Current Medical Research & Opinion Vol. 26, No.

3, 2010, 511–528

0300-7995 Article 5310/450296

doi:10.1185/03007990903498786 All rights reserved: reproduction in whole or part not permitted

Original article
Mixed treatment comparison and
meta-regression of the efficacy and safety
of prostaglandin analogues and comparators
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14

for primary open-angle glaucoma and ocular

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Abstract
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M. Orme
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S. Collins
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Objectives:
For personal use only.

Abacus International, Bicester, Oxfordshire, UK

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Primary open-angle glaucoma (POAG) is a chronic condition characterised by optic neuropathy and vision
H. Dakin
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loss. Elevated intraocular pressure (IOP) can damage the optic nerve and is a risk factor for glaucoma, thus
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Abacus International, Bicester, Oxfordshire, UK treatment usually comprises topical hypotensives. This analysis aims to address methodological issues
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University of Oxford, Oxford, UK associated with the synthesis of glaucoma clinical trial data, given variations in study methodology and IOP
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S. Kelly measurement.
J. Loftus
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Pfizer Ltd, Walton on the Hill, Surrey, UK Methods:

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Meta-regression was used to estimate how IOP varies over time for patients receiving treatment. Relative
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treatment effects were assessed using a random-effects mixed treatment comparison (MTC) in order to
ig

Address for correspondence:

Dr Sarah Collins, Abacus International, 4 Market
preserve randomisation and avoid selection bias. To produce clinically meaningful outputs, these analyses
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Square, Bicester, OX26 6AA, UK. were combined to obtain the mean on-treatment IOP and the proportion of patients achieving different IOP
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Tel.: þ44 (0)1869 241281; Fax: þ44 (0)1869 targets at different time points. A further MTC estimated the probability of hyperaemia events.
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323248; Sarah.collins@abacusint.com
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Results:
The analysis showed that after 3 months’ treatment, between 58 and 83% of patients will have a 20%
Un t

Key words:
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Meta-analysis – Meta-regression – Mixed treatment
comparison – Ocular hypertension – Open-angle
glaucoma – Prostaglandin analogues
Accepted: 20 November 2009; published online: 15 December 2009
Citation: Curr Med Res Opin 2010; 26:511–28
reduction in IOP and 70–93% of patients will have an absolute IOP 520 mmHg. Latanoprost and
bimatoprost were found to produce significantly lower on-treatment IOP compared with timolol
(p50.05); the difference between latanoprost and bimatoprost was not significant. Travoprost produced
a lower mean IOP compared with timolol (not significant). Latanoprost-timolol was found to produce
significantly lower IOP than latanoprost alone or -blockers. The probability of hyperaemia-type events
varied between treatments from 14.8 to 63.03%. Latanoprost had significantly lower odds of hyperaemia
than travoprost, bimatoprost, travoprost-timolol, or bimatoprost-timolol.

Conclusion:
This analysis suggests that latanoprost and bimatoprost produce a statistically significant reduction in IOP
compared with timolol, but are associated with a higher risk of hyperaemia. Out of all the prostaglandins,
latanoprost may achieve a good balance between tolerability and IOP efficacy. As with all forms of
meta-analysis, the results are based on the assumption that the studies and intervention groupings are
sufficiently similar to be compared.

