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Medical versus surgical interventions for open angle glaucoma

(Review)

Burr J, Azuara-Blanco A, Avenell A, Tuulonen A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 9
http://www.thecochranelibrary.com

Medical versus surgical interventions for open angle glaucoma (Review)


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 1.1. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 1 Mean change in visual field
score from baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Analysis 1.2. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 2 Mean change in IOP from
baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Analysis 1.3. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 3 Mean change in VA score from
baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Analysis 2.1. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 1 Progressive visual field
loss. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Analysis 2.2. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 2 Mean change in visual field
score (Friedmann) from baseline. Moorfields PTT 1994 not ITT. . . . . . . . . . . . . . . . . 37
Analysis 2.3. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 3 Mean difference in visual
field score (mean deviation) at five years (unadjusted). . . . . . . . . . . . . . . . . . . . . 38
Analysis 2.4. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 4 Mean difference in visual
field scores (mean deviation) according to baseline severity at five years (adjusted). . . . . . . . . . . 38
Analysis 2.5. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 5 Mean change in IOP from
baseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Analysis 2.6. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 6 Mean change in IOP from
baseline (exploratory analysis with assumptions). . . . . . . . . . . . . . . . . . . . . . . 40
Analysis 2.7. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 7 Mean difference in IOP up
to 9 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Analysis 2.8. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 8 Optic nerve progression at
five years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Analysis 2.9. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 9 Medium to long-term
reduction of VA. CIGTS 2001 adjusted OR. . . . . . . . . . . . . . . . . . . . . . . . 41
Analysis 2.10. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 10 Failure of randomised
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Analysis 2.11. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 11 Time to failure of
randomised treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Analysis 2.12. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 12 Need for ALT as an
additional treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Medical versus surgical interventions for open angle glaucoma (Review) i


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Medical versus surgical interventions for open angle glaucoma

Jennifer Burr1 , Augusto Azuara-Blanco2 , Alison Avenell3 , Anja Tuulonen4

1
School of Medicine, Medical and Biological Sciences Building, University of St Andrews, Fife, UK. 2 Health Services Research Unit,
University of Aberdeen, Aberdeen, UK. 3 Health Services Research Unit, Health Sciences Building, University of Aberdeen, Aberdeen,
UK. 4 Eye Centre, Tampere University Hospital, Tampere, Finland

Contact address: Jennifer Burr, School of Medicine, Medical and Biological Sciences Building, University of St Andrews, Fife, KY16
9TF, UK. jmb28@st-andrews.ac.uk.

Editorial group: Cochrane Eyes and Vision Group.


Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2012.
Review content assessed as up-to-date: 1 August 2012.

Citation: Burr J, Azuara-Blanco A, Avenell A, Tuulonen A. Medical versus surgical interventions for open angle glaucoma. Cochrane
Database of Systematic Reviews 2012, Issue 9. Art. No.: CD004399. DOI: 10.1002/14651858.CD004399.pub3.

Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Open angle glaucoma (OAG) is a common cause of blindness.

Objectives

To assess the effects of medication compared with initial surgery in adults with OAG.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7),
Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE
(January 1946 to August 2012), EMBASE (January 1980 to August 2012), Latin American and Caribbean Literature on Health Sciences
(LILACS) (January 1982 to August 2012), Biosciences Information Service (BIOSIS) (January 1969 to August 2012), Cumulative
Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2012), OpenGrey (System for Information on
Grey Literature in Europe) (www.opengrey.eu/), Zetoc, the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com)
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 1 August 2012. The National
Research Register (NRR) was last searched in 2007 after which the database was archived. We also checked the reference lists of articles
and contacted researchers in the field.

Selection criteria

We included randomised controlled trials (RCTs) comparing medications with surgery in adults with OAG.

Data collection and analysis

Two authors independently assessed trial quality and extracted data. We contacted study authors for missing information.
Medical versus surgical interventions for open angle glaucoma (Review) 1
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheies procedure in one trial and
trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial it was a beta-blocker.
The most recent trial included participants with on average mild OAG. At five years, the risk of progressive visual field loss, based on a
three unit change of a composite visual field score, was not significantly different according to initial medication or initial trabeculectomy
(odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54 to 1.01). In an analysis based on mean difference (MD) as a single index
of visual field loss, the between treatment group difference in MD was -0.20 decibel (dB) (95% CI -1.31 to 0.91). For a subgroup
with more severe glaucoma (MD -10 dB), findings from an exploratory analysis suggest that initial trabeculectomy was associated
with marginally less visual field loss at five years than initial medication, (mean difference 0.74 dB (95% CI -0.00 to 1.48). Initial
trabeculectomy was associated with lower average intraocular pressure (IOP) (mean difference 2.20 mmHg (95% CI 1.63 to 2.77) but
more eye symptoms than medication (P = 0.0053). Beyond five years, visual acuity did not differ according to initial treatment (OR
1.48, 95% CI 0.58 to 3.81).
From three trials in more severe OAG, there is some evidence that medication was associated with more progressive visual field loss and
3 to 8 mmHg less IOP lowering than surgery. In the longer-term (two trials) the risk of failure of the randomised treatment was greater
with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; hazard ratio (HR) 7.27, 95% CI 2.23 to 25.71). Medications
and surgery have evolved since these trials were undertaken.
In three trials the risk of developing cataract was higher with trabeculectomy (OR 2.69, 95% CI 1.64 to 4.42). Evidence from one trial
suggests that, beyond five years, the risk of needing cataract surgery did not differ according to initial treatment policy (OR 0.63, 95%
CI 0.15 to 2.62).
Methodological weaknesses were identified in all the trials.
Authors conclusions
Primary surgery lowers IOP more than primary medication but is associated with more eye discomfort. One trial suggests that visual
field restriction at five years is not significantly different whether initial treatment is medication or trabeculectomy. There is some
evidence from two small trials in more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is
associated with more glaucoma progression than surgery. Beyond five years, there is no evidence of a difference in the need for cataract
surgery according to initial treatment.
The clinical and cost-effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhy-
drase inhibitors) compared with primary surgery is not known.
Further RCTs of current medical treatments compared with surgery are required, particularly for people with severe glaucoma and
in black ethnic groups. Outcomes should include those reported by patients. Economic evaluations are required to inform treatment
policy.

PLAIN LANGUAGE SUMMARY


Medications or surgery for the treatment of open angle glaucoma
Open angle glaucoma (OAG) is the most common form of glaucoma and an important cause of blindness. Having a high intraocular
pressure (IOP) is an important risk factor. Treatment for OAG aims to lower the IOP and thus reduce the risk of progressive loss of
vision. IOP can be lowered by medications (eye drops), laser therapy or surgery. There are many different types of eye drops available
and these are compared in a Cochrane review (Vass 2007). Surgery for glaucoma has also evolved in the last 40 years. The most common
type is called trabeculectomy, or drainage surgery, that creates an opening at the wall of the eye to release fluid and reduce the IOP.
Surgery may have complications during and after the operation and may fail in the long-term due to scarring. Drainage surgery forms
a bleb i.e. small blister like elevation on the surface of the eye which can sometimes be uncomfortable.
It is not clear whether medication or surgery is the better treatment for OAG. The purpose of this review was to review and assess
evidence from randomised studies to compare treatment with medications with surgical treatments in terms of how well they work,
their relative safety and cost-effectiveness. Four relevant trials were identified, treating 888 people. Three studies were in the UK and
one in the US. These trials had been initiated over many years from 1968 up to the most recent trial in 1993. The earlier trials
Medical versus surgical interventions for open angle glaucoma (Review) 2
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
used medications, and in one trial surgical techniques that are now rarely used. Findings of these studies suggest that, in mild OAG,
worsening of the condition was not different whether first treatment was medication or surgery, but surgery was associated with more
eye discomfort at five years. In more severe glaucoma, surgery lowered IOP significantly more than medications (not widely used
anymore) and reduced the risk of progressive loss of visual field. In three trials the risk of developing cataract was higher with surgery
(trabeculectomy), although in one trial with follow-up beyond five years there was no difference in the number of cataract surgeries
between treatment groups. There was insufficient evidence to determine how well more recently available medications work compared
with surgery in more severe OAG, and which was the more cost-effective treatment option. More research is required.

OAG is not defined by the presence of elevated IOP. Glaucoma-


BACKGROUND
tous optic neuropathy can develop in the absence of documented
elevated IOP. This condition has been termed normal pressure or
normal tension glaucoma. There is debate as to whether normal
tension glaucoma is a separate entity or a subtype of primary open
Description of the condition
angle glaucoma existing as a spectrum of the same disease. There
Glaucoma describes a group of eye diseases in which there is pro- may be different risk factors, different patterns of damage and dif-
gressive damage to the optic nerve characterised by specific struc- ferent natural history in normal tension glaucoma, but the clin-
tural abnormalities of optic nerve head and patterns of visual field ical findings and the treatment for progressive disease is similar
loss. The primary glaucomas (those that are not as a consequence (Caprioli 2001).
of other eye or systemic disease) can be classified as open angle In this review OAG includes the following subgroups.
glaucoma (OAG) or angle closure glaucoma. OAG is a multi-fac- 1. Primary open angle glaucoma (POAG) is characterised by:
torial optic neuropathy in which there is a characteristic acquired i) adult onset;
loss of retinal ganglion cells and atrophy of the optic nerve (AAO ii) mean untreated IOP above 21 mmHg;
2000) in which the drainage angle and trabecular meshwork is iii) open drainage angle on gonioscopy without any
clearly visible and has a normal appearance on gonioscopy. pathological features;
In 1990 the World Health Organization (WHO) estimated that iv) evidence of glaucomatous optic neuropathy from
38 million people were blind worldwide, with 15% due to glau- either the appearance of the optic disc or retinal nerve fibre layer
coma; second only to cataract as the leading cause of blindness and/or the presence of characteristic abnormalities in the visual
(WHO 2002). In Europe, glaucoma accounts for 7% to 15% of all field; and
blind registrations and is second to age-related macular degenera- v) absence of any secondary causes of IOP elevation.
tion as the main cause (Bunce 2010; Fuchs 1992; Ghafour 1983; 2. Normal pressure glaucoma
Klaver 1998). OAG is the most common form of glaucoma; it ac- All the features of POAG apart from a mean
counts for 75% to 95% of primary glaucomas except in people of pretreatment IOP less than or equal to 21 mmHg. Interventions
Eastern Asian (Mongoloid) descent, where angle closure glaucoma for normal pressure glaucoma are the subject of a separate
is more prevalent (Congdon 1992). The risk factors for develop- Cochrane review (Sycha 2003).
ing OAG, identified from population studies, are raised intraoc- 3. Pseudoexfoliative glaucoma
ular pressure (IOP), increasing age, African American or African All the features of POAG or normal pressure glaucoma
Caribbean ethnic origin, family history and myopia (Burr 2007; and additionally deposition of the characteristic exfoliative
Rudnicka 2006). The average age of diagnosis is estimated at 62 material on the anterior lens surface, pupil margin and other
years for non-white and 70 years for white populations (Leske parts of the anterior segment of the eye.
1983). Blindness due to OAG occurs in an estimated 4% of cases 4. Pigmentary glaucoma
in a white population, but is more common (8%) and occurs at All the features of POAG with the addition of
an earlier age in a non-white population (Quigley 1997). pigment deposition in the open drainage angle together with
OAG is painless. In the early stages of disease the visual loss is characteristic pigment dispersion in the anterior segment of the
in the mid-peripheral field of vision and individuals are generally eye (Krukenberg spindle - pigment on the corneal endothelium
asymptomatic (Mills 2001). In the later stages of disease visual field and transillumination of the mid-periphery of the iris).
loss impacts on central vision and affects health-related quality of Treatment aims to prevent visual disability and preserve overall
life (Gutierrez 1997).
Medical versus surgical interventions for open angle glaucoma (Review) 3
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
well-being for patients with glaucoma. The visual loss in glaucoma primary treatment modality in OAG although its use is usually re-
is due to the death of retinal ganglion cells, which is thought to served for those cases not responding to other modes of treatment
occur by a mechanism of genetically programmed cell death called because of the potential risk of serious loss of vision following the
apoptosis (Kerrigan 1997). Vascular and or mechanical factors at procedure (Bloom 1997; Egbert 2001).
the optic nerve head may precipitate the cell death and IOP may be
implicated in either or both of these mechanisms (Fechtner 1994).
Other factors, such as elevated nitric oxide and glutamate levels (3) Surgical
in the eye and autoimmune mechanisms, may also contribute to Glaucoma drainage surgery aims to lower the IOP by creating
this process. Research is ongoing for therapies other than reducing an alternative route for aqueous humour outflow. Glaucoma sur-
IOP which might be of benefit (Dreyer 1999). Currently, IOP is gical techniques have evolved over the last 40 years from full
the only risk factor that can be treated, and lowering IOP has been thickness procedures, to guarded filtration procedures (trabeculec-
shown to be beneficial in reducing progression of visual field loss tomy). Full thickness procedures are now not recommended due
in glaucoma (AGIS 2000; CNTGSG 1998; Heijl 2002). to a higher risk of complications compared with guarded filtration
procedures.

Description of the intervention


(a) Trabeculectomy
Trabeculectomy is a guarded filtration procedure whereby the IOP
is lowered by creation of a fistula to drain aqueous humour from
(1) Medical
within the eye globe into the subconjunctival space to create a
filtering bleb. It was developed in the UK in 1968 and is currently
the standard operation in OAG (Cairns 1968; Watson 1981), al-
(a) Drugs though it can be associated with potentially vision-threatening
Medical treatment can be delivered topically as eye drops or sys- complications such as over-filtration, hypotony and infection. Suc-
temically. For more than two decades the first line of medical treat- cess rates for trabeculectomy depend on the criteria used to de-
ment for OAG has been topical beta-blockers. These lower IOP fine success, the level of IOP or long-term visual field stability.
but with the possibility of adverse systemic side effects, particu- The development of scar tissue under the conjunctiva leads to
larly in an elderly population (Diggory 1995). Carbonic anhy- inadequate drainage in trabeculectomy procedures. Anti-scarring
drase inhibitors taken systemically lower IOP and can be used as agents such as 5-Fluorouracil, Mitomycin-C and Beta-Radiation
long-term medication but they are often poorly tolerated. With can be used as an adjunct to trabeculectomy to limit the scarring
the introduction of newer topical agents their use is now restricted process. Cochrane reviews of 5-Fluorouracil and Mitomycin-C
to refractory cases. In the mid-1990s, alternative medical treat- found that their use appears to improve success rates of surgery,
ments such as topical carbonic anhydrase inhibitors, alpha2-ago- but may increase the incidence of complications (Wilkins 2005;
nists and prostaglandin analogues were introduced, increasing not Wormald 2001). Trabeculectomy with beta irradiation has a lower
only the therapeutic options but also the cost of medical antiglau- risk of surgical failure compared to trabeculectomy alone (Kirwan
coma treatment (Bateman 2001). Reduced surgical rates for glau- 2002). The comparative effectiveness of beta irradiation versus
coma are felt to be a consequence of the introduction of the new anti-metabolite is uncertain.
treatments (Bateman 2002). Long-term medication may not be
acceptable or possible as individuals may have difficulties adher-
ing to treatment. In developing countries, medications may not (b) Non-penetrating trabeculectomy
be available or may be too costly for long-term use. Medical inter- Non-penetrating surgical procedures (viscocanalostomy and deep
ventions for primary OAG are the subject of a Cochrane review sclerectomy) have been developed, which avoid full thickness pen-
(Vass 2007). etration into the anterior chamber of the eye. These have report-
edly fewer complications but may have limited effectiveness at
lowering IOP (Netland 2001).
(2) Laser
An alternative or additive treatment to the use of medications is
discrete laser ablation to areas of the trabecular meshwork of the (c) Glaucoma drainage devices
drainage angle. Laser trabeculoplasty is the subject of a Cochrane Aqueous shunt devices have been developed which aim to main-
review (Rolim de Moura 2007). Transscleral cyclophotocoagula- tain drainage of aqueous humour in spite of subconjunctival scar-
tion uses a laser to deliver thermal energy to the ciliary body and ring (Lim 1998); these are usually reserved for situations where tra-
decreases the production of aqueous humour. It has been used as a beculectomy is unlikely to succeed and is not generally accepted as

Medical versus surgical interventions for open angle glaucoma (Review) 4


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
an alternative to standard filtration surgery (Gedde 2012; Minckler METHODS
2006).

