Meta-analysis of randomised controlled trials comparing
latanoprost with brimonidine in the treatment of open-angle
glaucoma, ocular hypertension or normal-tension
A T Fung, S E Reid, M P Jones, P R Healey, P J McCluskey, J C Craig
............................................................... ............................................................... .....
Search strategy is available
online at http://bjo.bmj.
See end of article for
A T Fung, Sydney Eye
Sydney, NSW 2000,
Accepted 3 August 2006
Published Online First
6 September 2006
Br J Ophthalmol 2007;91:62–68. doi: 10.1136/bjo.2006.096693
Aim: To compare the efficacy and tolerability of latanoprost versus brimonidine in the treatment of open-
angle glaucoma, ocular hypertension or normal-tension glaucoma.
Method: Systematic review of randomised controlled trials comparing latanoprost and brimondine, identified
by searches including Medline, Embase and Cochrane Controlled Trials Register. Two reviewers
independently assessed trials for eligibility and quality and extracted data. Data were synthesised (random
effects model) and expressed as the absolute mean intraocular pressure (IOP) reduction difference from
baseline to end point for efficacy and relative risk for adverse events. Subgroup analysis and regression were
used to explore heterogeneity according to patient characteristics, trial design and quality.
Results: 15 publications reporting on 14 trials (1784 participants) were included for meta-analysis. IOP
reduction favoured latanoprost (weighted mean difference (WMD)=1.10 mm Hg (95% confidence interval
(CI) 0.57 to 1.63)). Significant heterogeneity was present (x213=38.29, p=0.001, I2=66.0%). Subgroup
analysis showed greater WMD for studies where data were analysed from end points .6 months duration,
cross-over design, open-angle glaucoma or ocular hypertension and monotherapy. Multiple regression
showed no significant association of WMD with trial duration (t9=1.92, p=0.09), trial design (t9=1.79,
p=0.11), trial quality (t9=20.46, p=0.66), or monotherapy or adjunctive therapy (t9=22.14, p=0.06).
Fatigue was less commonly associated with latanoprost (RR=0.27, 95% CI 0.08 to 0.88). Publication bias
was not evident on visual inspection of a funnel plot.
Conclusion: Latanoprost is more effective than brimonidine as monotherapy in lowering IOP. Brimonidine is
associated with a higher rate of fatigue.
glaucoma (OAG) or angle-closure glaucoma (ACG).1
Despite advances in laser and surgical treatments, lowering of
intraocular pressure (IOP) with topical drugs remains the initial
and a2-agonists are two common classes of topical anti-
glaucomatous treatments that are being increasingly prescribed.3
Latanoprost (Xalatan; Pharmacia, Peapack, New Jersey,
USA) is a prodrug of a prostaglandin F2a analogue that
increases aqueous outflow predominantly through the uveoscl-
Brimonidine tartrate (Alphagan; Allergan,
Irvine, California, USA) is a highly selective a2-adrenergic
agonist that increases uveoscleral outflow and reduces aqueous
humor production.5For many patients, latanoprost is now the
preferred treatment for glaucoma,6and is now the most
commonly prescribed ocular hypotensive in the Republic of
Ireland.7Despite this, several studies have suggested greater or
comparable IOP-lowering efficacy or fewer adverse events with
brimonidine.8–13There is sufficient uncertainty to warrant a
systematic review comparing these two drugs.
Two meta-analyses have compared latanoprost and brimoni-
dine in the treatment of glaucoma, both favouring greater IOP-
lowering effects with latanoprost over brimonidine. One of these
did not include any head-to-head trials between the two drugs.14
The other used 1-month peak and trough IOP-lowering effects as
their end point, and only included articles written in English,
German, French or Dutch published up to December 2003.15Only
laucoma is the second leading cause of visual loss
worldwide. It is estimated that by 2010, there will be
about 60 million people worldwide with open-angle
two trials comparing latanoprost and brimonidine were identi-
fied.9 16In both meta-analyses, adverse events were not studied.
Given the clinical significance of glaucoma, we believe that
another meta-analysis comparing the efficacy and tolerability
of latanoprost versus brimonidine is warranted. This should
include all randomised controlled trials (RCTs) directly
comparing the two drugs, unrestricted by trial duration,
outcome and language, and include the several studies that
have been published since the two meta-analyses mentioned
earlier. In addition to OAG and ocular hypertension (OHT), we
have included normal-tension glaucoma (NTG) in the target
population. This decision was made on the basis of the
similarity in interventions (topical anti-glaucomatous agents)
and outcome measures (IOP) in these groups.