! 2010 Informa UK Ltd www.cmrojournal.com Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 511
 Current Medical Research & Opinion Volume 26, Number 3 March 2010
Introduction
This paper describes an analysis that was conducted to
address the methodological issues associated with the syn-
thesis of glaucoma clinical trial data. The issues became
apparent while developing an economic model comparing
prostaglandin analogues for the treatment of ocular hyper-
tension (OH) and primary open-angle glaucoma (POAG).
The dataset required for such a model should compare all
the drugs used in UK clinical practice and use as much data
from the literature as possible and the data analysis should
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be based on relative treatment effects while preserving
randomisation. Furthermore, the authors required outputs
that were clinically relevant, in that the authors needed to
predict the ‘on-treatment’ effect and how this would vary
over the course of treatment, as well as the proportion of
patients who would meet the clinically relevant treatment
targets. In the following sections the authors describe the
disease area and details of the methodological issues that
were encountered.
POAG is a chronic, irreversible condition characterised
by optic neuropathy and visual field loss1. Glaucoma is the
most common preventable cause of blindness in the UK1:
around 17 000 people were registered as blind and 15 500
For personal use only.
were registered as partially sighted in the UK in 2006 as a
result of the condition2,3. OH is elevated intraocular pres-
sure (IOP) above the normal range (normal IOP being
between 10 and 20 mmHg4). Though OH can exist with-
out visual field changes or any discernible glaucomatous
damage to the optic nerve head5, it can damage the optic
nerve, leading to glaucomatous optic neuropathy6. OH is
therefore a key risk factor for glaucoma and reducing IOP is
currently the only established method for preventing glau-
coma progression4,7–10. If left untreated, around 9.5% of
patients with OH will develop glaucoma within 5 years10.
If OH is detected in the early stages through regular screen-
ing by community optometrists, measures to prevent or
minimise disease progression can be taken; these usually
consist of early IOP-lowering therapy10 that reduces the
risk of further visual field loss7 and thus aims to maintain
patients’ quality of life4.
Topical ocular hypotensives are recommended as the
first-line treatment for glaucoma, or for preventing glau-
coma in patients with OH but no visual field loss4,11.
Topical therapies have displaced ophthalmic surgery and
systemic therapies, which are now rarely used in UK prac-
tice (though the guidance published by the National
Institute for Health and Clinical Excellence (NICE)
in 2009 still feature these treatment options11).
Prostaglandin analogues (latanoprost, bimatoprost, travo-
prost), -blockers (timolol, carteolol, betaxolol), carbonic
anhydrase inhibitors (CAIs; brinzolamide, dorzolamide),
2-adrenergics (A2As; brimonidine) and combinations
of these classes are the most commonly used topical thera-
pies in the UK.
512 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al.
Assessing the effectiveness of IOP-lowering therapies is
not straightforward. Diurnal (daily) IOP fluctuations of up
to 5 mmHg can be observed in the normal population
without any indication of pathology12. A patient’s IOP
will vary each time the IOP is measured, making it difficult
to assess whether an observed increase in a patient’s IOP is
a genuine loss of IOP control or simply due to natural
variation. In practice, when starting a patient on a new
IOP-lowering therapy, the treating physician will not set a
fixed IOP target, but initially will look for a sizeable drop in
IOP shortly after starting treatment (since this shows the
treatment works for this patient). Thereafter the ophthal-
mologist will monitor the patient’s IOP at regular intervals
to ensure the IOP stabilises at a suitably low value
(allowing for fluctuations in measurements provided the
measurements remain below an appropriate threshold).
Typical treatment targets would be an initial IOP reduc-
tion of 20% at the first follow-up visit compared with the
pre-treatment IOP, and the patient’s IOP maintained
below a threshold of 20 mmHg at subsequent follow-ups
(or lower for high-risk patients)4.
Given the wide range of topical treatments that are
available, the choice of which treatment to use in practice
is subject to debate, though trends in glaucoma treatment
in the UK indicate a general shift from -blockers to pros-
taglandin analogues for first-line use4,13. Despite a large
number of clinical trials evaluating topical hypotensives
(500 randomised controlled trials (RCTs) published by
March 2007), it is not immediately apparent what conclu-
sions can be drawn from the clinical evidence regarding
the relative efficacy of different treatments. This is due to
differences in the way IOP is measured and recorded (for
example, different ways of averaging multiple IOP mea-
surements at a follow-up visit), but also a lack of consis-
tency in the way trial endpoints are reported, and the
definition of what constitutes treatment ‘success’. This
means that differences between treatments for some IOP
endpoints are given undue weight (given the natural fluc-
tuation in diurnal IOP, a statistically significant difference
between treatments at a single measurement is not neces-
sarily an indication of a clinically meaningful difference in
efficacy; the difference would need to be sustained over
many measurements). There are also variations in study
characteristics and design, such as variable study quality
(e.g., inadequate randomisation methods), transparency
(e.g., not reporting sufficient study details), and complete-
ness of the data reported (e.g., not providing sufficient
baseline data and selective reporting of IOP endpoints).
In addition to this, it is difficult to relate the treatment
effects reported in these clinical trials (e.g., absolute
change in IOP from baseline, or absolute IOP measured
at different times of the day) to the IOP treatment targets
used to assess a patient’s response to treatment in actual
practice. To address this issue and explore potential meth-
odological options for integrating trial data, a systematic
www.cmrojournal.com ! 2010 Informa UK Ltd