(d) Other procedures Criteria for considering studies for this review
Alternative microsurgical procedures on the trabecular meshwork
(trabecular aspiration, goniocurettage, laser trabecular ablation,
angle shunting devices and trabeculotomy) have been described as Types of studies
a means of lowering IOP in OAG. These techniques are not widely All randomised controlled trial (RCTs) and quasi-RCTs were eli-
used and their safety and effectiveness is not known (Chihara 1993; gible for inclusion.
Jacobi 2000). Lowering the IOP may also be achieved by reducing
the production of aqueous humour by the ciliary body by laser or
cryo ablation. Types of participants
Participants in the trials were adults with a diagnosis of open an-
gle glaucoma (OAG). We did not include trials with participants
How the intervention might work under 18 years. We did not impose any restrictions according to
Medications lower IOP by either decreasing aqueous production gender or nationality.
or increasing aqueous outflow. Surgery creates an alternative route
for aqueous humour outflow. Lowering IOP reduces the risk of
progressive visual field loss, (AGIS 2000; CNTGSG 1998; Heijl Types of interventions
2002) and the likelihood of progression to visual impairment. We included all trials where medical ocular hypotensive therapy
was compared with:
1. trabeculectomy with or without the use of anti-scarring
Why it is important to do this review agents;
2. non-penetrating trabeculectomy with or without the use of
Early trials in the UK of initial medical treatment versus tra-
anti-scarring agents;
beculectomy suggest that there is less deterioration of visual fields
3. any other anti-glaucomatous surgery, including glaucoma
in the trabeculectomy first group (Jay 1988; Migdal 1994). Re-
drainage devices; or
ports of five-year clinical outcomes of a trial of initial medical ver-
4. laser treatment to the ciliary body, transscleral
sus surgical therapy for OAG show no difference in IOP reduction
cyclophotocoagulation.
or rates of visual field progression between the treatment groups,
We included trials where the medical arm included surgery or laser
but show a higher incidence of cataract and local eye symptoms
in the treatment sequence (if medical treatment was inadequate),
in the surgically-treated group (Lichter 2001). With the develop-
or vice versa for initial surgical treatment as a comparison of initial
ment of newer medications for OAG and the refinement of sur-
medical versus initial surgical treatment.
gical techniques, the relative effectiveness of medical and surgi-
We did not include trials of medical therapy compared to laser
cal treatments on long-term visual outcomes and quality of life is
trabeculoplasty as these are the subject of a separate published
uncertain. It is also unclear whether the treatment choice should
Cochrane review (Rolim de Moura 2007).
be different for individuals identified at higher risk of blindness,
such as people of black ethnicity or people with severe disease at
presentation. Types of outcome measures

Primary outcomes
OBJECTIVES
1. Progressive visual field loss, according to the measures and
1. To study the comparative effectiveness of medical and criteria defined in the study design.
surgical treatment for OAG in terms of measures of glaucoma 2. Health-related quality of life.
progression and patient reported health-related quality of life.
2. To investigate these treatment effects in people of black race Secondary outcomes
and for people with different disease severity.
1. Intraocular pressure (IOP) reduction.
3. To describe any reported costs or economic evaluations of 2. Progression of optic disc damage or nerve fibre layer loss
medical and surgical treatment. according to the criteria defined in the study design.

Medical versus surgical interventions for open angle glaucoma (Review) 5


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3. Reduction of LogMAR score equal or greater than 0.3 Health Sciences (LILACS) (January 1982 to August 2012), Bio-
approximating to a Snellen visual acuity of two lines or more. sciences Information Service (BIOSIS) (January 1969 to Au-
4. Failure of randomised treatment as per a priori definitions gust 2012), Cumulative Index to Nursing and Allied Health
specified in the individual studies. Literature (CINAHL) (January 1937 to August 2012), Open-
Grey (System for Information on Grey Literature in Europe) (
www.opengrey.eu/), Zetoc, the metaRegister of Controlled Tri-
Adverse effects als (mRCT) (www.controlled-trials.com) and the WHO Interna-
Any adverse systemic or ocular adverse effects related to either tional Clinical Trials Registry Platform (ICTRP) (www.who.int/
intervention including: ictrp/search/en). We did not use any date or language restrictions
1. mortality; in the electronic searches for trials. We last searched the elec-
2. loss of an eye due to infection or inflammation; tronic databases on 1 August 2012. The National Research Regis-
3. severe irreversible reduction in vision; ter (NRR) was last searched in 2007 after which the database was
4. visually significant cataract; archived.
5. cataract surgery; See: Appendices for details of search strategies for CENTRAL
6. the need for additional medication or surgery as a (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix
consequence of a surgical complication; 3), LILACS (Appendix 4), BIOSIS (Appendix 5), OpenGrey (
7. systemic side effects, including the onset or worsening of Appendix 6), CINAHL (Appendix 7), Zetoc (Appendix 8), mRCT
chronic obstructive pulmonary disease, cardiovascular and (Appendix 9) and the ICTRP (Appendix 10).
central nervous system effects;
8. transient decrease in central vision secondary to
complications of surgical or medical treatment; or Searching other resources
9. local side effects (e.g. eye irritation, watering, redness and We searched the references of all retrieved studies and reviews for
discomfort). additional trials. We consulted the authors of the included studies
and experts in the field to find out if they knew of any relevant
published or unpublished RCTs that had not been identified. We
Economic data searched books relating to the management of glaucoma. We did
Any reports of cost or formal economic evaluation of the inter- not undertake manual searches of ophthalmology journals or con-
ventions are described. ference proceedings, and we did not contact pharmaceutical com-
panies or manufacturers of ophthalmic lasers and surgical equip-
ment.
Follow-up
The minimum length of follow-up required was one year.
The timing of the outcome assessment was: Data collection and analysis
1. short-term: outcomes up to one year, not including optic
disc/nerve fibre layer loss assessment or visual field data as these
are not useful measures in the short-term;
Selection of studies
2. medium-term: more than one year and less than five years;
3. long-term: five years or longer. Two review authors independently viewed the titles and abstracts
of all the studies identified by the electronic searches. Two review
authors then obtained the full-text copies of all possibly or defi-
nitely relevant studies and independently inspected them to deter-
Search methods for identification of studies mine whether they met the inclusion criteria. Where a difference
in opinion existed the review authors consulted a third review au-
thor as arbiter. We contacted study authors for clarification where
Electronic searches necessary.
We searched the Cochrane Central Register of Controlled Tri-
als (CENTRAL) 2012, Issue 7, part of The Cochrane Library.
www.thecochranelibrary.com (accessed 1 August 2012), Ovid Data extraction and management
MEDLINE, Ovid MEDLINE In-Process and Other Non-In- Two authors independently extracted data onto a modified version
dexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE of a form developed by the Cochrane Eyes and Vision group.
(January 1946 to August 2012), EMBASE (January 1980 to When data were missing or difficult to determine from the paper
August 2012), Latin American and Caribbean Literature on we contacted the authors for more information. All three review

Medical versus surgical interventions for open angle glaucoma (Review) 6


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
authors compared the extracted data and resolved discrepancies by high risk of bias: open random allocation; unsealed or non-
discussion. We extracted details as follows. opaque envelopes, alternation; date of birth
unclear risk of bias: not reported in sufficient detail to be
able to judge
Methods
(3) Blinding/masking (detection bias)
Methods of allocation, masking (outcome assessment), exclusions
Performance bias (masking of participants) from the
after randomisation, losses to follow-up, compliance and study
intervention received: trial participants could not be masked
design.
according to whether their allocation was medication or surgery
as the potential for bias was deemed uncertain
Participants low risk of detection bias: outcome assessment without
Country of enrolment, number randomised, age, sex, ethnicity, knowledge of group assignment or where outcome measurement
main inclusion and exclusion criteria. was not likely to have been influenced by lack of masking
high risk of bias: outcome assessment with prior knowledge
of group assignment where the outcome could be influenced by
Interventions lack of masking
Type and number of medications used, surgical method, use of unclear risk of bias: not reported in sufficient detail to be
anti-scarring agents, any immediate (within two weeks) postoper- able to judge
ative interventions. (4) Incomplete outcome data (attrition bias)
low risk of bias: no missing outcome data or missing
outcome data balanced across groups
Outcomes high risk of bias: reason for missing outcome data likely to
Relevant outcomes on which data were collected and length of be related to the true outcome with either imbalance in numbers
follow-up, exclusions/dropouts. or reasons for missing data across intervention groups; as treated
In the original review one author entered data into Review Man- analysis with substantial departure of intervention received from
ager (RevMan 2011) and a second author re-entered data using that assigned at outcome
the double data entry facility to check for errors and inconsisten- unclear risk of bias: not reported in sufficient detail to be
cies. One author (JB) entered the updated data from CIGTS into able to judge
RevMan.
(5) Selective outcome reporting
Low risk of bias: the study protocol is available and all of
Assessment of risk of bias in included studies the studys prespecified (primary and secondary) outcomes that
are relevant to this review are reported as prespecified; the study
Two authors independently assessed the methodological quality
protocol is not available but convincing narrative that published
of each included study according to the Cochrane Eyes and Vi-
reports include all expected outcomes
sion Group guidelines. One author (JB) updated the review and
high risk of bias: not all of the studys prespecified outcomes
assessed each trial for risk of bias, in terms of trial allocation se-
are reported; one or more primary outcomes is reported using
quence, allocation concealment, blinding (masking), incomplete
measurements that were not prespecified
data on outcomes and selective reporting of outcomes based on
unclear risk of bias: insufficient information to judge
guidelines given in Chapter 8 of the Cochrane Handbook for Sys-
tematic Reviews of Interventions (Higgins 2011). Uncertainties were
discussed and agreed with co-authors (AAB, AT) Measures of treatment effect
(1) Allocation sequence
low risk of bias: any truly random process, e.g. random
number table; computer random number generator) Categorical variables
high risk of bias: any non-random process, e.g. odd or even
date of birth; hospital or clinic record number) Where possible, we analysed visual field progression and visual
unclear risk of bias: not reported in sufficient detail to be acuity as categorical variables. If reported as a score, we analysed
able to judge the data as continuous variables. If summary effect measures were
reported, we entered the logarithm of the odds ratio (Ln OR) and
(2) Allocation concealment the standard error (SE) into RevMan (RevMan 2011) as generic
low risk of bias: telephone or central randomisation, serially inverse variance measures. When other studies presented similar
numbered sealed opaque envelopes outcomes using proportions, we calculated the OR and the 95%

Medical versus surgical interventions for open angle glaucoma (Review) 7


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
confidence interval (CI) and the Ln OR and its SE from the 95% Dealing with missing data
CI and entered them into RevMan as a generic inverse variance To deal with missing primary outcome data, we used available
effect measure. case analysis, i.e. whether participants were analysed in the groups
to which they were originally randomised without imputing any
data for the patients for whom the outcomes were not reported.
Continuous variables
For the secondary outcome of IOP in trials which had excluded
We analysed Intraocular pressure (IOP) as a continuous variable. failures from the point of failure, we did an exploratory analysis
For each study we calculated the mean IOP change from baseline, of the effect of including the treatment failures in the analysis and
including the standard deviation (SD) of change for each interven- the failures were assumed to have the worse case scenario with no
tion group, when possible. If the SD of change was not reported, lowering of IOP by treatment. We assigned the pretreatment IOP
we calculated this assuming a correlation of 0.5 between the base- as the final IOP level, and included all the randomised participants
line and endpoint IOP measures (Follmann 1992). In trials where in the analysis.
we excluded study failures from the randomised treatment from
the IOP analysis, we assigned treatment failures the IOP at base-
line. The effect of this assumption was tested in a sensitivity analy- Assessment of heterogeneity
sis. When means and standard deviations (SDs) were not reported
We examined the results to look for obvious differences between
directly, we extracted baseline and endpoint means and the cor-
the trials in the review. We checked for heterogeneity by examin-
responding SD from published graphs, if possible. If neither the
ing:
SD of change nor the SD of the endpoint measures were available,
1. the characteristics of the study;
we used an imputed SD from one of the other included trials.
2. the forest plot of the results of the studies; and
When visual field and visual acuity outcomes were reported as
3. statistical heterogeneity by inspecting the CIs for the results
mean scores, we analysed data as mean score change from baseline
of individual studies for poor overlap, and an I2 value. An I2
and the SD of change. In addition, mean scores over time were
measurement greater than 50% was taken to indicate substantial
presented in one trial (CIGTS) and we included these differences
heterogeneity (Deeks 2011).
in the analysis. One study reported health-related quality of life
as an outcome (CIGTS). The health-related quality of life scores
are reported as the differences in mean scores between the medical
Data synthesis
and surgical groups over the study period. The coefficients from
repeated measures analysis of variance over time are presented. Due to the variable methods used in the trials of collecting and
analysing data, pooling of the results was inappropriate apart from
the IOP analysis where Goldmann applanation tonometry (a stan-
Survival data dard measure of IOP) was used in all trials.
We assessed time to glaucoma progression (failure of randomised
treatment) and time to cataract surgery for the treatment compar-
isons using the log HR and its SE (variance), extracted directly or Subgroup analysis and investigation of heterogeneity
indirectly from the trial data (Parmar 1998). We had planned a subgroup analysis for participants of black race
and a separate analysis for groups with differing severity of glau-
coma (early, moderate and severe). No trials were identified with
Unit of analysis issues participants solely of black race. In one trial, 44% of the partici-
pants were non-white (CIGTS). Trials did vary according to the
stage of disease of the participants. Outcome measures for each
Data analysis study were analysed separately and described alongside the stage
We examined studies as to whether the unit of randomisation was of disease severity, as specified in each trial.
eyes or people. In all four included studies, the unit of randomi-
sation was one eye per patient. Wherever possible, we extracted
data on the basis of an intention-to-treat analysis. Where trial data Sensitivity analysis
were presented in several publications and with a variable length of For the pooled data we conducted a sensitivity analysis to assess
follow-up for the participants, we used only the most up-to-date the effect of:
report unless the papers reported different outcomes, in which case 1. excluding studies judged to be of lower methodological
we used earlier reports. We analysed outcomes where possible, in quality; and
a stratified manner according to short-, medium- and long-term 2. excluding studies where assumptions regarding outcomes
outcome assessment. on the failures of randomised treatment had been made.

