, resulting in successful completion of the study by only 23%‐24% and 35% of patients in the 3 groups.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Heijl 2000

Methods	RCT. Double‐masked. Placebo controlled.
Participants	90 people with OHT, 37% (timolol group) and 23% (placebo group) had PEX or PDS. Racial constitution is not reported. Inclusion criteria: mean untreated IOP of 22 mmHg or more, normal visual fields (Competer and Goldmann), open angles by gonioscopy, one of the following risk factors: suspicious disc, positive family history, PEX or pigment dispersion syndrome, diabetes, mean IOP of at least 27 mmHg without additional risk factors. Exclusion criteria: mean untreated IOP of 35 mmHg or above, medication known to affect IOP, history of intraocular surgery, visual acuity of 0.3 or less.
Interventions	Timolol 0,5% twice daily. Placebo.
Outcomes	Incidence of glaucomatous visual field defect.
Notes	10 years follow up, for better comparability with the other trials data concerning 5 years follow up were used for meta‐analysis. 49 drop‐outs within 10 years (26 timolol: 2 due to adverse reaction; 23 placebo: 1 due to adverse reaction). 33 drop‐outs within 5 years (19 timolol: 2 due to adverse reaction; 14 placebo: not related to adverse reactions).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Kaiser 1994

Methods	RCT. Double‐masked until 18 months. Active controlled.
Participants	44 participants, all Caucasian. Inclusion criteria: POAG with IOP at least 24 mmHg, early glaucomatous field defect. Exclusion criteria: diabetes mellitus, other local treatment or systemic medication with beta‐blockers, previous laser treatment or glaucoma surgery.
Interventions	Timolol 0.5% twice daily. Betaxolol 0.5% twice daily.
Outcomes	Change of visual field mean sensitivity and mean defect.
Notes	Allocation concealment deemed likely, based on double‐masked design. 4 years follow up. Double‐masked until 18 months, thereafter open label. 15 drop‐outs (8 timolol: 1 local and 1 systemic side effect; 7 betaxolol: 2 local side effects).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Kamal 2003

Methods	RCT. Double‐masked. Placebo controlled.
Participants	356 participants with OHT. Racial constitution is not reported. Inclusion criteria: IOP between 22 and 35 mmHg, normal visual field. Exclusion criteria: systemic beta‐blockers, diabetes mellitus.
Interventions	Betaxolol 0.5% twice daily. Placebo.
Outcomes	Incidence of reproducible glaucomatous visual field defect.
Notes	Median follow‐up time 60 months (for those completing the trial). 102 drop‐outs: 48 betaxolol group (8 local and 3 systemic adverse effects), 53 placebo group (7 local, and 4 systemic adverse effects). Intent‐to‐treat analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Kass 1989

Methods	RCT. Double‐masked. Placebo controlled.
Participants	62 participants with OHT (6% with PEX). Fellow eye served as control. 40% of the participants were African American. Inclusion criteria: IOP between 24 and 35 mmHg, difference in baseline IOP between right and left eyes less than or equal to 3 mmHg, age 40 years or greater, open angles. Exclusion criteria: visual acuity below 20/50, previous intraocular surgery or laser, systemic medication that alters IOP
Interventions	Timolol 0.25% or 0.5% twice daily. Untreated control (contralateral eye).
Outcomes	Incidence of reproducible glaucomatous visual field defect (Goldmann kinetic and static perimetry with Humphrey 30‐2 and Octopus 32). Incidence of progressive optic disc cupping (stereophoto).
Notes	Mean follow up 56.1 months. 19 drop‐outs: 5 systemic adverse events caused by timolol.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Kass 2002