review was conducted to provide a large evidence base
from which to draw the data for the provisional meta-
analyses described in this paper. The main objective of
the analysis was then to assess the relative efficacy of the
different treatments in terms of on-treatment IOP levels
while preserving randomisation and preventing study
selection bias, and then to transform the meta-analysis
results into clinically relevant outcomes, such as the pro-
portion of patients meeting IOP targets. Glaucoma clinical
data have not been analysed in an MTC before because of
challenges described above and previous IOP analyses
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have not attempted to translate the results into treatment
targets. This paper therefore focuses upon describing the
steps taken towards our objectives and the analysis
methodology.
A secondary objective was to assess the safety of the
ocular hypotensives, particularly with regard to hyperae-
mia-type adverse events. Patients with asymptomatic dis-
ease may be less willing to tolerate treatment-related
adverse events since they are not able to perceive any
immediate benefit from treatment. Medication side-effects
have been cited by patients as one of the reasons for non-
compliance with topical hypotensives14–16. The safety
For personal use only.
analyses focussed on counts of hyperaemia-type events
(adverse events categorised in the clinical trial as hyper-
aemia, conjunctival hyperaemia, conjunctivitis, red eye
and follicle conjunctivitis), as these are common to all
topical therapies, though these events are more prevalent
with prostaglandin analogues. The Glaucoma Adherence
and Persistency Study (GAPS) indicated that 37% of
patients experiencing hyperaemia associated with prosta-
glandin analogues will discontinue treatment17.
Methods
Systematic literature search and data extraction
Medline, Embase and the Cochrane library were searched
systematically up to March 2007 with a combination of
disease, drug type and trial design terms. MeSH terms
were used where available. The search terms included,
but were not restricted to: glaucoma, ocular hypertension,
randomised controlled trials, clinical trial, bimatoprost,
latanoprost, travoprost. Reference lists of identified trial
reports were searched and the Science Citation Index was
used to search for reports that cited the identified relevant
studies. Experts, investigators, and pharmaceutical compa-
nies working in the field of glaucoma were also contacted
for details of further studies and unpublished studies.
The review included all relevant RCTs that met the
following inclusion criteria:
 Included at least one treatment arm in which a pros-
taglandin analogue was given.
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 3 March 2010
 Trial participants were adults (18 years) with POAG
and/or OH.
 Studies including populations with secondary glau-
coma, those at risk of primary or secondary angle clo-
sure glaucoma, and those with occludable anterior
chamber angles were excluded. The rationale for
excluding secondary glaucoma (e.g., diabetic eye dis-
ease, pseudo-exfoliation), is that these conditions are
difficult to treat, and while IOP-lowering treatment
may be of some benefit, the relative treatment effect
associated with ocular hypotensives would be different
in these indications than in POAG.
 Retrieved articles were restricted to English language.
For the meta-analysis, a further restriction was imposed in
that only trials with at least 20 patients were analysed.
Initially trials of any duration were included in the system-
atic review, although the meta-analyses for efficacy
imposed additional limits on study duration.
IOP analyses
Two separate analyses were conducted on mean absolute
IOP:
 MTC to assess the relative efficacy of treatments,
 Meta-regression to calculate the rate at which IOP
values change over time and assess how mean
on-treatment IOP varies between populations with dif-
fering baseline IOP.
The results of these analyses were combined to predict
mean IOP at different time points with each treatment.
In addition to the inclusion criteria for the systematic
review, studies that did not report mean absolute IOP after
at least 1 month’s treatment were excluded from the meta-
analyses on efficacy. If the standard deviation (SD) was not
reported, it was calculated from the standard error
p
(SE: SE ¼ SD/ N, where N is the total number of patients
included in the mean absolute IOP at this follow-up
point).
In all studies patients had their IOP measured at fol-
low-up; this may involve the patient having repeated mea-
surements taken in close succession during the follow-up
visit (e.g., three IOP measurements all taken at 10 a.m. on
the 3-month visit), or may have had repeated measure-
ments taken at different times of day during the follow-up
visit (e.g., IOP measured at 10 a.m., 12 p.m. and 2 p.m.
during the 3-month visit).
The authors aimed to use as much of the IOP data as
possible in the analysis and to use the data in an objective
manner. Most trials that took repeated measurements
during one follow-up visit reported either the mean diurnal
IOP (the mean diurnal IOP across all the patients
followed-up in that study arm, where diurnal IOP is the
mean of the IOP measurements for that patient during
the follow-up visit) or the overall mean IOP (average of
Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 513
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