Medical versus surgical interventions for open angle glaucoma (Review) 8


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
RESULTS Setting and participants
Three trials (Glasgow Trial 1988; Moorfields GT 1968; Moorfields
PTT 1994) were in the UK and one trial (CIGTS) in the USA.
Description of studies All of the participants had newly diagnosed OAG with no prior
treatment for glaucoma. The four included trials randomised a
See: Characteristics of included studies; Characteristics of excluded
total of 943 participants, however one trial was a three-arm trial
studies. randomising participants to either medical treatment, laser tra-
beculoplasty or trabeculectomy surgery. Data on participants ran-
domised to laser were excluded from the analysis for this review
Results of the search
and therefore the number of participants included in the review is
The original electronic and manual searches (2002) revealed 2735 888.
citations. We screened these and retrieved 35 full-text articles
for further assessment. We excluded four studies (Dastur 1994;
Egbert 2001; Stewart 1996; Watson 1984) as they were either not Interventions
randomised studies or were not comparisons of medical versus Three trials randomised participants to initial treatment with med-
surgical treatment. The reasons for exclusion are detailed in the ications or initial treatment with trabeculectomy. In one trial the
Characteristics of excluded studies table. Four trials, reported in surgical intervention was a modified Scheies procedure, i.e. a sec-
31 papers, met the criteria for inclusion (CIGTS; Glasgow Trial tor iridectomy combined with scleral cautery (Moorfields GT
1988; Moorfields GT 1968; Moorfields PTT 1994). 1968). We did not find any trials comparing medical therapy
with non-penetrating trabeculectomy, any other anti-glaucoma-
tous surgery or laser treatment to the ciliary body (transscleral cy-
Updated searches clophotocoagulation).
We conducted an updated search in April 2007. We identified one
additional potential study (Anand 2007), however, we excluded
this study as it was not a randomised or quasi- randomised study; Disease severity
the intervention was allocated according to patient preference. Moorfields GT 1968: The mean baseline IOP was 25 mmHg; the
The updated search identified three additional reports associated stage of glaucoma was not described.
with CIGTS 2001. Two reports related to the strategies of visual Glasgow Trial 1988: The mean baseline IOP was 36 mmHg; 65%
field testing in the study (Gillespie 2003; Musch 2005) and did of participants had moderate glaucomatous visual field loss, and
not provide any additional data for the review. One study (Jampel 35% had severe glaucoma (according to the study definition).
2007) described depression and mood indicators in the whole Moorfields PTT 1994: The mean baseline IOP was 35 mmHg;
trial cohort at baseline, but did not provide any data according to 48% of participants had severe glaucoma (according to the study
randomised group to add to the review. Finally, one study (Jampel definition).
2005) described perioperative complications of those randomised CIGTS: The mean baseline IOP was 27 mmHg. Participants had
to initial trabeculectomy, however, this report did not provide any on average mild glaucoma based on visual field score. The average
additional data on safety or effectiveness to include in this updated baseline CIGTS visual field score was 4.8 on a scale of 0 (no
review. defect) to 20 (severe defect); the average mean deviation (MD)
We undertook a further update search in August 2012, which from visual field testing was -5.5 dB. One hundred and sixty-eight
yielded 1020 new records. We screened the title and abstracts (27%) participants had no visual field defect, and were included
of the references and rejected 1014 abstracts as not eligible for on the basis of IOP >= 27 mmHG and an optic disc appearance
inclusion in the review. We obtained full-text copies of six papers compatible with glaucoma.
which are all additional reports related to the CIGTS study (Janz The details and definitions of glaucoma severity for each study are
2009; Musch 2006; Musch 2008; Musch 2009; Parrish 2009; provided in the Characteristics of included studies table.
Wren 2009). Musch 2006, Musch 2008, Musch 2009 and Parrish
2009 provided usable longer-term follow-up data (beyond five
years) on CIGTS participants in terms of need for cataract surgery, Types of outcome measures
IOP, visual field and optic disc findings respectively.
A summary of the included studies is given below, full details can
be found in the Characteristics of included studies table. Main outcomes
1. The primary outcome measure in all the trials was visual
field progression as measured using visual field analysers
Included studies (perimeters) available at the time of the study. The methods of

Medical versus surgical interventions for open angle glaucoma (Review) 9


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
perimetry, definitions of progression, and analysis of outcome reported for all eyes having surgery but this included fellow eyes
varied for each of the trials and are described in detail in the not included in the study, therefore analysis of adverse events was
Characteristics of included studies table. not possible according to the randomised group (CIGTS). Adverse
2. Health-related quality of life was a patient reported events were not reported in two studies (Moorfields GT 1968;
outcome in one trial (CIGTS). Moorfields PTT 1994).

Other outcomes Economic measures


1. All trials measured IOP at 12 months. Three trials reported One trial reported costs for each treatment arm (Glasgow Trial
IOP at latest analysis, with follow-up at 84 months (CIGTS; 1988). Costs were estimated at 1989 prices and were National
Moorfields GT 1968; Moorfields PTT 1994). Two trials Health Service (NHS) hospital costs. Costs to patients and pri-
excluded failures from the IOP analysis from the point of failure, mary care were not included. In this study the average costs per
which was inadequate control of IOP (Glasgow Trial 1988; patient per year were calculated and then adjusted for the observed
Moorfields PTT 1994). mortality rate in the trial population to estimate a prospective cost
2. Optic disc appearance was an outcome measure in one trial per patient for a glaucoma population. The trial costs were based
(Glasgow Trial 1988). In the CIGTS study longer-term optic on an average inpatient stay of 7.6 days for trabeculectomy. Costs
disc findings are reported (Parrish 2009). were also estimated on the basis of a shorter inpatient stay. In this
3. All trials assessed visual acuity at latest follow-up. review we report the estimated costs for patients not eyes.
4. The need for cataract surgery was reported in two trials
(CIGTS; Moorfields PTT 1994). Following contact with the
Excluded studies
author, further information was received for a third trial
(Glasgow Trial 1988). We excluded five studies and further information can be found in
5. The need for additional medicine or surgery as a the Characteristics of excluded studies table.
consequence of intervention failure was reported by all the
studies except for Moorfields GT 1968.
Risk of bias in included studies
The risk of bias is presented graphically in Figure 1. Three of the
Adverse events included studies were conducted in the 1980s or earlier and a full
Adverse events were reported by intervention group in one trial protocol was not available. Limited reporting was the main reason
(Glasgow Trial 1988). In one trial surgical complications were for the rating of an unclear risk of bias

Medical versus surgical interventions for open angle glaucoma (Review) 10


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Risk of bias summary: Review authors judgements about each risk of bias item for the primary
outcome for each included study.

Allocation
ity of life in one study (CIGTS); the interviewers were masked to
In all four trials the method of randomisation and allocation con- the intervention received although the participants were aware of
cealment was judged to be at low risk of selection bias. The method their randomised intervention. The measure of the primary clini-
of concealment was reported in two trials (CIGTS; Moorfields GT cal outcome for this review (visual fields) was objective, although
1968) and in the other two trials further information supplied by based on subjective responses by the patient, and was well de-
the study authors suggests that the method was adequate (Glasgow scribed in the included studies. The CIGTS used standard auto-
Trial 1988; Moorfields PTT 1994). mated perimetry as the primary outcome measure of visual field
loss and as the reading is automated it was judged as low risk of
Blinding detection bias. In the other three included studies (Glasgow Trial
1988; Moorfields GT 1968; Moorfields PTT 1994), although the
The assessment of outcomes was not masked for any of the trials
scoring system was well described it was unclear as to whether
apart from the telephone interviews recording health-related qual-

Medical versus surgical interventions for open angle glaucoma (Review) 11


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the assessor was independent. The risk of detection bias of open CIGTS was judged as low risk of attrition bias for the primary
outcome assessment was, on this basis, judged as unclear for these visual field outcome at five years. Visual field outcome beyond five
three studies. years is at high risk of attrition bias.
Medium-term health-related quality of life: Patient reported out-
come data at four years, were available for 266 (89%) of partici-
Incomplete outcome data pants randomised to initial surgery and 283 (93%) of participants
randomised to initial medication (Janz 2001).
Moorfields GT 1968: In this study the participants were followed
Long-term health-related quality of life: At five years, data were
for up to 18 years. In the latest reported analysis, the median fol-
available for 195 (65%) participants randomised to initial surgery
low-up time was 51 months, and six patients in total were lost
and 210 (68%) participants randomised to initial medication (Janz
to follow-up; five of these in the group assigned to medical treat-
2001). As missing outcome data were balanced across groups the
ment. This trial was not an intention-to-treat analysis as four par-
health-related quality of life outcome assessment was judged as low
ticipants who either refused or did not receive surgery remained
risk of attrition bias for the health-related quality of life outcome.
under review, but were not included in the data analysis.
Glasgow Trial 1988: Recruitment into the trial was approximately
25 participants each year. In the analysis for this review the out-
come assessment for visual acuity loss and visual field change in-
cluded data on all the trial participants who had completed at least Selective reporting
one year in the study and was from diagnosis to latest follow-up. CIGTS: The primary endpoint of the CIGTS study was sustained
Participants therefore had a varying length of follow-up at the time progression in visual field loss ascertained by a CIGTS score de-
of the outcome assessment. This may be a source of bias as at the rived from standard automated perimetry. Progression was defined
end of year five the length of follow-up between treatment groups as an increase in visual field score of three units or more from base-
was not comparable. Twenty-five out of 57 participants (44%) in line reference score. The timing of the primary endpoint was not
the group treated with medications and 30/50 participants (60%) stated. Secondary outcomes were IOP and health-related quality
treated by primary trabeculectomy were available for the final anal- of life using an instrument designed for the study. Interim out-
ysis. IOP was not an endpoint for this study and participants not comes are reported at five years. Subsequent reports report long-
controlled by the randomised treatment were excluded from the term follow-up of the primary outcome measured by mean devia-
IOP analysis. Analysis of IOP reduction was not an intention-to- tion, a different index of visual field loss derived from the standard
treat analysis. automated perimetry output. Interim outcomes are based on the
Moorfields PTT 1994: A survival analysis for the outcome time CIGTS score and deemed low risk of reporting bias. CIGTS scores
to failure of the randomised treatment accounts for the variable were not reported for longer-term outcomes (five years or longer).
length of follow-up and losses to follow-up. visual field analysis by The study was thus judged at high risk of selective reporting bias.
Humphrey automated perimetry was introduced two years into For Glasgow Trial 1988; Moorfields GT 1968; Moorfields PTT
the study; there may already have been differential progression be- 1994, study protocols were not available, although study design
tween treatment groups at two years and therefore any differences was described in the primary study reports. These three studies
in terms of visual field progression from this post-randomisation report as to predefined primary outcome but losses to follow-
baseline may not be apparent in this analysis. up were poorly reported; thus they are judged as unclear risk of
The IOP and visual field outcomes, as assessed by Friedman selective reporting bias.
perimetry, were not analysed according to the intention-to-treat
principle in that once a participant had failed the assigned treat-
ment they were excluded from the main outcome analysis.
These three studies were judged to be high risk of attrition bias.
Effects of interventions
CIGTS: The study protocol, Musch 1999 did not specify the The included trials were initiated over many years from the earliest
timing of the primary outcome. Interim data were presented before trial in 1968 up to the most recent trial in 1993. Not only have
all participants had reached a five-year outcome. glaucoma medications and surgical techniques changed over this
Long-term visual field: Five-year visual field data were available for period but there have been marked technological developments in
255 (85%) in the initial surgery group and 269 (87%) of the initial the measurement of glaucoma visual field loss. Combining study
medication group. Data analysis was adjusted for time in the study. results with such heterogeneous treatments and outcome measures
Higher risk of bias for longer-term visual field data: At seven years, was not sensible and therefore we have described the results for
visual field data were available for 198 (72%) in the initial surgery individual studies, apart from the IOP data where data synthesis
group and 218 (74%) of the initial medication group. At eight for trials using similar medications was meaningful. For the main
years, visual field data were available for 142 (47%) of the initial outcome, progressive visual field loss, an increased score means
surgery group and 153 (50%) of the initial medication group. worsening of visual field, i.e. progression.

Medical versus surgical interventions for open angle glaucoma (Review) 12


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Initial medical treatment versus primary Scheies Progressive visual field loss
procedure (Analysis 1)
One trial examined this comparison (Moorfields GT 1968). The Risk of progressive visual field loss (Analysis 2.1)
results are presented for 43/52 (82%) included participants; 22
received primary medical treatment and 21 had primary surgery
with an average of six to eight years follow-up. Five participants in
the medicine treatment group had moved away and no follow-up Medium-term (more than one year and less than five years)
data were available. Four participants who did not receive surgery Glasgow Trial 1988: At the latest follow-up, mean of 4.6 years, 27/
were excluded from the trial data analysis. 57 (47%) participants initially treated with medical therapy had
progressed by at least one stage of visual field severity compared
to 13/50 (26%) participants undergoing primary trabeculectomy
Progressive visual field loss (odds ratio (OR) 2.56, 95% CI 1.12 to 5.83).
Long-term (five years or longer)
Participants treated medically had significantly more increase in Moorfields PTT 1994: In a secondary analysis with visual field
visual field score from baseline than participants having a primary assessed by Humphrey automated perimetry introduced two years
Scheies surgical procedure (mean difference (MD) in change in into the study, (Hitchings 2004), 25/40 (63%) participants in
visual field score from baseline was 14.62 (95% CI 4.67 to 24.57)); the initial medication group had progressive visual field loss (two
a higher visual field score indicating progression of visual field loss consecutive, significant (P < 0.05 level) negative regression slopes)
(Analysis 1.1). compared with 34/48 (71%) participants treated by initial tra-
beculectomy (OR 0.69, 95% CI 0.29 to 1.67).
CIGTS: Using repeated measures logistic regression, at interim
Intraocular pressure reduction follow-up (five years) there was no evidence of a difference in the
risk of progressive visual field loss of at least three CIGTS units
Initial surgery was associated with significantly greater IOP reduc- from baseline between the treatment groups after adjusting for
tion than medical treatment of 8 mmHg in the short-term (MD baseline visual field score, age, sex, race, diagnosis, diabetes and
in change of IOP from baseline was 8.0 (95% CI 4.42 to 11.58)) time in study (OR 0.74, 95% CI 0.54 to 1.01). This effect estimate
and about 6 mmHg at long-term follow-up (MD 5.6, 95% CI did not change with adjustment for cataract (OR 0.75, 95% CI
2.02 to 9.18) (Analysis 1.2). 0.55 to 1.02); analysis plot not shown (Lichter 2001).
At five and eight years post-randomisation, Musch 2009 reports
no statistically significant difference in the risk of visual field pro-
Visual acuity gression (defined as -3 dB or more from baseline) according to
initial randomised treatment. Effect estimate and 95% CIs were
There was no statistically significant difference in visual acuity not reported. (Musch 2009).
reduction (MD 5.80, 95% CI -18.43 to 30.03). In both groups the
visual acuity decreased markedly over the study period (Analysis
1.3). Mean difference in visual field scores (Analysis 2.2; Analysis
2.3; Analysis 2.4)
Moorfields PTT 1994: The primary trial report of Migdal 1994
reported the mean difference in visual field score based on Fried-
Adverse events
mann perimetry with a minimum of five-year follow-up. The anal-
At the last follow-up (mean 6.8 years) in the one included study ysis excluded the 10 treatment failures in the medicine treated
(Moorfields GT 1968), 9/52 (17%) participants had died. The group and the one failure in the trabeculectomy group. Partici-
deaths were not reported according to treatment group. It was re- pants treated successfully by medical treatment, as defined by an
ported that there were no serious surgical disasters. The develop- IOP of less than 22 mmHg, had a greater increase in visual field
ment of cataract or side effects from medications was not reported. score from baseline (worsening of visual fields) than participants
treated successfully by primary trabeculectomy. The mean differ-
ence in visual field score from baseline, where the mean score of
the last three fields was compared to the mean score of the first
Initial medical treatment versus initial
three measured fields, was 3.92 (95% CI 2.02 to 5.82) in favour
trabeculectomy (Analysis 2)
of primary trabeculectomy (Analysis 2.2).
Three studies examined this comparison (CIGTS; Glasgow Trial CIGTS: Musch 2009 report visual field (mean deviation) scores
1988; Moorfields PTT 1994). up to nine years post-randomisation with the baseline taken as two