MATERIALS AND METHODS
All randomised and quasi-randomised controlled trials directly
comparing topical latanoprost and brimonidine in the treatment
of OAG (primary or secondary), OHT or NTG as defined by the
investigators were included. Studies needed to have measured
efficacy, tolerability or both in humans. Comparisons between
combinations of latanoprost and other anti-glaucomatous
agent(s) and brimonidine with the same anti-glaucomatous
Abbreviations: ACG, angle-closure glaucoma; IOP, intraocular pressure;
IOPR, intraocular pressure reduction; OAG, open-angle glaucoma; OHT,
ocular hypertension; NTG, normal-tension glaucoma; RCT, randomised
controlled trial; WMD, weighted mean difference
agent(s) were accepted. There were no age or sex limitations.
Trials with treatment duration ,1 month for either intervention
We comprehensively searched Medline via Ovid (1966—March
week 2, 2006), Embase via Embase.com (1980—week 11, 2006),
the Cochrane Central Register of Controlled Trials in the
Cochrane Library (CENTRAL, Issue 1, 2006) and Scientific
Citation Index Expanded (1945—March 2006; appendix A).
The strategy included populations (OAG, OHT or NTG), inter-
ventions (latanoprost and brimonidine) and publication type
(randomised or quasi-randomised controlled trials). In addition,
Current Controlled Trials, ClinicalTrials.gov, CenterWatch and
the United Kingdom National Research Register were searched.
There were no limitations on language,date orpublicationstatus.
References of included publications were reviewed until no
further relevant studies were found. Authors were contacted to
clarify duplications and trial methods, and to identify further
relevant trials. When duplication was confirmed, only the most
complete trial was included.
Two reviewers (ATF and SER) independently screened com-
bined search results to determine trial eligibility and extract
data on to a standardised form. Authors of trial, sample size,
location, design, interventions, patient characteristics, baseline
and endpoint values, trial quality (allocation concealment,
blinding, measurement bias, completeness of follow-up and
intention-to-treat analysis) and adverse events were recorded.
Disagreements were resolved by discussion or consensus
involving a third reviewer (JCC) when required.
For efficacy, the mean IOP reduction (IOPR) from baseline to end
point was determined. Daily mean values were analysed, given
the tendency for IOP to fluctuate throughout the 24-h cycle.17For
three trials,9 11 12IOP at its peak effect after drug administration
was used because daily mean values were not reported.
For tolerability, adverse events were analysed in the following
subgroups: itch/discomfort, hyperemia, eyelid disorder, visual
disturbance, conjunctival disorder, keratopathy, dry eye, hyper-
trichosis, increased iris pigmentation, fatigue and headache.
Quantitative data synthesis and analysis
Extracted data were pooled for summary estimates using
Continuous outcomes were expressed as weighted mean
difference (WMD), with values .0 favouring latanoprost, and
dichotomous outcomes as relative risk (RR), with values ,1
favouring latanoprost. Both outcomes were reported with 95%
For studies that only reported absolute values for IOP at
baseline and end point, the IOPR and standard deviation (SD)
of the IOPR (SDIOPR) were calculated as follows:
SDIOPR=!(SDbaseline2+SDend point222rSDbaselineSDend point)
and was calculated from trials with known SDIOPR.
For studies that only reported standard errors (SEs), SD was
calculated by the formula SD=SE6!n. Six trials contained at
least a component of crossover design.11 12 17–21For these trials,
only the initial parallel phase was analysed. To minimise unit-
of-analysis error, the sample size analysed in each arm was the
true sample size divided by two.
For continuous data (IOP), the sample size was based on
intention-to-treat analysis or last observation carried forward
only if the authors of the trial clearly stated that this was the
process used. Otherwise, available case analysis was used. For
dichotomous data (adverse events), available case analysis was
undertaken irrespective of how the original trialists explored
the data to avoid imputing data.
Intertrial statistical heterogeneity was explored using the
Cochran Q test, with calculated I2indicating the percentage of
the total variability in effect estimates among trials that is due
to heterogeneity rather than chance.22Results for efficacy and
tolerability were calculated using a random effects model. This
assumes that each study estimates different but related
treatment effects, and is more conservative than a fixed effects
model in the presence of heterogeneity.22
Subgroup analyses were determined a priori and included
duration (,6 months, >6 months), study type (parallel v
crossover), peak versus trough IOP readings, glaucoma type
(OAG/OHT v NTG) and monotherapy versus adjunctive therapy.
For trials in which end points were reported at more than one
duration, only the longest duration was analysed.