all the IOP measurements taken at that follow-up visit
across all patients in that study arm). Diurnal or overall
mean IOP was used in the analysis whenever it was
reported. Single IOP measurements were used if diurnal/
average measurements were not given in the publications.
In some trials where patients had IOP measured at several
time points during the follow-up visit, the study publica-
tion did not report the patient’s diurnal IOP but reported
instead the study arm average for all measurements by time
of day, e.g. reported separately the average of all IOP mea-
surements taken at 10 a.m. during follow-up visit, average
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Whereas standard meta-analyses evaluate the relative
efficacy of just two treatments based on head-to-head trials
only, MTC (or network meta-analysis) comprises an
extension of these methods in which treatment effects
are calculated for a network of treatments18–20. MTC
takes account of indirect comparisons, as well as head-
to-head trials, thereby enabling treatment effects to be
estimated for comparisons between treatments that have
not been compared directly in clinical trials. These meth-
ods build on the principles of indirect comparisons21,22 and
preserve the randomised comparisons within each trial.

of all IOP measurements taken at 12 p.m. during follow-up The MTC analysis of IOP included only studies that
visit, etc. In this case the crude mean across all reported reported mean IOP 3 months after start of treatment, as
means was used in the analysis for this follow-up point; this comprised the most frequently reported follow-up
the crude mean was used as the number of patients being point in RCTs that met our inclusion criteria.
measured at each time of day was not always reported. Techniques to allow for repeated measurements of a con-
Corresponding pooled SDs were calculated using tinuous outcome measure in MTC are still in develop-
Equation 1. ment. The authors therefore conducted our analysis in
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi two steps: first estimating the treatment effects at a
u Pk
u ðni  1Þsi single follow-up point (using MTC), then investigating
sp ¼ t P1k ð1Þ how on-treatment IOP changes over time while control-
1 ðni  1Þ ling for the treatment used (using meta-regression).
where sp¼ is the pooled SD, ni is the sample size of the ith To ensure consistency with the meta-regression and
allow covariates to be explored in sensitivity analyses, stu-
For personal use only.

set of IOP measurements, si is the SD of the ith set of IOP

measurements, and k is the number of mean IOP measure-
ments being combined.
Mixed treatment comparison on absolute IOP
An MTC meta-analysis was conducted to estimate the
relative efficacy of all commonly used ocular hypotensives
in terms of the absolute on-treatment IOP at a single
follow-up point.
dies were only included if they also reported baseline IOP
and both the number of patients with IOP measurements
at 3 months and the SD or SE around the mean. Studies
were also excluded from the MTC if they were not con-
nected to the evidence network (Figure 1): for example,
one study23 comparing latanoprost plus carteolol versus
latanoprost plus dorzolamide was excluded from the effi-
cacy MTC as neither combination has been evaluated in
any other studies meeting the inclusion criteria for this
systematic review.

CAI-Timolol
Timolol

2 1 Other BB
1 5
1
Latanoprost- 1 1
Timolol Latanoprost
1 3 CAI
2
2
Bimatoprost 1
Other UC
1
Travoprost 1

Travoprost-
Timolol

Figure 1. Network diagram for the mixed treatment comparison of absolute IOP after 3 months’ therapy. Treatment network diagram: each node in the
network represents a treatment strategy and the solid lines between nodes represent pairwise comparisons for which direct (head-to-head) evidence is
available from clinical trials. The numbers indicate the number of head-to-head studies for each direct comparison. The mixed treatment comparison model
was used to evaluate all pairwise comparison in the network, including indirect comparisons for which no head-to-head data are available from clinical trials.
BB, -blockers; CAI, carbonic anhydrase inhibitors; UC, unfixed combination.