Medical versus surgical interventions for open angle glaucoma (Review) 13


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
years post-randomisation. At eight and nine years, data were avail- primary surgery was associated with approximately 5% more dys-
able on 48% and 25% of trial participants respectively. Repeated function than initial medical treatment (P = 0.02). In Musch 2009
measures models explored factors associated with long-term visual vision specific quality of life data are reported in the longer-term
field outcomes. (median of 7.7 years) but not by randomised group.
Mean difference in visual field scores (unadjusted): At five years Glaucoma specific measures: There were no treatment specific differ-
(long-term), based on 269 (88%) of participants randomised to ences on the Glaucoma Health Perceptions Index. Using a measure
initial medication and 255 (85%) randomised to initial trabeculec- specifically designed for CIGTS, the Symptom Impact Glaucoma
tomy, there was no evidence of a difference in MD scores between Scale, the participants treated by initial trabeculectomy reported
groups (mean difference -0.20 dB, 95% CI -1.31 to 0.91) (Analysis 22.3% more symptoms on the total score (P = 0.005), 9.4% more
2.3). symptoms on the visual function subscale (P = 0.15) and 20.2%
At eight years, based on available data on 153 (50%) participants more symptoms on the local eye symptom subscale (P = 0.03)
in the initial medication group and 142 (47%) participants in the compared with patients treated with initial medical treatment.
initial surgery group, there was no evidence of a difference in MD
scores between groups (mean difference 0.20 dB, 95% CI -0.91
to 1.31); analysis plot not shown. Other outcomes
The mixed models provide additional data on the prespecified sub-
(1) IOP reduction (Analysis 2.5; Analysis 2.6; Analysis 2.7)
group of black ethnicity and glaucoma severity. Thirty-seven per
Glasgow Trial 1988; Moorfields PTT 1994: In 190 participants,
cent of CIGTS participants were of black ethnicity. The treatment
IOP reduction was 6 mmHg greater by initial trabeculectomy than
effect was not modified by ethnic status (black ethnicity and no
by initial medical treatment at one year (mean difference 6.14,
cataract), (mean difference -0.31 dB, 95% CI -0.76 to 0.14). Par-
95% CI 4.25 to 8.02). In 106 participants with medium-term
ticipants of black ethnicity, undergoing cataract surgery had more
follow-up, IOP reduction was no different between the groups
visual field loss over time than white participants, (mean difference
(mean difference 1.6, 95% CI -0.69 to 3.89) but a difference of
-3.65dB, 95% CI-4.43 to -2.87). Data reported by Musch 2009.
3.4 mmHg greater IOP reduction by primary trabeculectomy was
Analysis plots not shown.
shown for 102 participants with long-term follow-up at five years
In the long-term (five years) for participants with more severe glau-
(mean difference 3.4, 95% CI 1.04 to 5.76) (Analysis 2.5). Both
coma (MD -10 dB) at baseline (two years post-randomisation),
of these trials had excluded failures from the point of failure. In
those treated surgically had a marginally better visual field score
an exploratory analysis (Analysis 2.6) we assigned the pretreat-
than those treated medically (mean difference 0.74 dB (95% CI
ment IOP as the final IOP level, and included all the randomised
-0.00 to 1.48). There was no evidence of a difference for those
participants in the analysis and with these assumptions surgery
with milder glaucoma at baseline (MD -2.0 dB), mean difference
lowered IOP more than medication at one year, up to five years
-0.22 dB (95% CI -0.69 to 0.25) (Analysis 2.4).
and beyond. The results of this exploratory analysis did not differ
from the primary analysis apart from in the medium-term where
surgery lowered IOP more than medicine.
Health-related quality of life CIGTS: In this study a target IOP outcome had been calculated
CIGTS: At a minimum of four years follow-up 409/607 (67%) for each trial participant based on the severity of the glaucoma.
participants had received treatment to the fellow eye. The analysis This target IOP is the estimated IOP level at which the risk of
of the health-related quality of life data was undertaken on 210/ progressive disease is minimised. For this reason the reduction of
222 participants (95%) treated initially with medications and for IOP by treatment is not strictly comparable with earlier trials. In
195/215 (91%) of participants treated by initial trabeculectomy. these trials an acceptable IOP (one that did not trigger a medica-
The number of participants in each treatment arm without health- tion change) was 20 mmHg to 22 mmHg, whereas CIGTS aimed
related quality of life follow-up data was the same, i.e. 85 par- for an individual target IOP and therefore the differences in IOP
ticipants in each group. This was due to either death or that the between the groups were likely to be small. In 595 participants
follow-up interval had yet to occur. at one year mean difference in decrease of IOP from baseline was
Generic measures: The repeated measures ANOVA models did not 3.6 mmHg (3.60, 95% CI 2.78 to 4.42) favouring trabeculec-
find any statistically significant differences at latest follow-up (min- tomy. Up to nine years, based on data from 578 participants (293
imum four years) between the treatment groups. initial medication and 2852 initial trabeculectomy), mean IOP
Vision specific measures: No statistically significant treatment group was higher in the medication group compared to the group ran-
differences were found for the total score of the visual activities domised to initial trabeculectomy (mean difference 2.20 mmHg
questionnaire or the subscale for peripheral vision. However, on (95% CI 1.63 to 2.77)) (Analysis 2.7).
the visual activities questionnaire acuity subscale, using repeated (2) Optic disc change
measures analysis of variance and with adjustment for baseline Glasgow Trial 1988: Using a change of vertical cup to disc ratio
quality of life score, age, gender, education and systemic disease, of +/- 0.1 or more, no significant difference in the appearance of

Medical versus surgical interventions for open angle glaucoma (Review) 14


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the optic discs was reported between treatment groups at latest CIGTS: no statistically significant difference was demonstrated
follow-up, mean 33 months. in the risk of failure of randomised treatment, defined as need to
CIGTS: Parrish 2009 report the optic disc findings, based on crossover from medicine to surgery or vice-versa, over the five-year
stereo-photographs of study eyes, obtained from available data in follow-up period of initial medical treatment compared to initial
a six-month window of the five-year follow-up assessment. 18/ trabeculectomy (HR 1.07, 95% CI 0.62 to 1.86) (Analysis 2.11).
185 (10%) in the initial medication group and 4/163 (3%) of
the initial trabeculectomy group progressed based on optic nerve (b) Need for argon laser trabeculoplasty (Analysis 2.12)
criteria, (OR 4.28, (95% CI 1.42 to 12.94)) (Analysis 2.8). CIGTS: Argon laser trabeculoplasty (ALT) was the penultimate
treatment step in the medical arm, whereas in the surgically-treated
(3) Visual acuity loss (Analysis 2.9) group ALT was the second treatment step after failure of the pri-
Glasgow Trial 1988: At final follow-up, mean 4.6 years, there was mary trabeculectomy. Participants treated initially with medica-
no evidence of a difference in visual acuity loss of at least 2 lines of tions were significantly more likely to need ALT at one year (OR
Snellen acuity between treatment groups (OR 1.48, 95% CI 0.58 2.36, 95% CI 1.52 to 3.67) and at four years (OR 1.46, 95%
to 3.81). CI 1.01 to 2.13) in the medical group compared to primary tra-
CIGTS: Initial medical treatment was associated with half the risk beculectomy.
of a visual acuity loss of at least LogMAR 0.3 (approximates to
2 Snellen lines) compared with surgically treated participants, ad-
justing for age, race, history of diabetes, time in study and cataract Adverse events
surgery (OR 0.5, 95% CI 0.33 to 0.75) at up to five years follow-
up (Lichter 2001). The report of longer-term follow-up of CIGTS
participants did not report visual acuity outcomes (Musch 2009).
Moorfields PTT 1994: At five years, the visual acuity of the partic-
ipants treated successfully by trabeculectomy (n = 56) was reported (1) Mortality
as less than half a Snellen line of acuity lower than the participants Glasgow Trial 1988: At the latest follow-up (mean 4.6 years) 16/
remaining on medical treatment (n = 46), and no significant dif- 112 (14%) participants recruited to the trial were known to have
ference in mean acuity scores over the five-year follow-up period. died. Seven of these deaths were in the group allocated to initial
Insufficient data were reported to allow inclusion of these findings medical treatment, and eight people who had undergone initial
in the analysis plot (Migdal 1994). trabeculectomy. For one death information is not available as to
(4) Need for additional medication or surgery as a consequence of which initial treatment was received.
inadequate glaucoma control (Analysis 2.10; Analysis 2.11; Analysis
2.12). Moorfields PTT 1994: Not reported.
(a) Failure of randomised treatment, i.e. treatment crossover CIGTS: With up to nine years follow-up, 16 (5%) participants
(Analysis 2.10; Analysis 2.11) were reported to have died in those randomised to initial medica-
The indications for treatment crossover varied across the trials. tion and 26 (9%) in those randomised to initial surgery (Musch
In two trials, initial medical treatment was less likely to achieve 2009).
satisfactory IOP control compared to initial trabeculectomy
(Glasgow Trial 1988; Moorfields PTT 1994).
Glasgow Trial 1988: 17/53 (32%) participants had failed medical
treatment at one year and had required trabeculectomy, whereas
(2) Loss of an eye due to infection or inflammation
7/46 (15%) eyes in the trabeculectomy treated group had required
additional medical therapy to achieve satisfactory IOP control This outcome was not reported in any of the trials.
(OR 2.63, 95% CI 0.98 to 7.08). At an average follow-up of three
years the differences were significant with the participants treated
with conventional medical therapy being almost four times more
likely to have failed compared to trabeculectomy participants (OR (3) Severe irreversible reduction in vision
3.90, 95% CI 1.60 to 9.53) (Analysis 2.10).
Glasgow Trial 1988: At one year, 6/46 (13%) eyes in the medical
group had lost central fixation and in the subsequent two years of
Moorfields PTT 1994: Over a five-year follow-up, initial medical
follow-up a further two participants in this group had lost central
treatment was less likely to achieve an IOP 22 mmHg or less than
fixation. No participants in the trabeculectomy group lost central
primary trabeculectomy, and required crossover to one of other of
fixation over a mean follow-up time of 33 months.
the alternative treatment arms (hazard ratio (HR) 7.27, 95% CI
Moorfields PTT 1994 and CIGTS did not report on irreversible
2.23 to 23.71) (Analysis 2.11).
severe visual loss.

Medical versus surgical interventions for open angle glaucoma (Review) 15


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(4) Visually significant cataract total estimated prospective cost per patient, adjusted for survival,
Overall in the three trials with follow-up to five years (CIGTS; over an eight-year period at 1989 prices was GBP 2569 for par-
Glasgow Trial 1988; Moorfields PTT 1994), 57/403 (14%) of ticipants receiving initial medical therapy compared to GBP 2560
participants treated by trabeculectomy developed cataract com- for initial trabeculectomy, based on an average inpatient stay for
pared to 24/416 (6%) treated medically (OR 2.69, 95% CI 1.64 surgery of 7.6 days. For participants with unilateral disease, (46/
to 4.42). Analysis plot not shown. 104), the comparative cost estimates were GBP 1920 for medical
therapy and GBP 2139 for surgery. A cost estimate of the effect of
reducing the inpatient stay for surgery to one day was undertaken;
for participants with bilateral OAG the cost estimate was GBP
(5) Cataract surgery 1405 for initial medical therapy (including the cost of surgery for
This outcome was not reported in Glasgow Trial 1988 and 17/53 participants who failed initial medical therapy) compared
Moorfields PTT 1994. In CIGTS, at up to three years follow- to GBP 1130 for initial trabeculectomy.
up (medium-term), primary trabeculectomy was associated with CIGTS and Moorfields PTT 1994 did not assess economic mea-
almost three times the risk of requiring cataract surgery (HR 2.72, sures.
95% CI 1.51 to 4.89). Longer-term, based on data on 290 (94%)
participants randomised to initial medication and 287 (96%) to
trabeculectomy, primary trabeculectomy was associated with al-
most four times the risk of requiring cataract surgery (HR 3.76,
95% CI 2.16 to 6.54) (Lichter 2001). Beyond five years, there was
no statistically significant differences in the risk of cataract surgery DISCUSSION
between randomised groups (HR 0.63, 95% CI 0.15 to 2.62),
analysis plot not shown; data reported in Musch 2006.