Regression models exploring heterogeneity were performed
with SAS statistical software V.8. A priori determined covari-
ates included trial duration analysed, trial design (parallel v
crossover), trial quality (allocation concealment) and treatment
(monotherapy v adjunctive therapy). Publication bias was
assessed by visually inspecting a funnel plot.
A total of 16 publications (15 trials) met the eligibility criteria for
the systematic review. These were published in 10 different
journals, written in English, except one (Portuguese),23and
included 1824 participants. One trial23had insufficient informa-
tion for statistical analysis, leaving 15 publications (14 trials) and
1784 participants for meta-analysis8–13 16–21 24–26(fig 1). Seven of
these acknowledged direct financial support from a pharmaceu-
tical company.9 11 12 16 20 21 24No unpublished data were identified.
All trials reported greater IOPR for latanoprost than brimoni-
dine,except for thoseby
(WMD=21.17, 95% confidence interval (CI) 22.78 to 0.44)
and DuBiner et al9(WMD=20.30, 95% CI 21.58 to 0.98). The
pooled summary estimate for all 14 trials favoured latanoprost,
and was significant (WMD=1.10, 95% CI 0.57 to 1.63).
Significant heterogeneity was present (x213=38.29, p=0.001,
I2=66.0%), reflecting quantitative heterogeneity in the differ-
ence of treatment effect.
The pooled summaryestimate for trialswheredatawereanalysed
from end points .6 months duration (WMD=1.64, 95% CI 0.92
to 2.36) was greater than that for end points ,6 months in
duration (WMD=0.76, 95% CI 0.12 to 1.39; fig 2). After
subgrouping by trial design, the WMD was greater with crossover
design (WMD=1.48, 95% CI 0.66 to 2.31) than parallel design
(WMD=0.97, 95% CI 0.24 to 1.71) but still retained significance
in each favouring latanoprost. Participants with OAG or OHT
(WMD=1.10, 95% CI 0.48 to 1.72) responded similarly to those
with NTG (WMD=0.97, 95% CI 0.02 to 1.93). The WMD was
greater when both drugs were prescribed as monotherapy
(WMD=1.56, 95% CI 0.90 to 2.23) than as an adjunct to other
Meta-analysis of randomised controlled trials 63
treatments(WMD=0.58,95%CI20.04 to 1.19).Theoverlapping
95% CIs of each of the four subgroup pairings indicates no
significant difference between them.
Trial quality was inconsistently reported (table 2). We were
confident of adequate allocation concealment in only seven
trials,9 12 13 17 24 25double blinding in four trials9 12 20 21and
intention-to-treat analysis in five trials.11 16 17 24 25Withdrawals
ranged from 0% to 19%.
After adjustment for other covariates, there was no significant
association of WMD of IOPR with trial duration (t9=1.92,
p=0.09; fig 3), trial design (t9=1.79, p=0.11), trial quality
(t9=20.46, p=0.66), or monotherapy or adjunctive therapy
Three trials (four papers) reported on ocular haemodynamics.
Latanoprost was found to considerably increase ocular blood
flow,18 23peak systolic velocity of the ophthalmic artery10and
ocular perfusion pressure.19Brimonidine did not significantly
alter these parameters.
None of the adverse events showed a significant difference
between the treatment arms, except for fatigue (RR=0.27, 95%
CI 0.08 to 0.88, p=0.03). In all, 11 of 211 (5%) (brimonidine)
versus 3 of 247 (1%) (latanoprost) participants from three
trials16 20 26complained of fatigue (table 3).
multicentre, 7 single-centre; 11 were parallel in design and 4 crossover. Follow-up ranged between 2 and 12 months. All trials compared latanoprost 0.005%
eye drops once daily directly with brimonidine 0.2% twice daily, nine as monotherapy and six as adjuvant therapy. Of the data available on sex, 864 (48.3%) of
participants were men and 923 (51.7%) were women. Mean ages ranged from 52 to 77 years. Of the data available on type of glaucoma, 1299 (72%)
participants had open-angle glaucoma, 390 (22%) had ocular hypertension, 64 (4%) had normal-tension glaucoma and 60 (3%) had other or mixed glaucoma
(table 1). Mean baseline intraocular pressure (IOP) ranged from 15.5 to 26.4 mm Hg (latanoprost) and from 15.5 to 26.5 mm Hg (brimonidine), with good
comparability between the two intervention groups in each trial (only one trial26had a mean baseline IOP difference .0.4 mm Hg).