Methods	RCT. Observer masked. Multicenter.
Participants	1636 participants with OHT. 25% African American. Inclusion criteria: IOP between 24 and 32 mmHg in one eye and between 21 and 32 mmHg in the other eye, 2 normal and reliable visual fields, normal optic discs on stereophotographs. Exclusion criteria: visual acuity below 20/40, previous ocular surgery (uncomplicated cataract surgery allowed), diabetic retinopathy.
Interventions	Any topical medical antiglaucomatous treatment. No treatment.
Outcomes	Incidence of reproducible visual field defects or reproducible deterioration of optic discs attributable to POAG. IOP.
Notes	Median follow up 6 years. 173 drop‐outs (89 timolol group, 84 no treatment group).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Kitazawa 1990

Methods	RCT. Double‐masked. Placebo controlled.
Participants	20 participants with OHT. Racial constitution is not reported. Inclusion criteria: moderate OHT with IOP that has never exceeded 30 mmHg, normal visual field.
Interventions	Timolol 0.5% twice daily. Placebo.
Outcomes	Incidence of glaucomatous visual field defect.
Notes	Allocation concealment deemed likely, based on double‐masked design. Masking not stated but likely. 2 years follow up. Drop‐outs: 2 patients in each group (not adverse‐event related). Both eyes included, analysis both on basis of patient and eye.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Leblanc 1998

Methods	RCT. Double‐masked. Active controlled. Multicenter (7).
Participants	483 participants with POAG (55%) or OHT. 10% were African American. Inclusion criteria: IOP between 23 and 35 mmHg in each eye and both eyes within 5 mmHg of each other. Exclusion criteria: visual acuity below 20/80, active external ocular disease, severe dry eye, c/d ratio of 0.8 or greater or advanced visual field loss in either eye, history of ocular surgery or laser within 6 months, history of uncontrolled hypertension or diabetes, medication with any drug that could have a substantial effect on IOP or interact with the effects of alpha‐adrenergic agonists.
Interventions	Brimonidine 0.2% twice daily. Timolol 0.5% twice daily.
Outcomes	IOP. Horizontal c/d ratio. Incidence of visual field defect or defect progression.
Notes	Allocation concealment deemed likely, based on double‐masked design. 1 year follow up. Uneven randomisation schedule 3:2. 40 drop‐outs: 149/292 brimonidine (76 adverse events), 48/191 timolol (9 adverse events).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Novack 1989

Methods	RCT. Double‐masked. Multicenter (10).
Participants	391 participants with OAG or OHT (65%). 20% African American. Inclusion criteria: bilateral IOP of 23 mmHg or higher. Exclusion criteria: use of adrenergic augmenting psychotropic drugs, topical or systemic corticosteroids, severe diabetes mellitus requiring changes in insulin dosage, aphakia, chronic ocular inflammation, severe OAG uncontrolled by concomitant administration of 2 or more drugs.
Interventions	Levobunolol 0.5% twice daily. Levobunolol 1% twice daily. Timolol 0.5% twice daily.
Outcomes	IOP. Horizontal c/d ratio. Incidence or progression of glaucomatous visual field defect.
Notes	Allocation concealment deemed likely, based on double‐masked design. 4 years follow up. 107 drop‐outs (70 due to reasons unrelated to study medication) and 95 IOP failures: levobunolol 0.5% (4 systemic and 6 local side effects), levobunolol 1% (7 systemic and 13 local side effects), timolol (7 systemic and 3 local side effects).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Ravalico 1994

Methods	RCT. Open label.
Participants	26 paricipants with OHT. Racial constitution is not reported. Inclusion criteria: IOP between 22 and 30 mmHg, vision 20/20, cup/disc ratio below 0.5. Exclusion criteria: glaucoma within the family, narrow angle, other ocular pathologies.
Interventions	Levobunolol 0.5% twice daily. Untreated.
Outcomes	IOP. Change of visual field mean defect. Horizontal c/d ratio.
Notes	24 months follow up, but considerable attrition at 24 months. Drop‐out rate by 18 and 24 months: untreated group 7 and 11 of 23 eyes; levobunolol group 9 and 19 of 26 eyes (the number of participants who dropped out is not reported). The reasons for drop‐out are not detailed. The study appears to report mean values of both eyes where both eyes were included (most cases).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Schulzer 1991