Summary of main results


(6) Need for additional treatment as a consequence of a The aim of this review was to study the comparative effectiveness
surgical complication of medical and surgical treatment for patients with open angle in
CIGTS: Surgical complications were reported but included data terms of measures of glaucoma progression and patient reported
on fellow eyes treated, so the results are not specifically for the health-related quality of life. We included four trials involving 888
eyes included in the trial. The complications reported for all tra- participants with previously untreated OAG. Surgery was Scheies
beculectomies performed on the study participants, 73/517 (14%) procedure in one trial (Moorfields GT 1968) and trabeculec-
had shallow or flat anterior chambers during the first postoperative tomy in three trials (CIGTS; Glasgow Trial 1988; Moorfields
month, 61/517 (12%) had encapsulated blebs, 61/517 (12%) had PTT 1994). In three trials, primary medication was usually pi-
ptosis, 58/517 (11%) had serous choroidal detachment and 54/ locarpine (Glasgow Trial 1988; Moorfields GT 1968; Moorfields
517 (11%) had anterior chamber bleeding of hyphaema. PTT 1994) and in one trial (CIGTS) a beta-blocker. The most re-
Glasgow Trial 1988 and Moorfields PTT 1994 did not report this cent trial, CIGTS, included participants with OAG at the mild end
outcome. of the glaucoma spectrum. One hundred and sixty-eight (27%)
participants had pre-perimetric glaucoma (glaucoma defined in
the basis of raised IOP 27 mmHg and glaucomatous optic nerve,
but without a visual field defect. The average baseline visual field
(7) Systemic and local side effects of treatment score was 4.8 on a scale of 0 (no defect) to 20 (all points severely
CIGTS: These outcomes are measured in the health-related quality depressed compared with a normal visual field). Glasgow Trial
of life instruments. 1988, Moorfields GT 1968 and Moorfields PTT 1994 included
Glasgow Trial 1988 and Moorfields PTT 1994 did not assess these participants with more severe glaucoma.
outcomes. The evidence suggests that, in moderate to severe glaucoma and
using a treatment regime including pilocarpine (not now consid-
ered usual care), lower IOP and preservation of visual field is more
Economic data likely to be achieved with primary surgery rather than primary
Glasgow Trial 1988: Costs were estimated for 53 participants ran- medical treatment. In milder glaucoma, the findings from CIGTS
domised to initial medical therapy and 51 participants randomised suggest that in the longer- term (defined as five years or longer)
to initial trabeculectomy surgery. The four participants refusing there is no substantial difference in progressive visual field loss,
surgery and eight participants lost to follow-up were excluded from after adjustment between initiating medication (usually a beta-
the analysis. For participants with bilateral disease (58/104), the blocker) or primary trabeculectomy. In the long-term (follow-up

Medical versus surgical interventions for open angle glaucoma (Review) 16


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
up to nine years) there were more deaths in those treated with there was no significant difference in the need for cataract surgery
initial surgery. between groups (Musch 2006).
Musch 2009 reports longer-term follow-up of CIGTS. An ex- Adverse events were reported by treatment group in the Glasgow
ploratory subgroup analysis suggests that for those of black ethnic- Trial 1988, which reported loss of central fixation in four of the
ity and no cataract the treatment effect on visual field outcome was medically-treated participants and no events with trabeculectomy.
not modified by ethnic status. But, for participants of black ethnic- Side effects related to treatment were not specifically reported in
ity undergoing cataract surgery, the visual field loss over time was any of the trials, except for CIGTS where these would be captured
greater than white participants with cataract. In the long-term, for in the health-related quality of life measures.
a subgroup of participants with more severe glaucoma (MD -10 In two trials (Glasgow Trial 1988; Moorfields PTT 1994) at up to
dB), those treated with primary trabeculectomy had a marginally five-year follow-up medical treatment was associated with a greater
better visual field score than those treated medically. No difference risk of failure, in terms of IOP, than trabeculectomy. Medications
was found for those with milder glaucoma at baseline (MD -2.0 and surgery have evolved since these trials were undertaken. In
dB). Parrish 2009 reports the optic nerve findings at five-year fol- CIGTS at five years the risk of intervention failure was not statis-
low-up reporting a higher incidence of optic disc progression in tically significantly different between the treatment arms although
the initial medication group at five years. There was differential the medically-treated group were more likely to have progressed
availability of optic nerve photographs for analysis between groups in their treatment sequence to argon laser trabeculoplasty than the
and thus potential for attrition bias. surgically-treated group at one year. At four years this difference
Only one study assessed patient reported outcomes (CIGTS). Par- was smaller but still significant. This suggests that many treatment
ticipants who required bilateral treatment were randomised such steps are required with initial medical treatment to achieve the
that the fellow eye received initially the same treatment as the study desired target IOP, but over longer follow-up primary trabeculec-
eye. Several measures were used, both generic and glaucoma spe- tomy patients also require additional treatment.
cific. Overall, primary trabeculectomy was associated with more None of the trials included cost-effectiveness evaluations. The
difficulty with tasks related to visual acuity and with more symp- cost-analysis done in the Glasgow Trial 1988 shows that on a cost
toms related to local eye discomfort compared to patients treated only basis, trabeculectomy was slightly more costly than medi-
with initial medical treatment analysed over the five-year follow- cal treatment over an eight-year period. Modelling estimates of
up period. No differences were found between the treatment group the costs according to a reduced inpatient stay for surgery suggest
concerning overall visual function, systemic symptoms, and over- that by reducing the time of inpatient stay or performing day case
all well being. Using a measure specifically designed for CIGTS, surgery, trabeculectomy may be less costly than medical therapy. A
the Symptom Impact Glaucoma Scale, the participants treated by formal economic evaluation of the costs and benefits of alternative
initial trabeculectomy reported 22.3% more symptoms on the to- treatments is required.
tal score (P = 0.005). Musch 2009 reports longer-term vision spe-
cific scores with a median follow-up at 7.7 years. Scores were not
reported by randomised group and thus provided no usable data Overall completeness and applicability of
for this review. evidence
Visual acuity change did not differ according to initial treatment in
The review includes evidence on the effects of medical and surgical
Glasgow Trial 1988 or Moorfields PTT 1994 whereas in CIGTS,
interventions in mild and more severe OAG and includes trials
trabeculectomy was associated with an increased risk of deterio-
evaluating the medical versus surgical management of OAG initi-
ration of visual acuity, with up to five years follow-up (OR 0.47,
ated over a long period of time, 1968 to 1993. Medical and surgi-
95% CI 0.31 to 0.74). The reduced acuity may be due to early
cal treatments for OAG have evolved considerably since the first
cataract that did not require surgery.
trial of medical versus surgical therapy for OAG. Glasgow Trial
In three trials (CIGTS; Glasgow Trial 1988; Moorfields PTT
1988, Moorfields GT 1968 and Moorfields PTT 1994 included
1994), the risk of developing cataract was higher with trabeculec-
participants with moderate and severe glaucoma and evaluated in-
tomy. Overall, cataract surgery was more likely when the initial
terventions that are not now standard therapy for OAG; the results
treatment was trabeculectomy; this was only apparent in the largest
of these trials may not be of relevance to current practice.
trial (CIGTS). Surgical techniques for cataract have been modi-
Scheies surgery (the surgical intervention in the Moorfields GT
fied since the early trials with a trend toward surgery at an earlier
1968 trial) is not now considered as a surgical procedure for glau-
stage. It may be that there were safety concerns regarding cataract
coma; it is very effective at lowering IOP but it is associated with
surgery at the time of the early trials that may have precluded
a high rate of complications (Blondeau 1981). Trabeculectomy is
surgery. The Glasgow Trial 1988 found no significant difference
the current surgical procedure of choice. Advances in medical ther-
in the development of new cataract at one year between the two
apy for OAG have changed practice, topical prostaglandin ana-
groups, but this was not reported at final analysis. Longer- term
logues, alpha-2 agonists and carbonic anhydrase inhibitors were
outcomes of CIGTS are now reported; At seven year follow-up
introduced in the mid-1990s. We did not find any trials compar-

Medical versus surgical interventions for open angle glaucoma (Review) 17


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ing medical therapy to other surgical techniques, such as nonpene- Agreements and disagreements with other
trating surgery, tube drainage devices and transscleral cyclophoto- studies or reviews
coagulation. The latter two surgeries are usually reserved for cases
Other studies have confirmed the importance of lowering IOP as
of refractory OAG. In CIGTS the medical treatments were not
a predictor of better outcome in early and late glaucoma (AGIS
defined but treatment was usually a beta-blocker and the protocol
2000; CNTGSG 1998; Heijl 2002; Kass 2002). All the included
allowed medical treatments to be modified according to clinician
trials showed an increased lowering of IOP by surgery compared
choice and are likely to have included contemporary treatments.
to medical treatment at all time points. In CIGTS the differences
CIGTS is the most relevant study to current practice in Europe
were smaller, as expected from the design of the study in which
and the USA. The participants on average had mild glaucoma
a target IOP was set and treatment escalated accordingly to reach
(CIGTS visual field score 4.9 (scale of 0 to 20, with 20 indicating
this target. Similarly, the minimal visual filed loss over time may
severe glaucoma)). Findings from exploratory analyses suggest that
reflect the tight control of IOP in both treatment groups.
although there was no difference in the primary outcome (visual
field), progressive glaucomatous optic neuropathy was more likely
if initial treatment was medication, and that those with more se-
vere glaucoma may benefit from primary trabeculectomy; further
research is required. AUTHORS CONCLUSIONS
The failure of randomised treatment and the need for treatment
changes within an intervention arm are important outcomes, par- Implications for practice
ticularly when considering the economics of an intervention and Primary surgery lowers IOP more than an initial medication treat-
patient satisfaction with treatment. The Glasgow Trial 1988 com- ment policy. Evidence from one study suggests that at five years
pared costs of the alternative treatment strategies, but none of the follow-up, the average visual field loss is small (-0.2 dB) and not
included studies included an evaluation of the cost-effectiveness significantly different when primary contemporary medication is
of alternative initial management strategies. compared with trabeculectomy. For a subgroup with more severe
glaucoma (MD -10 dB), findings from an exploratory analysis
suggest that initial trabeculectomy is associated with marginally
less visual field loss at five years than initial medication, (mean dif-
Quality of the evidence ference 0.74 dB (95% CI -0.00 to 1.48)). Primary trabeculectomy
The design and conduct of trials comparing medical therapies ver- is associated with more local eye symptoms, a higher incidence of
sus surgery are complex to design. All the included studies had cataract and reduced visual acuity at up to five years follow-up. Be-
methodological weaknesses and the findings should be interpreted yond five years, there is no evidence of a difference in the need for
accordingly. The primary outcomes of this review were progres- cataract surgery according to initial medication or trabeculectomy.
sive visual field loss and health-related quality of life. Different The clinical and cost-effectiveness of alternative initial treatment
measures of the visual field and definitions of progression were policies is not known.
used in each study and thus limited any meta-analysis. This is un-
derstandable due to technological advances in visual field testing Implications for research
over the past two decades. In addition, visual field loss is subject Further RCTs of current medical treatments compared with
to short-term and long-term fluctuation, making the definition of surgery are required, particularly for people with severe glaucoma
true progressive visual field loss difficult; repeat testing is required and in black ethnic groups. Outcomes should include those re-
to establish that true change has occurred. ported by patients. Economic evaluations are required to inform
The extent of visual field loss is an important clinical outcome. A treatment policy.
standardised measure of visual field loss, measurement protocol,
and definition of clinical important change is required for future
studies. Ony one study (CIGTS) measured patient reported out-
comes using a questionnaire designed for the study, comprising
ACKNOWLEDGEMENTS
240 questions. The questionnaire was administered by telephone
six-monthly throughout the study. Patient reported outcomes are The Cochrane Eyes and Vision Group (CEVG) Trials Search Co-
an important complement to clinical outcomes when comparing ordinator and Cynthia Fraser, information scientist (Health Ser-
alternative treatment strategies. However the method of data col- vices Research Unit, University of Aberdeen), developed and ex-
lection, multiple measures with frequent administration by tele- ecuted electronic searches for all the databases. Dr Craig Ram-
phone interview which is not representative of current practice, say, senior statistician in the Health Services Research Unit in Ab-
may have diluted any differences in patient reported outcomes. erdeen provided statistical advice for this review. The principal in-
The effect of this attention is uncertain. vestigators of CIGTS, Glasgow Trial 1988, and Moorfields PTT

Medical versus surgical interventions for open angle glaucoma (Review) 18


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1994 were contacted and we are very grateful for the additional Foundation Trust and UCL Institute of Ophthalmology for a Spe-
information provided. We are also grateful to Scott Fraser, Catey cialist Biomedical Research Centre for Ophthalmology. The views
Bunce and Roberta Scherer for peer review and to Anupa Shah, expressed in this publication are those of the authors and not nec-
Managing Editor for CEVG for her assistance throughout the re- essarily those of the Department of Health.
view process.
Richard Wormald (Co-ordinating Editor for CEVG) acknowl- The Health Services Research Unit is core funded by the Chief
edges financial support for his CEVG research sessions from the Scientist Office of the Scottish Government Health Directorates.
Department of Health through the award made by the National The views expressed in this review are those of the authors and not
Institute for Health Research to Moorfields Eye Hospital NHS necessarily those of the funders.

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Cochrane Centre, The Cochrane Collaboration, 2011. Indicates the major publication for the study

Medical versus surgical interventions for open angle glaucoma (Review) 23


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

CIGTS

Methods Method of allocation: remote co-ordinating centre, using a minimisation


approach to achieve optimal balance across predefined strata, age, centre, gender race
and diagnosis
Masking outcome assessment: no, apart from the assessment of HRQOL which
was masked unless the participant revealed his or her treatment status
Exclusions after randomisation: 3 patients randomly assigned to surgery refused
surgery and were treated medically, 2 patients withdrew before medical treatment was
initiated, one died and one had a cardiovascular event
Duration: outcome assessment is ongoing. A minimum five year follow-up from
randomisation is required

Participants Country: USA


Number randomised: 607 people recruited between October 1993 and April 1997. Data
analysis includes only data on the first eye treated for each participant
Age in years: average 57.5 (range 28-75)
Sex: males and females
Ethnicity: 44% non-white
Disease severity: 91% enrollees had POAG, with on average mild visual field defects of
4.8 units on a scale of 0 to 20. C/D ratios (range of 0.6 to 0.7)
Inclusion criteria:
1. POAG, PXF and pigmentary in one or both eyes
2. One of three combinations of qualifying IOP > 20 mmHg, visual field changes
and optic disc findings:
i) OP > 20 mmHg, 24-2 three contiguous points on the total deviation plot at
< 2% level and GHT outside normal and optic discs compatible with glaucoma
ii) (b) IOP > 26 mmHg and 24-2 with at least two contiguous points in the
same hemi-field on total deviation probability plot at < 2% level and GON
iii) IOP > 27 mmHg with Glaucomatous Optic Neuropathy (GON), not
required to have visual field changes
3. Best corrected ETDRS > 70 (Snellen equivalent 20/40 in each eye)
Exclusion criteria:
1. Cumulative lifetime use of eye drops for glaucoma > 14 days
2. Any eye drops for glaucoma in 3 weeks prior to baseline visit 1(washout from < =
14 days permitted)
3. CIGTS score > 16.0 either eye
4. Other ocular disease that might affect IOP readings, assessment of visual
function, visual field testing and/or facility of aqueous outflow
5. Proliferative diabetic retinopathy, diabetic macular oedema or non-proliferative
diabetic retinopathy with more than ten microaneurysms by clinical count at baseline
6. Undergone ophthalmic laser, refractive, conjunctival or intraocular surgery in
either eye
7. Likely to require cataract surgery within a year of randomisation
8. Current or expected use of corticosteroids

Medical versus surgical interventions for open angle glaucoma (Review) 24


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CIGTS (Continued)

Interventions Medical treatment: sequence of medications, usually beginning with topical beta-blocker
followed by an alternative single topical agent, dual, triple then alternative topical and
or oral medications. If further treatment required, the next treatment step was ALT
followed by trabeculectomy (with or without 5-fluorouracil at the surgeons discretion),
repeat medication, repeat trabeculectomy with anti-fibrotic agents, repeat medication
Surgery: trabeculectomy (with or without 5-fluorouracil at the surgeons discretion)
within 14 days of randomisation, if failure then ALT then sequence of medications, then
repeat trabeculectomy with anti-fibrotic agents, then repeat medications. Criteria for
intervention failure had to be met each time that a further treatment step was initiated
Criteria for intervention failure:
Up to July 1996 - failure to meet a target IOP established at the time of
randomisation and/or evidence of progressive visual field loss on three consecutive tests
performed at separate clinic visits
After July 1996 - the criterion for IOP failure was changed because of concern
that the use of target IOP alone to arbitrate intervention failure might result in overly
aggressive advancement in treatment sequence. If field loss spared the central four
points, i.e. was paracentral then 20% to 25% tolerance above target IOP was allowed
before initiating the next treatment step