514 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. www.cmrojournal.com ! 2010 Informa UK Ltd

Due to the large number of treatments and treatment
combinations evaluated in RCTs, similar treatment regi-
mens were pooled by assuming that all doses, dosing fre-
quencies and formulations of the same molecule(s) were
equivalent; for example, once-daily treatment with a fixed
combination of latanoprost 0.005% plus timolol 0.5% was
considered equivalent to an unfixed combination of lata-
noprost 0.005% once-daily plus timolol 0.25% twice-daily.
Furthermore, because of a lack of data for individual CAIs,
dorzolamide and brinzolamide were assumed to be equiv-
alent within the IOP MTC analysis and were considered as
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a single treatment (‘CAI’), and all -blockers other than
timolol were pooled as ‘other -blocker’. The remaining
three unfixed combinations for which IOP data were avail-
able (timolol and pilocarpine, travoprost and brinzola-
mide, carteolol and pilocarpine) were pooled together as
‘other unfixed combination’. This assumption was neces-
sary in order to have a connected network and sufficient
statistical power to compare all treatments. However, the
results for ‘other unfixed combination’ should be inter-
preted with caution due to the diverse treatments that
this encompasses. We examine the limitations arising
from the pooling of treatments in the discussion.
For personal use only.
A random-effects MTC model was fitted to the data
using Bayesian Markov Chain Monte Carlo methods (spe-
cifically Gibbs sampling). The analysis was conducted
using WinBUGS software version 1.424–26. Random-
effects models allow the true treatment effect (e.g., the
weighted mean difference in IOP between two treatments)
to vary between studies due to heterogeneity; in our model
it was assumed that treatment effects are drawn from a
normal distribution. The model was based on treatment
effects relative to latanoprost, since this treatment had the
most RCT evidence; the efficacy of each treatment com-
pared with latanoprost was used to calculate the weighted
mean difference between all other pairs of treatments.
The authors adapted WinBUGS code for random-
effects MTC on continuous outcomes that was developed
by Bristol University18,27 to allow for studies with up to
four treatment arms. No covariates were included in the
base-case MTC, although a sensitivity analysis was con-
ducted that controlled for the mean baseline IOP in each
study as a covariate. In this sensitivity analysis, baseline
IOP was assumed to affect the weighted mean difference
between each treatment and latanoprost.
The model used for the MTC of the efficacy outcomes
at 3-months is shown in Equation 2. For each study j that
compares treatment k with treatment b, the absolute IOP
myjk in the treatment k arm after 3 months of treatment is
given by:
 affect the mean value for each coefficient.
j, b if k ¼ b
myj, k ¼ ð2Þ
j, b þ j, k, b if k 6¼ b
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 3 March 2010
where dj,k,b  N(db,k,  2)  N(d1,k  d1,b,  2); yj,k  N(myj,k,
 y,j,k) yj,k is the absolute IOP observed in study j for treat-
ment k; j,b is the mean absolute IOP for treatment b in
study j;  y,j,k is the observed SE around the mean absolute
IOP for treatment arm k of study j; db,k is the overall
weighted mean difference in absolute IOP at 3 months
between treatment k and treatment b, where treatment
k ¼ 1 is the overall baseline treatment (latanoprost); and
 2 is the between-studies SD (or heterogeneity), which is
assumed to be common for all treatments.
The authors account for the correlation between treat-
ment effects for studies with three/four treatment arms as
described by Ades et al.27.
Uninformative normal priors were used for all model
parameters except for the between-studies SD for which
an uninformative uniform prior (range 0–10) was used.
Two chains were run simultaneously using different (arbi-
trarily chosen) initial values; convergence to a stable solu-
tion was checked by viewing plots of the sampled
simulations. Convergence was found to be adequate after
running 100 000 samples for both chains. These samples
were then discarded and a further 20 000 sampled simula-
tions were produced for the base-case analysis to ensure
that the results were as robust as possible.
Meta-regression analysis
Meta-regression is another generalisation of meta-analysis
that attempts to explain the heterogeneity in the results
observed in different studies by controlling for one or more
covariate28,29. The authors used standard frequentist
meta-regression techniques to assess how mean absolute
IOP varies over time, while controlling for the treatment
received and baseline IOP. Meta-regression was conducted
in Intercooled Stata version 8.2, using the meta-regression
module STB-42 sbe2328.
For simplicity, each follow-up point for each arm within
each study was treated as an independent data point. Since
this part of the analysis was not based on relative treatment
effects between the arms of each RCT, the treatment
effects calculated in this analysis are prone to confound-
ing22 (e.g., by differences in patient population).
Consequently, inferences about the relative efficacy of
each treatment were based on the MTC (which overcomes
this problem by focussing on the weighted mean differ-
ences in absolute IOP between study arms), not the
meta-regression. Although the authors recognise that
treating outcomes from the same study at different time
points as independent observations may cause the preci-
sion of coefficients to be overestimated, this is unlikely to
The meta-regression included all studies that met the
inclusion criteria for the systematic review and reported
the mean absolute IOP for each study arm at baseline, the
Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 515
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