Flow chart showing the process of identification of randomised controlled trials (RCTs) for inclusion in the systematic review. In all, 8 trials were
64 Fung, Reid, Jones, et al
Characteristics of trials included in the review
Akman et al
Y (3rd line)?
Camras et al
DuBiner et al
Y (2nd line)1
Inan et al
Kampik et al
Simmons and Samuelson
Y (3rd line)??
Simmons et al
Y (2nd line)`` 41/59
Sodhi et al
Y (? line)
Waldock et al
Liu et al
Orzalesi et al
Stewart et al
Stewart et al
Y (2nd line)*** 41/59
?, value unknown; bd, twice daily; F, female; M, male; n, number of units of analysis (‘‘eyes’’ randomised); N, no; NTG, normal-tension glaucoma; OAG, open-angle glaucoma; od, once daily; OHT, ocular hypertension; Y, yes.
*Sums may be less than n if authors excluded some withdrawals in this analysis.
?Both arms also received Timolol/dorzolamide combination 0.5%/2% (07:30/19:30).
`Proportion in all nine arms.
1The latanoprost group received fixed combination latanoprost 0.005%/Timolol 0.5% (08:00), the brimonidine group received the unfixed combination of brimonidine 0.2% and timolol (0.5%) (08:00/20:00).
?Patients not achieving clinical success (15% intraocular pressure reduction at 1 month) were crossed over to other treatment at 1 month.
**Total trial duration 6 months. Analysed end point at 1 month before crossover of patients not achieving clinical success.
??Both arms also received a topical b-blocker and either dorzolamide or pilocarpine.
``Both arms also received a topical b-blocker.
11Duration of treatment arm. Entire duration of trial was 3 months.
??Duration of treatment arm. Entire duration of trial was 5 months.
***The latanoprost group received latanoprost 0.005%/Timolol 0.5% (nightly), the brimonidine group received brimonidine 0.2% and timolol (0.5%) (08:00/20:00).
Meta-analysis of randomised controlled trials65
Trials subgrouped by duration analysed. IOPR, intraocular pressure reduction; WMD, weighted mean difference.
Trial quality assessment
ITT analysis or
Average of 3
Akman et al
Camras et al
DuBiner et al
Sanchez et al
Inan et al
Kampik et al
Simmons et al
Sodhi et al
Waldock et al
Liu et al
Orzalesi et al
17Y (list of random
Y Different (2)NSY0Y
Stewart et al
Stewart et al
?, value unknown; GAT, Goldmann applanation tonometer; ITT, intention-to-treat; N, no; NS, not stated or uncertain; Y, yes.
*Unless otherwise stated, multicentre trials were assumed to have different examiners. ?For trials in which all patients were treatment naive, this is reported as Yes (Y).
`Patients masked to bottles, not to frequency (ie morning placebo not specified for latanoprost arm). 1At 1 month. Unable to ascertain percentage (authors did not
specify from which arms withdrawals originated). **Washout occurred before beginning the trial, but not between crossover arms.
??Insufficient information to determine whether all withdrawals were reported.
66Fung, Reid, Jones, et al
A funnel plot of all trials did not show asymmetry suggestive of
Importance of IOP in glaucoma
The diagnosis of glaucoma depends on visual field, optic disc
and retinal nerve fibre layer assessment, with less emphasis
placed on IOP. Despite this, IOPR is the mainstay of treatment.2
Several studies have shown this to reduce the progression of
optic nerve damage and visual field loss in patients with
increased IOP28–30or NTG.31
Summary of key findings
Our meta-analysis is the first to directly compare efficacy and
tolerability of topical latanoprost versus brimonidine for OHT or
glaucoma. Latanoprost was found to be significantly more
effective in reducing IOP, even after subgrouping by duration,
trial design or glaucoma type. This advantage was not as
significant as adjunctive therapy.
In six studies,8 11–13 21 25latanoprost and brimonidine were
compared as adjuncts to either topical b-blockers (eg, timolol) or
Theoretically, we can expect the reduced aqueous production
effects of b-blockers and dorzolamide32to be additive to the
additional benefit with brimonidine, which acts by both these
mechanisms.5This would suggest an even greater difference
between latanoprost and brimonidine when given as adjunctive
therapy rather than as monotherapy. Instead, we only found a
significant difference as monotherapy. It is possible that a ceiling
effect for IOPR is responsible for the discordance between theory
and evidence. An alternative explanation is the bias against
latanoprost in two trials,21 25where the adjuvanttimolol 0.5% was
prescribed twice daily in the brimonidine group but only once
daily in the latanoprost group.
heterogeneity in WMD of IOPR between latanoprost and brimo-
nidine. It is possible that the variability is explained by another
hidden cofactor, or more likely, by a combination of factors.