Outcomes Progressive visual field loss: Humphrey 24-2 perimetry, with a scoring method designed
for the study*, recorded every three months
HRQOL: measured using disease specific and generic measures = (1) symptom and
health problem check list, (2) Visual Activities Questionnaire, (3) Glaucoma Health
Perceptions Index (4) Sickness Impact Profile, (5) Centre for Epidemiological studies -
Depression Score(CES-D), (6) Health Perceptions Index
IOP: Goldmann applanation tonometry recorded three monthly
Visual acuity: ETDRS
Incidence of cataract surgery
Treatment crossover after intervention failure
Adverse events: mortality (overall deaths but not by intervention group); surgical com-
plications reported but for all eyes (i.e. including the other eye not included in the trial)

Notes Lichter 2001 reports interim outcome data through four years after treatment initiation.
161 participants had not yet achieved 5 years after treatment initiation. Musch 2009
and Musch 2008 report longer-term visual field and IOP outcomes up to 9 years. The
measure of VF used in Musch 2009 was based on mean deviation (MD) as a measure of
VF. The CIGTS investigators moved away from analysing visual field outcomes using
the CIGTS score due to its problematic distributional properties - i.e., floor and ceiling
effects that are not shared by the MD (correspondence with the author). there is potential
for bias due to selective reporting of the primary clinical outcome. Parrish and colleagues
( Parrish 2009) report the optic disc findings, based on follow stereophotographs of
study eyes, obtained from available data in a six month window of the 5-year follow-up
assessment. readers were masked to randomised allocation

Risk of bias

Bias Authors judgement Support for judgement

Medical versus surgical interventions for open angle glaucoma (Review) 25


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CIGTS (Continued)

Random sequence generation (selection Low risk Treatment assignment was determined by
bias) the co-ordinating centre.... Minimisation
was used for treatment allocation

Allocation concealment (selection bias) Low risk Method of allocation: remote coordinating
centre

Blinding (performance bias and detection Unclear risk Masking outcome assessment: Examiners of
bias) visual field were not masked according to
Primary Outcome: visual field progression; treatment status, perimetry is automated
HRQoL and therefore considered a low risk of bias
in terms of assessment of a continuous out-
come (MD) and the CIGTS score.The as-
sessment of HRQOL, by trained telephone
interviewers, was masked unless the partic-
ipant revealed his or her treatment status.
The potential for bias is uncertain

Incomplete outcome data (attrition bias) Low risk Long-term VF: 5-year VF data were avail-
Primary outcome: visual field; HRQoL able on 255 (85%) initial surgery group
and 269 (87%) initial medication group.
Higher risk of bias for longer-term VF data:
At 8 years VF data were available on 142
(47%) initial surgery group and 153 (50%)
of initial medication group
Medium-term HRQOL: Patient reported
outcome data at 4 years, were available
on 266 (89%) of participants randomised
to initial surgery and 283 (93%) of par-
ticipants randomised to initial medication
(Janz 2001)
Long-term HRQoL: At five years, data were
available on 195 (65%) of participants ran-
domised to initial surgery and 210 (68%)
of participants randomised to initial medi-
cation (Janz 2001)

Selective reporting (reporting bias) High risk The index of measurement of the visual
field outcome was changed for reporting of
longer-term visual field outcomes (Musch
2009)

Medical versus surgical interventions for open angle glaucoma (Review) 26


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Glasgow Trial 1988

Methods Method of allocation: random number tables with concealed allocation in serially
numbered opaque envelopes
Masking of outcome assessment: no
Exclusions after randomisation: 4 patients refused early surgery and were excluded
from the study
Unusual study design: A sub-group analysis, not outlined in the study design, was
performed according to severity of VF loss examining differences in VF outcome
between treatment groups
Duration: Recruitment from 1980 to 1985, maximum follow-up 7 years (mean 4.
6)

Participants Country: UK
Number randomised: 116
Sex: males and females
Ethnicity: white
Disease severity: 66/107 (62%) of participants were classified as severe disease at baseline
with no significant difference between randomised groups. Severe disease was defined
in this study as field stage 2 to 5**. The severity of visual field loss of the 5 participants
who died and 4 exclusions in the first year was not reported
Inclusion criteria: all of the following:
(1) previously undiagnosed case of primary open angle glaucoma, or open angle glaucoma
with pseudoexfoliation
(2) untreated IOP of >26 mmHg(Goldmann) on two occasions
(3) visual field defects characteristic of glaucoma
Exclusion criteria: not stated

Interventions Medical treatment: up to a maximum of 3 different topical or systemic ocular hypotensive


agents. If maximum tolerated medical treatment was insufficient to control IOP or
prevent visual field loss then trabeculectomy was performed. Treatments used could
include miotics, beta blockers, guanethidine, adrenaline and systemic carbonic anhydrase
inhibitors
Surgery: trabeculectomy, without prior medical treatment except where necessary for a
few days to reduce IOP preoperatively. Subsequent medical therapy was introduced as
clinically indicated
Criteria for intervention failure: no fixed criteria, treating ophthalmologists clinical
judgement

Outcomes Progressive visual field loss: visual field measured using Tubingen manual perimetry.
Classified into five stages of loss**. Significant change defined as at least one full stage of
classification from diagnosis
IOP: Goldmann applanation tonometry
Progressive optic disc damage : change in vertical cup to disc ratio of > +/- 0.1
Snellen visual acuity
Intervention failure: short-term outcome data only
Adverse events: mortality; severe irreversible reduction of vision; onset of cataract

Notes Participants were recruited at approximately 25/year


Outcome assessment, proportion with visual field progression, proportion with loss of
visual acuity and mean IOP were reported at fixed time points before all had reached
that time point, consequently trial participants had variable lengths of follow-up at final
Medical versus surgical interventions for open angle glaucoma (Review) 27
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Glasgow Trial 1988 (Continued)

analysis.
Figures were not available for optic disc change by randomised group.
Figures were presented for proportion progressing in subgroups defined by early or severe
visual field loss, summary effect measures could not be calculated as the total number of
participants in each subgroup of visual field loss was not reported

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection Low risk Method of allocation: random number ta-
bias) bles

Allocation concealment (selection bias) Low risk Serially numbered opaque envelopes
opened by the investigator. Information re-
ceived from study authors suggests low risk
of bias

Blinding (performance bias and detection Unclear risk Visual fields were undertaken at the trial
bias) centre at yearly intervals and undertaken by
Primary Outcome: visual field progression; trained perimetrists. The change in visual
HRQoL status was assessed by an experienced ob-
server. It is not clear whether the observer
was masked to the treatment status. Ob-
jective measure with well described scoring
system

Incomplete outcome data (attrition bias) High risk Data on 25 (44%) in the group treated
Primary outcome: visual field; HRQoL with medications and 30 (60%) partici-
pants treated by primary trabeculectomy
were available for the final analysis

Selective reporting (reporting bias) Unclear risk Deemed as low risk of bias as visual field
status is recognised as an appropriate pri-
mary outcome. All expected outcomes were
reported

Moorfields GT 1968

Methods Method of allocation: random number tables. The allocation was remote from the
person entering the patient into the study
Masking outcome assessment: not reported
Exclusions after randomisation: 4 in the surgery group
Losses to follow-up: 6 patients in total were lost to follow-up, 5 of these in the
group assigned medical treatment
Duration: 1968 to 1982

Medical versus surgical interventions for open angle glaucoma (Review) 28


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Moorfields GT 1968 (Continued)

Participants Country: UK
Number randomised: 52
Age at entry in years: range 35 to 70
Sex: 37 male and 15 female
Ethnicity: Black race excluded
Inclusion criteria:
(1) IOP > = 23 mmHg on two occasions
(2) visual field loss compatible with glaucoma
(3) glaucomatous cupping
Exclusion criteria:
(1) previous glaucoma surgery
(2) black race
(3) other ophthalmic abnormalities of importance

Interventions Medical: any medical treatment deemed necessary. The most common medication was
pilocarpine 2% and 4%, guanethidine, adrenaline, oral carbonic anhydrase inhibitors.
In 1979 Timoptol was used as a study medication. Participants underwent surgery if the
IOP was deemed not sufficiently well controlled by medical treatment
Surgery: modified Scheies procedure with sector iridectomy. Supplementary medical
treatment was used if the IOP was deemed not sufficiently well controlled

Outcomes Progressive visual field loss: Lister manual perimetry and a visual field score was generated.
Outcome measured as mean score difference between the intervention groups
IOP: Goldmann applanation tonometry. Short and long-term outcome data
Snellen Visual acuity: expressed as a percentage, 6/6 = 100%, 6/9 = 66%, 6/12 = 50%,
6/18 = 33%, 6/24 = 25%, 6/36 = 16%, 6/60 = 10%, CF = 5%, PL acc = 2%, PL inacc
= 1%, NPL = 0%. Long-term outcome measured as score difference
Need for additional medicine or surgery due to intervention failure: only reported for
medical group

Notes It took 7 years to find the required number of suitable patients. The data were analysed
at various times during the trial (1968, 1970 and 1986). Data were analysed according
to interval in trial. This resulted in small numbers available for analysis at these times.
The 1986 data are used in this analysis as this has the most complete follow-up

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection Low risk Method of allocation: random number ta-
bias) bles

Allocation concealment (selection bias) Low risk The allocation was remote from the per-
son entering the patient into the study. In-
formation received from study authors sug-
gests low risk of bias

Medical versus surgical interventions for open angle glaucoma (Review) 29


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Moorfields GT 1968 (Continued)

Blinding (performance bias and detection Unclear risk Masking outcome assessment: not reported
bias) (visual field). Visual fields were assessed by
Primary Outcome: visual field progression; a well described scoring system. The visual
HRQoL field examiner was not reported

Incomplete outcome data (attrition bias) High risk Visual field: Analysis was not by intention
Primary outcome: visual field; HRQoL to treat analysis as four participants who ei-
ther refused or did not receive surgery re-
mained under review but were not included
in the data analysis

Selective reporting (reporting bias) Unclear risk The study was conducted in the 1960s be-
fore it was a requirement to publish the pro-
tocol. Deemed as low risk of bias as visual
field status is recognised as an appropriate
primary outcome. All expected outcomes
were reported

Moorfields PTT 1994

Methods Recruitment started in 1983, and 168 participants were randomised, minimum follow-
up 5-years
Method of allocation: randomly allocated using computer selection and remote
from the ophthalmologist recruiting the participant. In bilateral asymmetric disease the
worse eye was included in the study. In symmetric disease the eye to be included was
randomly allocated
Masking outcome assessment: not stated
Exclusions after randomisation: none
Losses to follow-up: not stated
Unusual study design: the participants were randomly allocated to 3 groups
(medicine, surgery or laser therapy as a primary treatment)
Treatment was considered unsuccessful if IOP was > 22 mmHg on two occasions. In
the event of failure, the alternative therapy from the remaining options was randomly
assigned by computer selection. Failures in each treatment group were excluded from
the calculation of the results from time to failure
Duration: minimum of five years follow-up

Participants Country: UK
Number randomised: 168 patients randomised to primary medical (56), laser (55) or
surgery (57). The participants randomised to initial laser therapy are not included in
this review
Mean age: 62.4 years
Sex: not stated
Ethnicity: 10 participants were black and 10 were Asian
Disease severity: staged according to Friedmann visual field loss at presentation****. 33/
113 (29%) early, 26/113 (23%) middle, 54/113 (48%) late glaucoma

Medical versus surgical interventions for open angle glaucoma (Review) 30


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Moorfields PTT 1994 (Continued)

Interventions Medicine: Pilocarpine and or a sympathomimetic and or Timolol as a primary therapy,


increasing to maximum tolerated medical therapy which could in individual cases require
three topical medications and an oral carbonic anhydrase inhibitor
Surgery: Cairns type trabeculectomy, using either a fornix-based or limbal-based con-
junctival flap. The surgery was performed by consultants, residents or fellows
Criteria for intervention failure: IOP > 22 mmHg on two occasions

Outcomes (1) Progressive visual field loss: Visual fields(Friedmann) measured at 3 months and then
every 4 months. Humphrey automated perimetry 6 monthly from two years into the
study
(2) IOP reduction: Goldmann applanation tonometry
(3) Visual Acuity: Snellen mean visual acuity score
(4) Intervention failure: Kaplan-Meier survival analysis to point of failure. Failure defined
as IOP > 22 mmHG on two occasions

Notes (1) Friedmann: The mean scores were determined by calculating the mean of the first
three visual field scores after entry into the trial and the mean of the final three visual
field scores
In this study failures, defined as failure to maintain an IOP < 22 mmHg on two occasions,
were excluded from the calculation of results for all outcome assessments except for a
final report measuring visual field progression using automated perimetry

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection Low risk Method of allocation: randomly allocated
bias) using computer selection. In bilateral asym-
metric disease the worse eye was included
in the study. In symmetric disease the eye
to be included was randomly allocated

Allocation concealment (selection bias) Low risk Allocation was remote from the ophthal-
mologist recruiting the participant

Blinding (performance bias and detection Unclear risk Visual field: Masking outcome assessment:
bias) not stated. Objective measure with well de-
Primary Outcome: visual field progression; scribed scoring system. The visual field ex-
HRQoL aminer was not reported

Incomplete outcome data (attrition bias) High risk Losses to follow-up: not stated
Primary outcome: visual field; HRQoL Unusual study design: the participants were
randomly allocated to 3 groups (medicine,
surgery or laser therapy as a primary treat-
ment). Treatment was considered unsuc-
cessful if IOP was > 22 mmHg on two oc-
casions. In the event of failure, the alter-
native therapy from the remaining options

Medical versus surgical interventions for open angle glaucoma (Review) 31


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Moorfields PTT 1994 (Continued)

was randomly assigned by computer selec-


tion. For analysis by Friedman visual fields
failures in each treatment group were ex-
cluded from the calculation of the results
from time to failure. Automated perime-
try became available 2 years into the study.
Final visual field outcome (by automated
perimetry) was analysed according to inten-
tion to treat. However, mean change was
based on baseline two years after randomi-
sation

Selective reporting (reporting bias) Unclear risk The study was conducted in the 1980s be-
fore it was a requirement to publish the pro-
tocol. Deemed low risk as visual field sta-
tus is recognised as an appropriate primary
outcome. Visual field measurement using a
different measure are reported in a separate
publication

Classification of visual field changes:


*CIGTS 2001
The overall visual field score was generated from the total deviation probability plots on the Humphrey 24-2. Each of the 52 points in
the field were a point of defect if its probability value was 0.05 or less in the same hemifield. A weight was assigned depending on the
minimum depth of defect and the two most defective neighbouring points. A point without two neighbouring points depressed to at
least 0.05 is given a weight of 0. The weights are all summed and scaled to 0 (no defect) to 20 (all points showing a defect at P < 0.005
level).
**Glasgow 1988
Stage 1. Early relative defects(to 1.0/10asb Tubingen; equivalent to 1-2e Goldmann) in arcuate area or nasal step.
Stage 2 Absolute defects (to 1.0/00asb Tubingen; equivalent to 1-4e Goldmann) outside 10 degrees of fixation in all quadrants.
Stage 3. As stage 2 but encroaching between 5 and 10 degrees from fixation in 1 to 4 quadrants.
Stage 4. As stage 2 but within 5 degrees of fixation in 1 to 3 quadrants.
Stage 5. As stage 2 but within 5 degrees of fixation in all quadrants.
***Moorfields GT 1968
The Lister-Hamblin chart was ruled with 24 radial lines giving a total number of 960 line degrees in the central 40 degrees of field.
Visual field retained was measured as the number of line degrees present (x) in the 40 degree field. Therefore, percentage field retained
is x/960x100.
****Moorfields PTT 1994
Friedmann (Mark 1) analyser used for baseline visual field at entry into the trial and for monitoring progress throughout the trial. The
threshold was estimated at intensities of 0.4 log units greater than the threshold intensity then at steps of 0.2 log units up to maximum
intensity. A field score of the number of spots missed was calculated at each visit for the relative and absolute spots missed, giving two
numeric values for the trial eye at each visit. The mean scores were determined by calculating the mean of the first three visual field
scores after entry into the trial and the mean of the final three visual field scores.
Humphrey automated perimetry: two years after the commencement of the trial Humphrey 30-2 fields, using a size 3 target unless
the severity of the visual field defect necessitated the use of a size 5 target, were measured in addition to Friedmann fields. Change was
determined by linear regression analysis on each individual retinal points. Those points showing two consecutive significant (at the
0.05% level) positive or negative regression slopes were considered to have improved or worsened respectively. To confirm the visual
field loss two significant regression slopes were required, the second field measured after an interval of six months.