Methods	RCT. Open label.
Participants	137 people with OHT. Racial constitution is not reported. Inclusion criteria: IOP above or equal to 22 mmHg, normal visual fields (Goldmann perimeter). Exclusion criteria: Obvious sign of glaucomatous disc changes, ocular infections, trauma or surgery within 6 months before the study, resting pulse of 50 beats or less, systemic beta‐blockers.
Interventions	Timolol 0.5% twice daily. No treatment.
Outcomes	Incidence of reproducible visual field defect. Incidence of disc haemorrhages. Incidence of stereophotographically documented optic nerve changes.
Notes	6 years follow up. 22 drop‐outs: 12 timolol (2 adverse drug reaction) and 10 untreated. The reasons for drop‐out are not specified.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Schuman 1997

Methods	RCT. Double‐masked. Active controlled.
Participants	374 people with POAG (62%) or OHT (only 188 participants examined with perimetry twice). Racial constitution is not reported. Inclusion criteria: IOP between 23 and 35 mmHg (untreated). Exclusion criteria: patients using more than 2 ocular hypotensive agents, visual acuity below 20/100, abnormally low heart rate or blood pressure, long‐term treatment with any other topical or systemic alpha‐adrenoceptor agonist or antagonist, treatment with adrenergic‐augmenting psychotropic drugs, dry eye, asymmetry of IOP of more than 5 mmHg, extensive visual field loss, ocular surgery or laser within 6 months, c/d‐ratio of 0.8 or more.
Interventions	Brimonidine 0.2% twice daily. Timolol 0.5% twice daily.
Outcomes	IOP. Incidence of visual field defect or defect progression.
Notes	1 year follow up. Drop‐outs due to adverse events: 35 brimonidine (25 ocular and 10 systemic adverse events), 4 timolol (2 ocular and 2 systemic adverse events). Most patients have been treated with opical beta‐blocker before washout of the study. Visual field analysis available for subgroup only, comprising 77 patients recieving brimonidine and 111 with timolol. The difference between groups in proportion of patients participating in visual field analysis subgroup poses questions about randomisation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Schwartz 1995

Methods	RCT. Double‐masked. Placebo controlled.
Participants	37 participants with OHT. 3 African American in timolol group, only Caucasians in placebo group. Inclusion criteria: IOP between 21 and 35 mmHg, normal visual field, PEX allowed (1 in each group). Exclusion criteria: previous ocular surgery or laser treatment.
Interventions	Timolol 0,5% twice daily. Placebo.
Outcomes	Change of optic disk cupping (photogrammetric measurement). Change of RNFL thickness (photogrammetric measurement). Incidence of glaucomatous visual field defects.
Notes	Study duration 2 years, but effective mean duration 1.5 years. Drop‐out rate: 8 participants on timolol (2 systemic and 2 ocular adverse events), and 6 subjects on placebo (1 systemic and 2 ocular adverse events). The authors do not report visual field data in detail, but state that in both groups there was no incidence of visual field defects.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Sponsel 1987

Methods	RCT. Open label. Active controlled.
Participants	36 people with POAG. Racial constitution is not reported. Inclusion criteria: IOP above 21 mmHg on 2 occasions, optic disc cupping supportive of a diagnosis of glaucoma, visual field loss typical of nerve fibre bundle damage. Exclusion criteria: coexisting ocular pathlogy.
Interventions	Timolol 0.25% or 0.5% twice daily (adjustment according to IOP). Pilocarpine 2% or 4% twice daily (adjustment according to IOP).
Outcomes	IOP control. Progression rate of visual field score (Goldmann and Friedmann static suprathreshold perimetry).
Notes	Study duration 17 months. Due to early miotic intolerance, the follow‐up groups comprised 14 patients on pilocarpine, as compared to 22 patients on timolol. The number of originally included subjects is not stated. Miosis may have influenced the visual field results. The paper does not state whether data where averaged for both eyes or represent only one eye per patient.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Tsai 2005