mean absolute IOP for each arm after at least 4 weeks on
treatment and the number of patients for whom IOP was
measured at this time point. IOP measurements taken less
than 4 weeks after randomisation were excluded as IOP
tends to fall rapidly during the first month of treatment
before stabilising7,30. A total of 27 studies were excluded
from the analysis because the maximum follow-up point
was less than 4 weeks. One further trial that assessed the
impact of switching patients from latanoprost/timolol/dor-
zolamide triple therapy to latanoprost/timolol/brinzola-
mide with no washout period31 was also excluded, since
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mean on-treatment IOP, the SD was assumed to equal the
mean SD across all treatments.
In the meta-regression analysis, the mean IOP for treat-
ment TX at time point T (IOPTX,T,BL) was assumed to be
an additive, linear function of the treatment received
(TreatmentTX), baseline IOP (BaselineIOP) and the
time point at which the on-treatment IOP measurement
was taken (T), as shown in Equation 3, Table 1.
The meta-regression modelled treatment effects using
dummy variables for all treatments other than latanoprost
monotherapy; latanoprost comprised the reference treat-

baseline IOP values did not reflect a true pre-treatment ment as it had most RCT evidence, with 60.3% (44/73)
baseline. For studies that did not report SD or SE around

Table 1. Models used in meta-regression analyses.

Equation 3: Model used in meta-regression analysis:

X
IOPTX, T, BL ¼ Constant þ BaselineIOP  BaselineIOP þ T  T þ TX  TreatmentTX ð3Þ

Equation 4: General equation for calculating the mean on-treatment IOP based on the results of the MTC and the meta-regression:
IOPTX, T, BL ¼ IOPTX, 3mths, IOP¼23:54 þ BaselineIOP  ðBaselineIOP  23:54Þ þ T  ðT3Þ ð4Þ
Equation 5: Equation used to calculate the values shown in Table 5:
IOPTX, T, BL ¼ IOPTX, 3mths, IOP¼23:54 þ 0:2313  ð24:24  23:54Þ þ 0:02947  ðT  3Þ ð5Þ
For personal use only.

Abbreviation Definition and interpretation Value used in Equation 5

Dependent variable
IOPTX,T,BL Mean IOP for a population of patients who have been receiving TX for T Results shown in Table 4
months and had a mean baseline IOP of BaselineIOP
Independent variables
TreatmentTX A series of dummy variables equal to 1 or 0, depending on the treatment –
considered in that arm of the study. Latanoprost comprised the
baseline treatment and was not allocated a treatment dummy.
BaselineIOP For Equation 3: The mean baseline IOP value in that study arm –
For Equation 4: The mean baseline IOP for the population of interest 24.24 mmHgz
T The time in months between the start of treatment and the IOP 1–18 months
measurement
Regression coefficients
Constant The constant term in the meta-regression –
BaselineIOP Regression coefficient for baseline IOP. This shows the increase in mean 0.2313 (SE: 0.04896)*
on-treatment IOP for each 1 mmHg increase in mean baseline IOP.
This is assumed to be independent of treatment and time
T Regression coefficient for time elapsed between start of treatment and 0.02947 (SE: 0.03765)*
IOP measurement. The regression coefficient was found to be positive
indicating an increase in IOP over time. Note that such an increase in
IOP has been observed in long term studies30,46 but has no clinical
interpretation. It should be also noted that the model is based on IOP
measurements taken after 4 weeks of therapy; subsequently this
regression coefficient does not capture the initial drop in IOP that
occurs in the first month of therapy
TX Regression coefficient for the treatment received Data not shown
Additional terms specific to Equations 4 and 5
IOPTX,3mths,IOP¼23.54 Mean IOP of patients who have been receiving TX for 3 months and who Table 2y
had a mean baseline IOP of 23.54
23.54 Mean baseline IOP across the trials included in the MTC. This was used to 23.54 mmHgy
adjust for the small difference in mean IOP between the 18 trials
included in the MTC (mean baseline IOP ¼ 23.54 mmHg) and the 73
trials included in the meta-regression (mean baseline
IOP ¼ 24.24 mmHg)
3 Time point (in months) used in the MTC. This was used to adjust for the 3 months
time since start of treatment and predict IOP at T months