Medical versus surgical interventions for open angle glaucoma (Review) 32


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Glaucoma severity:
Early : Visual field score of < 2 absolute defects(commonly in the arcuate region).
Middle: Visual field score of 2 to 12 defects (commonly in arcuate region).
Late: > 12 absolute defects.
ALT: argon laser trabeculoplasty
CF: counting fingers
ETDRS: Early Treatment of Diabetic Retinopathy Study
GON: Glaucomatous Optic Neuropathy
HRQOL: health-related quality of life
IOP: intraocular pressure
NPL: no perception of light
PL acc / PL inacc.: perception of light accurate/inaccurate

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Anand 2007 This was not a randomised comparison of medical versus surgical treatment. 60 patients were randomised to three
groups: 1. medical treatment; 2. A choice of surgery or medication; and 3. Educational package on glaucoma and an
option to have surgery or medical treatment

Dastur 1994 Not a randomised study. Patients with early open angle glaucoma in both eyes were included in the study. The eyes
with a higher IOP were treated by trabeculectomy and the fellow eye was treated medically

Egbert 2001 This study randomised newly diagnosed OAG to receive TSCPC at one of two energy delivery settings, low energy
versus higher energy. This study was not a study of TSCPC versus medical treatment

Stewart 1996 A retrospective matched pair design. Not a randomised comparative study

Watson 1984 This was a study of patients with severe OAG or patients who had failed medical treatment. The study randomised
participants to receive ALT or Trabeculectomy. ALT as the randomised treatment did not include medical therapy

ALT: argon laser trabeculoplasty


IOP: intraocular pressure
OAG: open angle glaucoma
TSCPC: transscleral cyclophotocoagulation

Medical versus surgical interventions for open angle glaucoma (Review) 33


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Initial medical treatment versus Scheies procedure

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Mean change in visual field score 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
from baseline
1.1 Long-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Mean change in IOP from 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
baseline
2.1 Short-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Long-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Mean change in VA score from 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
baseline
3.1 Long-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

Comparison 2. Initial medical treatment versus initial trabeculectomy

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Progressive visual field loss 3 Odds Ratio (Fixed, 95% CI) Totals not selected
1.1 Medium-term 1 Odds Ratio (Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Long-term (Moorfields 2 Odds Ratio (Fixed, 95% CI) 0.0 [0.0, 0.0]
PTT 1994 baseline at 2 years
into study)
2 Mean change in visual field score 1 Mean Difference (IV, Random, 95% CI) Totals not selected
(Friedmann) from baseline.
Moorfields PTT 1994 not ITT
2.1 Long-term 1 Mean Difference (IV, Random, 95% CI) 0.0 [0.0, 0.0]
3 Mean difference in visual field 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
score (mean deviation) at five
years (unadjusted)
4 Mean difference in visual 1 Mean Difference (Fixed, 95% CI) Totals not selected
field scores (mean deviation)
according to baseline severity at
five years (adjusted)
4.1 mild severity at baseline 1 Mean Difference (Fixed, 95% CI) 0.0 [0.0, 0.0]
(-2 dB)
4.2 severe severity at baseline 1 Mean Difference (Fixed, 95% CI) 0.0 [0.0, 0.0]
(-10 dB)
5 Mean change in IOP from 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
baseline
5.1 Short-term 2 190 Mean Difference (IV, Fixed, 95% CI) 6.14 [4.25, 8.02]
5.2 Medium-term 1 106 Mean Difference (IV, Fixed, 95% CI) 1.60 [-0.69, 3.89]
Medical versus surgical interventions for open angle glaucoma (Review) 34
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5.3 Long-term 1 102 Mean Difference (IV, Fixed, 95% CI) 3.40 [1.04, 5.76]
6 Mean change in IOP from 2 Mean Difference (IV, Fixed, 95% CI) Totals not selected
baseline (exploratory analysis
with assumptions)
6.1 Short-term 2 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.2 Medium-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.3 Long-term 1 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Mean difference in IOP up to 9 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
years
8 Optic nerve progression at five 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
years
9 Medium to long-term reduction 2 Odds ratio (Fixed, 95% CI) Totals not selected
of VA. CIGTS 2001 adjusted
OR
10 Failure of randomised 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
treatment
10.1 Short-term 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
10.2 Medium-term 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
11 Time to failure of randomised 2 Hazard ratio (Fixed, 95% CI) Totals not selected
treatment
11.1 Long-term 2 Hazard ratio (Fixed, 95% CI) 0.0 [0.0, 0.0]
12 Need for ALT as an additional 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not selected
treatment
12.1 Short-term 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
12.2 Medium-term 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 1.1. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 1 Mean change
in visual field score from baseline.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 1 Initial medical treatment versus Scheies procedure

Outcome: 1 Mean change in visual field score from baseline

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Long-term
Moorfields GT 1968 22 25.71 (16.43) 21 11.09 (16.84) 14.62 [ 4.67, 24.57 ]

-100 -50 0 50 100


Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 35


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.2. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 2 Mean change
in IOP from baseline.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 1 Initial medical treatment versus Scheies procedure

Outcome: 2 Mean change in IOP from baseline

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Short-term
Moorfields GT 1968 22 -2 (7.1) 21 -10 (4.7) 8.00 [ 4.42, 11.58 ]

2 Long-term
Moorfields GT 1968 22 0 (7.1) 21 -5.6 (4.7) 5.60 [ 2.02, 9.18 ]

-100 -50 0 50 100


Favours medicine Favours surgery

Analysis 1.3. Comparison 1 Initial medical treatment versus Scheies procedure, Outcome 3 Mean change
in VA score from baseline.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 1 Initial medical treatment versus Scheies procedure

Outcome: 3 Mean change in VA score from baseline

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Long-term
Moorfields GT 1968 22 -24 (39.2) 21 -29.8 (41.73) 5.80 [ -18.43, 30.03 ]

-100 -50 0 50 100


Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 36


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 1 Progressive
visual field loss.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 1 Progressive visual field loss

Study or subgroup Medicine Surgery log [Odds Ratio] Odds Ratio Odds Ratio
N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI

1 Medium-term
Glasgow Trial 1988 57 50 0.94 (0.42) 2.56 [ 1.12, 5.83 ]

2 Long-term (Moorfields PTT 1994 baseline at 2 years into study)


Moorfields PTT 1994 40 48 -0.37 (0.45) 0.69 [ 0.29, 1.67 ]

CIGTS 307 300 -0.3075 (0.16) 0.74 [ 0.54, 1.01 ]

0.02 0.1 1 10 50
Favours medicine Favours surgery

Analysis 2.2. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 2 Mean
change in visual field score (Friedmann) from baseline. Moorfields PTT 1994 not ITT.

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 2 Mean change in visual field score (Friedmann) from baseline. Moorfields PTT 1994 not ITT

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

1 Long-term
Moorfields PTT 1994 46 4.75 (5.62) 56 0.83 (3.74) 3.92 [ 2.02, 5.82 ]

-4 -2 0 2 4
Favours medication Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 37


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.3. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 3 Mean
difference in visual field score (mean deviation) at five years (unadjusted).

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 3 Mean difference in visual field score (mean deviation) at five years (unadjusted)

Mean Mean
Study or subgroup Medication Surgery Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

CIGTS 269 -5.5 (6.6) 255 -5.3 (6.4) -0.20 [ -1.31, 0.91 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]


Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours surgery Favours medication

Analysis 2.4. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 4 Mean
difference in visual field scores (mean deviation) according to baseline severity at five years (adjusted).

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 4 Mean difference in visual field scores (mean deviation) according to baseline severity at five years (adjusted)

Mean Mean
Study or subgroup Mean Difference (SE) Difference Difference
IV,Fixed,95% CI IV,Fixed,95% CI

1 mild severity at baseline (-2 dB)


CIGTS -0.22 (0.24) -0.22 [ -0.69, 0.25 ]

2 severe severity at baseline (-10 dB)


CIGTS 0.74 (0.38) 0.74 [ 0.00, 1.48 ]

-2 -1 0 1 2
Favours medication Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 38


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.5. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 5 Mean
change in IOP from baseline.

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 5 Mean change in IOP from baseline

Mean Mean
Study or subgroup Medicine Surgery Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Short-term
Glasgow Trial 1988 36 -15.1 (6.8) 47 -21.1 (8.8) 31.5 % 6.00 [ 2.64, 9.36 ]

Moorfields PTT 1994 51 -14 (6.8) 56 -20.2 (4.98) 68.5 % 6.20 [ 3.92, 8.48 ]

Subtotal (95% CI) 87 103 100.0 % 6.14 [ 4.25, 8.02 ]


Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0%
Test for overall effect: Z = 6.38 (P < 0.00001)
2 Medium-term
Moorfields PTT 1994 50 -18.6 (6.8) 56 -20.2 (4.98) 100.0 % 1.60 [ -0.69, 3.89 ]

Subtotal (95% CI) 50 56 100.0 % 1.60 [ -0.69, 3.89 ]


Heterogeneity: not applicable
Test for overall effect: Z = 1.37 (P = 0.17)
3 Long-term
Moorfields PTT 1994 46 -16.5 (6.8) 56 -19.9 (4.98) 100.0 % 3.40 [ 1.04, 5.76 ]

Subtotal (95% CI) 46 56 100.0 % 3.40 [ 1.04, 5.76 ]


Heterogeneity: not applicable
Test for overall effect: Z = 2.83 (P = 0.0047)
Test for subgroup differences: Chi2 = 9.39, df = 2 (P = 0.01), I2 =79%

-10 -5 0 5 10
Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 39


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.6. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 6 Mean
change in IOP from baseline (exploratory analysis with assumptions).

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 6 Mean change in IOP from baseline (exploratory analysis with assumptions)

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 Short-term
Glasgow Trial 1988 53 -10.3 (6.8) 46 -21.8 (8.8) 11.50 [ 8.37, 14.63 ]

Moorfields PTT 1994 56 -12.5 (6.8) 57 -19.96 (4.98) 7.46 [ 5.26, 9.66 ]

2 Medium-term
Moorfields PTT 1994 56 -14.3 (6.8) 57 -19.96 (4.98) 5.66 [ 3.46, 7.86 ]

3 Long-term
Moorfields PTT 1994 56 -13.5 (6.8) 57 -19.5 (4.98) 6.00 [ 3.80, 8.20 ]

-20 -10 0 10 20
Favours medicine Favours surgery

Analysis 2.7. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 7 Mean
difference in IOP up to 9 years.

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 7 Mean difference in IOP up to 9 years

Mean Mean
Study or subgroup Medicine Surgery Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

CIGTS 293 17.2 (2.7) 285 15 (4.1) 2.20 [ 1.63, 2.77 ]

-100 -50 0 50 100


Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 40


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.8. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 8 Optic nerve
progression at five years.

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 8 Optic nerve progression at five years

Study or subgroup medicine surgery Odds Ratio Odds Ratio


n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
CIGTS 18/185 4/163 4.28 [ 1.42, 12.94 ]

0.005 0.1 1 10 200


Favours medicine Favours surgery

Analysis 2.9. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 9 Medium to
long-term reduction of VA. CIGTS 2001 adjusted OR.

Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 9 Medium to long-term reduction of VA. CIGTS 2001 adjusted OR

Study or subgroup medicine surgery Odds ratio (SE) Odds ratio Odds ratio
N N IV,Fixed,95% CI IV,Fixed,95% CI
Glasgow Trial 1988 57 50 0.392 (0.482) 0.39 [ -0.55, 1.34 ]

CIGTS 307 300 -0.7 (0.2128) -0.70 [ -1.12, -0.28 ]

-1000 -500 0 500 1000


Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 41


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.10. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 10 Failure of
randomised treatment.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 10 Failure of randomised treatment

Study or subgroup Medicine Surgery Odds Ratio Odds Ratio


n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Short-term
Glasgow Trial 1988 17/53 7/46 2.63 [ 0.98, 7.08 ]

2 Medium-term
Glasgow Trial 1988 26/50 10/46 3.90 [ 1.60, 9.53 ]

0.1 0.2 0.5 1 2 5 10


Favours medicine Favours surgery

Analysis 2.11. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 11 Time to
failure of randomised treatment.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 11 Time to failure of randomised treatment

Study or subgroup medicine surgery log [Hazard ratio] Hazard ratio Hazard ratio
N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI

1 Long-term
Moorfields PTT 1994 56 57 1.984 (0.603) 7.27 [ 2.23, 23.71 ]

CIGTS 307 300 0.07 (0.28) 1.07 [ 0.62, 1.86 ]

0.001 0.01 0.1 1 10 100 1000


Favours medicine Favours surgery

Medical versus surgical interventions for open angle glaucoma (Review) 42


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.12. Comparison 2 Initial medical treatment versus initial trabeculectomy, Outcome 12 Need for
ALT as an additional treatment.
Review: Medical versus surgical interventions for open angle glaucoma

Comparison: 2 Initial medical treatment versus initial trabeculectomy

Outcome: 12 Need for ALT as an additional treatment

Study or subgroup Medicine Surgery Odds Ratio Odds Ratio


n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Short-term
CIGTS 73/307 35/300 2.36 [ 1.52, 3.67 ]