Methods	RCT. Open label. Active controlled.
Participants	39 participants with POAG. Racial constitution is not reported. Inclusion criteria: IOP 22 mmHg or greater, visual field defect in SAP, glaucomatous appearance of optic disc, normal open angle.
Interventions	Timolol 0.5% ophthalmic gel‐forming solution once daily. Brimonidine 0.2% twice daily.
Outcomes	Change in RNFL thickness (ellipse average, superior average, temporal average, inferior average, nasal average). IOP.
Notes	Study duration 2 years. Drop‐out rate: 2 participants on timolol (no adverse event), 3 participants on brimonidine (1 ocular adverse event). Visual field was examined at baseline only.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Vogel 1992

Methods	RCT. Observer masked. Active controlled.
Participants	189 people with POAG. Racial constitution is not reported. Inclusion criteria: IOP 22 mmHg or greater, visual field defect in SAP. Exclusion criteria: history of severe ocular trauma or intraocular surgery, ocular infection within 3 months before study start, concomitant medication known to affect IOP.
Interventions	Timolol 0.25% or 0.5% twice daily (adjustment according to IOP). Pilocarpine 2% or 4% twice daily (adjustment according to IOP).
Outcomes	Change of visual field mean sensitivity. IOP.
Notes	Study duration 2 years. Observer masked status is questionable because of miosis. At baseline, 51 patients were excluded. Drop‐outs during follow up: 18 timolol (4 adverse event or death) and 36 pilocarpine (7 adverse event or death). The authors do not state whether the adverse events or deaths were drug‐related.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Watson 2001

Methods	RCT. Open label. Active controlled.
Participants	153 participants with newly diagnosed OAG. Racial constitution is not reported. Inclusion criteria: IOP of 22 mmHg, visual field changes and/or disc changes suggestive of a diagnosis of POAG. Exclusion criteria: IOP over 32 mmHg together with marked reduction of visual field, history of ocular trauma or surgery.
Interventions	Timolol 0.25% twice daily. Betaxolol 0.5% twice daily. Carteolol 1% twice daily.
Outcomes	Change of visual field mean deviation. Incidence of visual field deterioration.
Notes	Median follow up: timolol group 42 months, betaxolol group 24 months, carteolol group 36 months. 29 drop‐outs: 12 timolol group (7 local and 3 systemic side effects), 17 betaxolol group (5 systemic side effects), 19 carteolol (6 systemic side effects).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Wishart 1992

Methods	RCT. Open label.
Participants	34 participants with OHT and open angles and 25 participants with OHT and narrow angles. Fellow‐eye served as control. Racial constitution is not reported. Inclusion criteria: IOP above 21 mmHg in both eyes, normal visual felds (Friedmann), normal optic discs. Exclusion criteria: history of anterior segment disease.
Interventions	Timolol 0.5% twice daily one eye. No treatment for the fellow eye.
Outcomes	Incidence of glaucomatous visual field defects or optic disc damage.
Notes	6 years follow‐up. Data of OHT with open angles and with narrow angles were analysed separately. Only the former are included in this review. No detailed information on dropouts is given.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

c/d ratio: cup to disk ratio
IOP: intraocular pressure
MD: mean defect
mmHG: millimetres mercury
OAG: open angle glaucoma
OHT: ocular hypertension
PDS: pigment dispersion syndrome
PEX: pseudoexfoliation
CLV: corrected loss variation
POAG: primary open angle glaucoma
RCT: randomised controlled trial
RNFL: retinal nerve fibre layer
SAP: standard automated perimetry

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Araie 2003	60% of the included patients had NTG.
EMGT 1999	This RCT included patients with OAG irrespectively to their IOP. Almost 50% of the subjects were NTG patients. Additionally the trial included also patients with PEX. The study intervention also included laser treatment in one group.
Holmin 1988	The study compares medical treatment with no treatment. The treatment allowed use of timolol, pilocarpine and a supplementation with acetazolamide.
Vainio 1999	This trial included both NTG and POAG with elevated IOP