Fatigue is a recognised side effect of brimonidine33related to
its a-adrenergic effect. Although some adverse events such as
hypertrichosis and increased iris pigmentation are known side
effects of latanoprost34 35but not brimonidine, the low sample
size and event rates may have hidden evidence of a difference.
The decision on whether our results apply to a particular patient
in twoof the trials, patients with IOP .30 mm Hg17or 34 mm Hg8
The greater IOPR effect of latanoprost over brimonidine that we
have shown does not necessarily indicate a greater anti-glauco-
matous effect with latanoprost. This is because IOP is a surrogate
measure for glaucoma, and the two drugs may act through
pathways independent of this mechanism. Brimonidine may
neuroprotect retinal ganglion cells.37It has been shown to prolong
in rats rendered ocular hypertensive.38 39Clinical trials, several of
which are in progress,37are still required to definitely show a
neuroprotective effect of brimonidine in human eyes.
The increased ocular haemodynamics with latanoprost but
not brimonidine may be secondary to vasomotor effects on
vessels supplying the optic disc.18This may be associated with a
more favourable prognosis for glaucoma.40
None of the studies provided assessment of visual fields, the
optic nerve head or retinal nerve fibre layer. Such studies are
required if a definitive answer on efficacy is sought; however,
these are difficult to perform, given the chronic nature of
glaucoma and multiple covariates.
In addition to efficacy and tolerability, other factors such as
adherence to treatment and cost are important when compar-
ing anti-glaucomatous drugs. Latanoprost has the advantage of
once-daily dosing. Two studies have shown better treatment
Trial duration analysed (months)
Weighted mean difference of IOPR
(latanoprost v brimonidine)
(IOPR) versus trial duration. Diamonds represent parallel design studies.
Squares represent cross-over design studies.
Weighted mean difference of intraocular pressure reduction
Crude event rate
RR (95% CI) RD (95% CI)I2(%)Latanoprost Brimonidine
Eyelid disorder (swelling,
Visual disturbance (photophobia,
blurred vision, floaters, diploplia)
Increased iris pigmentation
0.81 (0.40 to 1.61)
1.37 (0.84 to 2.25)
1.61 (0.47 to 5.48)
20.02 (20.11 to 0.06)
0.04 (20.02 to 0.10)
0.01 (20.02 to 0.05)
853/50446/4681.19 (0.88 to 1.61)0 (20.02 to 0.02)0
2 9/31327/2600.16 (0.01 to 5.09)
20.08 (20.18 to 0.01)82.3
0.69 (0.24 to 1.96)
0.76 (0.26 to 2.27)
10.37 (0.59 to 182.60)
5.48 (0.65 to 46.50)
0.27 (0.08 to 0.88)
0.43 (0.17 to 1.11)
20.03 (20.07 to 0.01)
20.02 (20.05 to 0.02)
0.03 (0 to 0.06)
0.03 (20.04 to 0.10)
20.04 (20.07 to 20.01)
20.02 (20.04 to 0.01)
I2, intertrial statistical heterogeneity (Cochran Q test); NA, not available; RD, risk difference.
Meta-analysis of randomised controlled trials67
persistence and adherence with prostaglandins than a-ago-
nists.41 42Of the included studies, only one attempted to
monitor adherence, the results of which were not reported.9
Latanoprost has been shown to be cheaper,43comparable44or
more expensive45than brimonidine on a per-day basis.
Latanoprost, 0.005%, once daily has greater IOP-lowering
effects as monotherapy than brimonidine 0.2% twice daily up
to 1 year after initial treatment for OAG, OHT and NTG. There is
significant variability in the IOP-lowering difference between
the two drugs that is unexplained by trial duration, design,
quality, and monotherapy or adjunctive therapy. Brimonidine is
more commonly associated with fatigue than latanoprost.
Application of our results depends on knowledge of individual
patient risks and benefits.
We thank Linda Heslop for assistance with the literature search,
Monique Cebola for translation of the manuscript and Les Irwig for
A T Fung, Sydney Eye Hospital, Sydney, New South Wales, Australia
S E Reid, M P Jones, J C Craig, School of Public Health, University of
Sydney, Camperdown, Sydney, New South Wales, Australia
P R Healey, Department of Ophthalmology, Centre of Vision Research,
Millennium Institute, University of Sydney, Westmead, New South Wales,
P J McCluskey, Department of Ophthalmology, South Western Sydney
Clinical School, University of New South Wales, Liverpool, New South
Competing interests: None.
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