2 Medium-term
CIGTS 86/307 63/300 1.46 [ 1.01, 2.13 ]

0.1 0.2 0.5 1 2 5 10


Favours medicine Favours surgery

APPENDICES

Appendix 1. CENTRAL search strategy


#1 MeSH descriptor Glaucoma, Open-Angle
#2 open near angle near glaucoma*
#3 poag
#4 primary near glaucoma*
#5 chronic near glaucoma*
#6 secondary near glaucoma*
#7 low near tension near glaucoma*
#8 low near pressure near glaucoma*
#9 normal near tension near glaucoma*
#10 normal near pressure near glaucoma*
#11 pigment near glaucoma*
#12 MeSH descriptor Exfoliation Syndrome
#13 exfoliat* near syndrome*
#14 exfoliat* near glaucoma*
#15 pseudoexfoliat* near syndrome*
#16 pseudoexfoliat* near glaucoma*
#17 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16)
#18 MeSH descriptor Adrenergic beta-Antagonists
#19 MeSH descriptor Timolol
#20 timolol*
#21 MeSH descriptor Metipranolol
Medical versus surgical interventions for open angle glaucoma (Review) 43
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#22 metipranolol*
#23 MeSH descriptor Carteolol
#24 carteolol*
#25 MeSH descriptor Levobunolol
#26 levobunolol*
#27 MeSH descriptor Betaxolol
#28 betaxolol*
#29 MeSH descriptor Carbonic Anhydrase Inhibitors
#30 carbonic near anhydrase near inhibitor*
#31 azetazolamide*
#32 brinzolamide*
#33 dorzolamide*
#34 MeSH descriptor Prostaglandins, Synthetic
#35 latanoprost*
#36 travoprost*
#37 bimatoprost*
#38 unoprostone*
#39 brimonidine*
#40 medical or medicine
#41 (#18 OR ( #19 AND #20 ) OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29)
#42 (#30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40)
#43 MeSH descriptor Lasers
#44 laser*
#45 MeSH descriptor Trabeculectomy
#46 trabeculectom*
#47 MeSH descriptor Sclerostomy
#48 sclerostom*
#49 sclerectom*
#50 viscocanalostom*
#51 MeSH descriptor Filtering Surgery
#52 filtrat* near surg*
#53 surgical or surgery
#54 MeSH descriptor Glaucoma Drainage Implants
#55 implant* or shunt* or device* or drain*
#56 (#43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55)
#57 (#41 OR #42 OR #56)

Appendix 2. MEDLINE (OvidSP) search strategy


1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
Medical versus surgical interventions for open angle glaucoma (Review) 44
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp open angle glaucoma/
34. (open adj2 angle adj2 glaucoma$).tw.
35. POAG.tw.
36. (primary adj2 glaucoma$).tw.
37. (chronic adj2 glaucoma$).tw.
38. (secondary adj2 glaucoma$).tw.
39. (low adj2 tension adj2 glaucoma$).tw.
40. (low adj2 pressure adj2 glaucoma$).tw.
41. (normal adj2 tension adj2 glaucoma$).tw.
42. (normal adj2 pressure adj2 glaucoma$).tw.
43. (pigment$ adj2 glaucoma$).tw.
44. exp exfoliation syndrome/
45. (exfoliat$ adj2 syndrome$).tw.
46. (exfoliat$ adj2 glaucoma$).tw.
47. (pseudoexfoliat$ adj2 syndrome$).tw.
48. (pseudoexfoliat$ adj2 glaucoma$).tw.
49. or/33-48
50. exp beta adrenergic receptor blocking agent/
51. exp timolol/
52. timolol$.tw.
53. exp metipranolol/
54. metipranolol$.tw.
55. exp carteolol/
56. carteolol$.tw.
57. exp levobunolol/
58. levobunolol$.tw.
59. exp betaxolol/
60. betaxolol$.tw.
61. exp carbonate dehydratase inhibitor/
62. (carbonic adj2 anhydrase adj2 inhibitor$).tw.
63. azetazolamide$.tw.
64. brinzolamide$.tw.
65. dorzolamide$.tw.
66. exp latanoprost/
Medical versus surgical interventions for open angle glaucoma (Review) 45
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
67. latanoprost$.tw.
68. exp travoprost/
69. travoprost$.tw.
70. exp bimatoprost/
71. bimatoprost$.tw.
72. exp unoprostone isopropyl ester/
73. unoprostone$.tw.
74. exp brimonidine/
75. brimonidine$.tw.
76. (medical or medicine).tw.
77. or/50-76
78. exp laser/
79. laser$.tw.
80. exp trabeculectomy/
81. trabeculectom$.tw.
82. exp glaucoma surgery/
83. sclerostom$.tw.
84. sclerectom$.tw.
85. viscocanalostom$.tw.
86. exp filtering operation/
87. su.fs.
88. (filtrat$ adj3 surg$).tw.
89. (surgical or surgery).tw.
90. exp glaucoma drainage implant/
91. (implant$ or shunt$ or device$ or drain$).tw.
92. or/78-91
93. 77 or 92
94. 49 and 93
95. 32 and 94
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (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/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
Medical versus surgical interventions for open angle glaucoma (Review) 46
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp open angle glaucoma/
34. (open adj2 angle adj2 glaucoma$).tw.
35. POAG.tw.
36. (primary adj2 glaucoma$).tw.
37. (chronic adj2 glaucoma$).tw.
38. (secondary adj2 glaucoma$).tw.
39. (low adj2 tension adj2 glaucoma$).tw.
40. (low adj2 pressure adj2 glaucoma$).tw.
41. (normal adj2 tension adj2 glaucoma$).tw.
42. (normal adj2 pressure adj2 glaucoma$).tw.
43. (pigment$ adj2 glaucoma$).tw.
44. exp exfoliation syndrome/
45. (exfoliat$ adj2 syndrome$).tw.
46. (exfoliat$ adj2 glaucoma$).tw.
47. (pseudoexfoliat$ adj2 syndrome$).tw.
48. (pseudoexfoliat$ adj2 glaucoma$).tw.
49. or/33-48
50. exp beta adrenergic receptor blocking agent/
51. exp timolol/
52. timolol$.tw.
53. exp metipranolol/
54. metipranolol$.tw.
55. exp carteolol/
56. carteolol$.tw.
57. exp levobunolol/
58. levobunolol$.tw.
59. exp betaxolol/
60. betaxolol$.tw.
61. exp carbonate dehydratase inhibitor/
62. (carbonic adj2 anhydrase adj2 inhibitor$).tw.
63. azetazolamide$.tw.
64. brinzolamide$.tw.
65. dorzolamide$.tw.
66. exp latanoprost/
67. latanoprost$.tw.
68. exp travoprost/
69. travoprost$.tw.
70. exp bimatoprost/
71. bimatoprost$.tw.
72. exp unoprostone isopropyl ester/
Medical versus surgical interventions for open angle glaucoma (Review) 47
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
73. unoprostone$.tw.
74. exp brimonidine/
75. brimonidine$.tw.
76. (medical or medicine).tw.
77. or/50-76
78. exp laser/
79. laser$.tw.
80. exp trabeculectomy/
81. trabeculectom$.tw.
82. exp glaucoma surgery/
83. sclerostom$.tw.
84. sclerectom$.tw.
85. viscocanalostom$.tw.
86. exp filtering operation/
87. su.fs.
88. (filtrat$ adj3 surg$).tw.
89. (surgical or surgery).tw.
90. exp glaucoma drainage implant/
91. (implant$ or shunt$ or device$ or drain$).tw.
92. or/78-91
93. 77 or 92
94. 49 and 93
95. 32 and 94

Appendix 4. LILACS search strategy


glaucom$ or (pigment$ and dispersion) or ((pseudoexfoliative or pseudo-exfoliat$ or exfoliat$) and syndrome)

Appendix 5. BIOSIS search strategy


#1 TS=trial*
#2 TS=randomised
#3 TS=randomized
#4 TS=placebo
#5 TS=randomly
#6 TS=groups
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 TS=poag
#9 TS=(open* SAME glaucoma*)
#10 TS=((primary or secondary or chronic) SAME glaucoma*)
#11 TS=((low or normal) SAME tension SAME glaucoma*)
#12 TS=((low or normal) SAME pressure SAME glaucoma*)
#13 TS=(pigment* SAME glaucoma*)
#14 TS=(exfoliat* SAME (syndrome* OR glaucoma*))
#15 TS=(pseudoexfoliat* SAME (syndrome* OR glaucoma*))
#16 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15
#17 #7 AND #16
#18 TS=(carbonic SAME anhydrase SAME inhibit*)
#19 CA=(9001-03-0)
#20 TS=(azetazolamide* OR acetazolamide*)
#21 CA=(59-66-5)
#22 TS=brinzolamide*
Medical versus surgical interventions for open angle glaucoma (Review) 48
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#23 CA=(138890-62-7)
#24 TS=dorzolamide
#25 CA=(120279-96-1)
#26 #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25
#27 #17 AND #26
#28 TS=latanoprost*
#29 CA=(130209-82-4)
#30 TS=travoprost*
#31 CA=(157283-68-6)
#32 TS=bimatoprost*
#33 CA=(155206-00-1)
#34 TS=unoprostone*
#35 CA=(120373-24-2)
#36 TS=brimonidine*
#37 CA=(59803-98-4)
#38 TS=prostaglandin analogue*
#39 #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38
#40 #17 AND #39
#41 TS=timolol
#42 CA=(26839-75-8)
#43 TS=metipranolol*
#44 CA=(22664-55-7)
#45 TS=carteolol*
#46 CA=(51781-06-7)
#47 TS=levobunolol*
#48 CA=(47141-42-4)
#49 TS=betaxolol*
#50 CA=(63659-18-7)
#51 TS=beta adrenergic antagonist*
#52 #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51
#53 #17 AND #52
#54 #27 OR #40 OR #53
#55 TS=surgery
#56 TS=surgical
#57 TS=trabeculectomy
#58 TS=(sclerectomy or sclerostomy)
#59 TS=viscocanalostomy
#60 TS=laser*
#61 TS=implant*
#62 TS=shunt*
#63 TS=drain*
#64 TS=device*
#65 #55 or #56 or #57 or #58 or #59 or #60 or #61 or #62 or #63 or #64
#66 #17 and #65
#67 #54 or #66

Medical versus surgical interventions for open angle glaucoma (Review) 49


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 6. OpenGrey search strategy
glaucoma

Appendix 7. CINAHL search strategy


S31 S21 or S29
S30 S21 or S29
S29 S4 and S10 and S28
S28 S22 or S23 or S24 or S25 or S26 or S27
S27 TX laser*
S26 TX viscocanalostom* OR TX implant* OR TX shunt* OR TX device* OR drain*
S25 TX surgery OR TX surgical OR TX filtrat* N3 surg* OR TX sclerectom* OR TX sclerostom*
S24 (MH Ocular Hypertension+/SU
S23 (MH Lasers
S22 (MH Surgery, Eye)
S21 S4 and S10 and S20
S20 S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19
S19 TX latanoprost* OR TX travoprost* OR TX bimatoprost* OR TX unoprostone* OR TX brimonidine* OR TX ( medical or
medicine )
S18 (MH Prostaglandins, Synthetic+)
S17 TX carbonic N2 anhydrase N2 inhibitor* OR TX acetazolamide* OR TX azetazolamide* OR TX dorzolamide* OR TX brinzo-
lamide
S16 TX timolol* OR TX metipranolol* OR TX carteolol* OR TX levobunolol* OR TX betaxolol*
S15 TX timolol* OR TX metipranolol* OR TX carteolol* OR TX levobunolol* OR TX betaxolol*
S14 (MH Carbonic Anhydrase Inhibitors+)
S13 (MH Timolol
S12 (MH Adrenergic Beta-Antagonists
S11 (MH Ocular Hypertension+/DT)
S10 S5 or S6 or S7 or S8 or S9
S9 TX pigment* N2 glaucoma* OR TX exfoliat* N2 syndrome* OR TX exfoliat* N2 glaucoma* OR TX pseudoexfoliat* N2 syndrome*
OR TX pseudoexfoliat* N2 glaucoma*
S8 TX low N2 tension N2 glaucoma* OR TX normal N2 tension N2 glaucoma* OR TX low N2 pressure N2 glaucoma OR TX
normal N2 pressure N2 glaucoma*
S7 TX primary N2 glaucoma* OR TX chronic N2 glaucoma* OR TX secondary N2 glaucoma
S6 TX (simple* N3 glaucoma*) OR TX (open N2 angle N2 glaucoma*) OR TX POAG
S5 (MH Glaucoma)
S4 S1 or S2 or S3
S3 TX randomly OR TX trial OR TX groups
S2 TX randomised OR TX randomized OR TX placebo
S1 PT clinical trial

Appendix 8. Zetoc search strategy


glaucoma

Medical versus surgical interventions for open angle glaucoma (Review) 50


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 9. metaRegister of Controlled Trials search strategy
((open and angle and glaucoma) or POAG)

Appendix 10. ICTRP search strategy


(Open Angle Glaucoma) OR POAG

WHATS NEW
Last assessed as up-to-date: 1 August 2012.

Date Event Description

8 August 2012 New citation required but conclusions have not changed Issue 9, 2012: Longer term follow-up data from the
CIGTS study included

8 August 2012 New search has been performed Issue 9, 2012: Updated searches yielded no new trials for
inclusion in this update

HISTORY
Protocol first published: Issue 3, 2003
Review first published: Issue 2, 2005

Date Event Description

5 November 2008 Amended Converted to new review format.

25 April 2007 New search has been performed Issue 1 2008: In this first update to the review, lat-
est search April 2007, one additional potential study
was identified (Anand 2007) which was subsequently
excluded as it was not a randomised comparison of
medicine versus surgery, and three additional reports
associated with CIGTS 2001. These reports did not
provide any additional data on safety or effectiveness to
include in this updated review. The conclusions of the
review are unchanged

27 January 2004 New citation required and conclusions have changed Substantive amendment

Medical versus surgical interventions for open angle glaucoma (Review) 51


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
Conceiving the review: Jennifer Burr (JB)
Designing the review: JB, Augusto Azuara-Blanco (AAB)
Co-ordinating the review: JB
Undertaking electronic searches: JB
Undertaking manual searches: JB
Screening search results: JB, AAB
Organising retrieval of papers: JB
Screening retrieved papers against inclusion criteria: JB, AAB
Appraising quality of papers: JB, AAB, Alison Avenell (AA), Anja Tuulonen (AT)
Abstracting data from papers: JB, AAB, AA, AT
Writing to authors of papers for additional information: JB
Obtaining and screening data on unpublished studies: JB
Data management for the review: JB
Entering data into RevMan: JB, AA
Analysis of data: JB, AA
Interpretation of data: JB, AAB, AA, AT
Writing the review: JB, AAB, AA, AT

DECLARATIONS OF INTEREST
JB has in the past received an educational grant from Pharmacia/Pfizer and support from Pharmacia and Allergan towards the cost of
attendance at international meetings.
AAB has received honoraria for speaking at meetings, support for attending international meetings, educational grants and sponsorship
for research from pharmaceutical companies, including Pharmacia/Pfizer, Allergan, Merck Sharpe & Dohme and Novartis.
AA - none known.
AT has no research or educational grants from health care industry nor advisory board memberships. All international glaucoma
meetings - with very few exceptions - are supported directly or indirectly by companies in health care industry. The major sponsors of
glaucoma meetings are Alcon, Allergan, Heidelberg Engineering, Merck Sharpe & Dohm, Pfizer and Santen. Direct support to AT has
included occasional honoraria for speaking at meetings and reimbursement of travel costs.

Medical versus surgical interventions for open angle glaucoma (Review) 52


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SOURCES OF SUPPORT

Internal sources
Health Services Research Unit, University of Aberdeen, UK.
Department of Ophthalmology, Grampian Universities Hospital NHS Trust, UK.

External sources
Chief Scientist Office of the Scottish Executive Health Department, UK.

INDEX TERMS

Medical Subject Headings (MeSH)


Glaucoma, Open-Angle [ drug therapy; surgery]; Pilocarpine [therapeutic use]; Randomized Controlled Trials as Topic; Trabeculec-
tomy [adverse effects; methods]; Vision Disorders [etiology]

MeSH check words


Aged; Humans; Middle Aged

Medical versus surgical interventions for open angle glaucoma (Review) 53


Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.