IOP: intraocular pressure
NTG: normal tension glaucoma
OAG: open angle glaucoma
POAG: primary open angle glaucoma
PEX: pseudoexfoliation
RCT: randomised controlled trial

Data and analyses

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Comparison 1. Beta‐blockers versus placebo or untreated

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	8	935	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.67 [0.45, 1.00]
Open in figure viewer Analysis 1.1 Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.
1.1 Timolol versus placebo or untreated	7	579	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.41, 1.05]
1.2 Betaxolol versus placebo or untreated	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.32, 1.51]
2 Drop‐out due to drug‐related adverse events Show forest plot	4	503	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.24 [0.59, 2.58]
Open in figure viewer Analysis 1.2 Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 2 Drop‐out due to drug‐related adverse events.
2.1 Timolol versus placebo	3	147	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.48 [0.61, 10.10]
2.2 Betaxolol versus placebo	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.40, 2.26]
3 Sensitivity analysis concerning the incidence of visual field defect progression Show forest plot	4	499	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.64 [0.34, 1.19]
Open in figure viewer Analysis 1.3 Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field defect progression.
3.1 Timolol versus placebo or untreated	3	143	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.19, 1.54]
3.2 Betaxolol versus placebo or untreated	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.32, 1.51]
4 Long‐term studies concerning the incidence of visual field progression Show forest plot	6	882	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.67 [0.45, 1.01]
Open in figure viewer Analysis 1.4 Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 4 Long‐term studies concerning the incidence of visual field progression.

Open in table viewer

Comparison 2. Comparison of timolol and carteolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	171	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.18 [0.05, 0.62]
Open in figure viewer Analysis 2.1 Comparison 2 Comparison of timolol and carteolol, Outcome 1 Incidence of visual field defect progression.

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Comparison 3. Comparison of timolol and levobunolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	290	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.20 [1.17, 4.14]
Open in figure viewer Analysis 3.1 Comparison 3 Comparison of timolol and levobunolol, Outcome 1 Incidence of visual field defect progression.
2 Drop‐out due to drug‐related adverse events Show forest plot	2	290	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.80 [0.34, 1.87]
Open in figure viewer Analysis 3.2 Comparison 3 Comparison of timolol and levobunolol, Outcome 2 Drop‐out due to drug‐related adverse events.

Open in table viewer

Comparison 4. Comparisons of timolol and betaxolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change of visual field mean sensitivity Show forest plot	6	258	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.43, 0.57]
Open in figure viewer Analysis 4.1 Comparison 4 Comparisons of timolol and betaxolol, Outcome 1 Change of visual field mean sensitivity.
2 Drop‐out due to drug‐related adverse events Show forest plot	5	238	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.40 [1.04, 5.53]
Open in figure viewer Analysis 4.2 Comparison 4 Comparisons of timolol and betaxolol, Outcome 2 Drop‐out due to drug‐related adverse events.

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Comparison 5. Comparison of timolol and brimonidine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	671	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.11 [0.60, 2.04]
Open in figure viewer Analysis 5.1 Comparison 5 Comparison of timolol and brimonidine, Outcome 1 Incidence of visual field defect progression.
2 Drop‐out due to drug‐related adverse events Show forest plot	3	957	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.14, 0.31]
Open in figure viewer Analysis 5.2 Comparison 5 Comparison of timolol and brimonidine, Outcome 2 Drop‐out due to drug‐related adverse events.

Open in table viewer

Comparison 6. All treatments versus placebo or untreated

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	10	3648	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.47, 0.81]
Open in figure viewer Analysis 6.1 Comparison 6 All treatments versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.
2 Sensitivity analysis concerning the incidence of visual field progression Show forest plot	6	3212	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.42, 0.81]
Open in figure viewer Analysis 6.2 Comparison 6 All treatments versus placebo or untreated, Outcome 2 Sensitivity analysis concerning the incidence of visual field progression.
3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study Show forest plot	5	1576	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.44, 0.98]
Open in figure viewer Analysis 6.3 Comparison 6 All treatments versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study.

Analysis 1.1

Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.

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Analysis 1.2

Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 2 Drop‐out due to drug‐related adverse events.

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Analysis 1.3

Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field defect progression.

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Analysis 1.4

Comparison 1 Beta‐blockers versus placebo or untreated, Outcome 4 Long‐term studies concerning the incidence of visual field progression.

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Analysis 2.1

Comparison 2 Comparison of timolol and carteolol, Outcome 1 Incidence of visual field defect progression.

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Analysis 3.1

Comparison 3 Comparison of timolol and levobunolol, Outcome 1 Incidence of visual field defect progression.

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Analysis 3.2

Comparison 3 Comparison of timolol and levobunolol, Outcome 2 Drop‐out due to drug‐related adverse events.

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Analysis 4.1

Comparison 4 Comparisons of timolol and betaxolol, Outcome 1 Change of visual field mean sensitivity.

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Analysis 4.2

Comparison 4 Comparisons of timolol and betaxolol, Outcome 2 Drop‐out due to drug‐related adverse events.

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Analysis 5.1

Comparison 5 Comparison of timolol and brimonidine, Outcome 1 Incidence of visual field defect progression.

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Analysis 5.2

Comparison 5 Comparison of timolol and brimonidine, Outcome 2 Drop‐out due to drug‐related adverse events.

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Analysis 6.1

Comparison 6 All treatments versus placebo or untreated, Outcome 1 Incidence of visual field defect progression.

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Analysis 6.2

Comparison 6 All treatments versus placebo or untreated, Outcome 2 Sensitivity analysis concerning the incidence of visual field progression.

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Analysis 6.3

Comparison 6 All treatments versus placebo or untreated, Outcome 3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study.

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Table 1. Methodological quality of included studies

Criteria	Number of trials
Allocation concealment adequate	16 / 26
Baseline comparability stated	19 / 26
Analysis: intention‐to‐treat	9 / 26
Withdrawals adequately reported	17 / 26
Drop‐out rate below 10%	1 / 26
Low methodological quality	16 / 26

Table 1. Methodological quality of included studies

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Table 2. Summary table for analyses of outcomes

Comparison	POAG	OHT	POAG & OHT	Drop‐out due to AE
Beta‐blockers vs. placebo or untreated		0.67 (0.45 to 1.00; n=935)		1.24 (0.59 to 2.58; n=503)
Longterm trials		0.67 (0.45 to 1.01; n=882)
Sensitivity analysis		0.64 (0.34 to 1.19; n=499)
Timolol vs. placebo or untreated		0.66 (0.41 to 1.05; n=579)		2.48 (0.61 to 10.10; n=147)
Timolo vs. carteolol	0.18 (0.05 to 0.62; n=171) +
Timolol vs. levobunolol			2.20 (1.17 to 4.14; n=290) #	0.80 (0.34 to 1.87; n=290)
Timolol vs. betaxolol	0.07dB (‐0.43dB to 0.57dB; n=158) $			2.40 (1.04 to 5.53; n=238) §
Timolol vs. brimonidine			1.11 (0.60 to 2.04; n=671)	0.21 (0.14 to 0.31; n=957) ++
All treatment vs. placebo or untreated		0.62 (0.47 to 0.81; n=3648)
Sensitivity analysis		0.58 (0.42 to 0.81; n=3212)
Sensitivity analysis without OHTS		0.66 (0.44 to 0.98; n=1576)
+ favours timolol; # favours levobunolol;	$ 14 participants with OHT included	§ favours betaxolol	++ favours timolol

Table 2. Summary table for analyses of outcomes

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Comparison 1. Beta‐blockers versus placebo or untreated

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	8	935	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.67 [0.45, 1.00]

1.1 Timolol versus placebo or untreated	7	579	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.41, 1.05]
1.2 Betaxolol versus placebo or untreated	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.32, 1.51]
2 Drop‐out due to drug‐related adverse events Show forest plot	4	503	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.24 [0.59, 2.58]

2.1 Timolol versus placebo	3	147	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.48 [0.61, 10.10]
2.2 Betaxolol versus placebo	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.40, 2.26]
3 Sensitivity analysis concerning the incidence of visual field defect progression Show forest plot	4	499	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.64 [0.34, 1.19]

3.1 Timolol versus placebo or untreated	3	143	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.19, 1.54]
3.2 Betaxolol versus placebo or untreated	1	356	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.32, 1.51]
4 Long‐term studies concerning the incidence of visual field progression Show forest plot	6	882	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.67 [0.45, 1.01]

Comparison 1. Beta‐blockers versus placebo or untreated

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Comparison 2. Comparison of timolol and carteolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	171	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.18 [0.05, 0.62]

Comparison 2. Comparison of timolol and carteolol

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Comparison 3. Comparison of timolol and levobunolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	290	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.20 [1.17, 4.14]

2 Drop‐out due to drug‐related adverse events Show forest plot	2	290	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.80 [0.34, 1.87]

Comparison 3. Comparison of timolol and levobunolol

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Comparison 4. Comparisons of timolol and betaxolol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change of visual field mean sensitivity Show forest plot	6	258	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.43, 0.57]

2 Drop‐out due to drug‐related adverse events Show forest plot	5	238	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.40 [1.04, 5.53]

Comparison 4. Comparisons of timolol and betaxolol

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Comparison 5. Comparison of timolol and brimonidine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	2	671	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.11 [0.60, 2.04]

2 Drop‐out due to drug‐related adverse events Show forest plot	3	957	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.21 [0.14, 0.31]

Comparison 5. Comparison of timolol and brimonidine

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Comparison 6. All treatments versus placebo or untreated

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Incidence of visual field defect progression Show forest plot	10	3648	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.62 [0.47, 0.81]

2 Sensitivity analysis concerning the incidence of visual field progression Show forest plot	6	3212	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.42, 0.81]

3 Sensitivity analysis concerning the incidence of visual field progression; without OHTS study Show forest plot	5	1576	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.44, 0.98]

Comparison 6. All treatments versus placebo or untreated

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Referencias

References to studies included in this review

Alexander 1988 {published data only}

Collignon‐Brach 1992 {published data only}

Collignon‐Brach 1994 {published data only}

Drance 1998 {published data only}

EGPS 2005 {published data only}

Epstein 1989 {published data only}

Fama 1996 {published data only}

Flammer 1992 {published data only}

Geyer 1988 {published data only}

Heijl 2000 {published data only}

Kaiser 1994 {published data only}

Kamal 2003 {published data only}

Kass 1989 {published data only}

Kass 2002 {published data only}

Kitazawa 1990 {published data only}

Leblanc 1998 {published data only}

Novack 1989 {published data only}

Ravalico 1994 {published data only}

Schulzer 1991 {published data only}

Schuman 1997 {published data only}

Schwartz 1995 {published data only}

Sponsel 1987 {published data only}

Tsai 2005 {published data only}

Vogel 1992 {published data only}

Watson 2001 {published data only}

Wishart 1992 {published data only}

References to studies excluded from this review

Araie 2003 {published data only}

EMGT 1999 {published data only}

Holmin 1988 {published data only}

Vainio 1999 {published data only}

References to studies awaiting assessment

CGSG 2006 {published data only}

Hommer 2007 {published data only}

Kanno 2006a {published data only}

Kanno 2006b {published data only}

Noecker 2007 {published data only}

Schmier 2006 {published data only}

Sherwood 2006 {published data only}

Whitson 2006 {published data only}

Additional references

Armaly 1980

Caprioli 1998

CNTGS 1998

Diggory 1998

Gandolfi 2005

Glanville 2006

Higgins 2006a

Higgins 2006b

Maier 2005

Ontoso 1997

Quigley 1983

Quigley 2005

Rossetti 1993

Schulzer 1990

Sycha 2005

Takamoto 1985

Waldock 2000

Wiysonge 2006

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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