*Value calculated from the meta-regression analysis.

yValue calculated in the mixed treatment comparison.
zMean baseline IOP across the studies included in the meta-regression analysis.
IOP, intraocular pressure; SE, standard error; T, time; TX, treatment.

516 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. www.cmrojournal.com ! 2010 Informa UK Ltd

of trials included in the meta-regression evaluating
latanoprost.
Calculating the proportion of patients meeting
IOP targets
The results of the MTC and the meta-regression were
combined in order to predict mean on-treatment IOP
and the proportion of patients meeting different IOP
thresholds for each treatment at monthly time points
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(1 month to 18 months of treatment). These outputs
were chosen to be of clinical relevance and to provide
a comprehensive dataset for an economic model
that allowed different IOP treatment targets to be
investigated32.
For the first follow-up (which occurs 1–3 months after
starting a new treatment33), the treatment targets are
based on a percentage reduction in IOP compared with
baseline4. For subsequent follow-ups, treatment guide-
lines4 suggest that patients should achieve an absolute
IOP below 20 mmHg on treatment (i.e., within the
normal range and below the cut-off for ocular hyperten-
sion4) though many clinicians may set much lower IOP
For personal use only.
targets for patients with a high risk of disease progression
(e.g., below 16 mmHg).
In this paper the authors present results for the most
conservative IOP thresholds, though the methods
described were used to produce estimates for other treat-
ment targets and any time point between 1 and 18 months
since start of treatment. Two different methods were used
to predict the percentage of patients meeting the initial
IOP target and subsequent follow-up target:
(1) Computer simulation techniques were used to predict
the percentage of patients with a 20% reduction in
IOP at first follow-up compared to pre-treatment IOP
(see section Calculating the proportion of patients meet-
ing a percentage change target).
(2) Probability distributions were used to calculate the
percentage of patients with IOP 520 mmHg at
subsequent time points (see section Calculating the
proportion of patients with IOP below an absolute IOP
target).
For both analyses, IOP was assumed to follow a gamma dis-
tribution, based on published empirical observation34,35.
Calculating the proportion of patients meeting a
percentage change target
The relationship between the distribution around patients’
absolute IOP values before treatment and on treatment
and the distribution around the percentage change in
IOP is unknown. Therefore a computer simulation tech-
nique was used to calculate the proportion of patients
whose percentage reduction in IOP met treatment targets
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 3 March 2010
at first follow-up. For each monthly time point (assuming
first follow-up would be between 1 and 3 months after
starting treatment) and for each treatment, 60 000 hypo-
thetical patients were generated, with each patient being
randomly assigned a baseline IOP and an on-treatment
IOP that were independently sampled from gamma
distributions.
Sampling was conducted in Microsoft Excel 2007 using
the GAMMADIST and RAND functions. Each hypothet-
ical patient’s baseline IOP and on-treatment IOP was gen-
erated using the formula GAMMADIST(RAND(), , ).
For baseline IOP,  and  are given by:
Baseline IOP2 Baseline SD2
¼ ; ¼ ð6Þ
Baseline SD2 Baseline IOP
In the analysis presented here, the mean baseline IOP was
24.24 mmHg with an SD of 2.79, based on the mean and
SD of the baseline IOP across all 73 studies included in the
meta-regression analysis.
For mean IOP for treatment TX at time point T (where
T ¼ 1, 2 or 3 months),  and  are given by
IOP2TXT SD2
¼ ; ¼ ð7Þ
SD2 IOPTXT
In this analysis, the mean on-treatment IOP
(IOPTX,T,BL) was calculated using Equation 5 (results
shown in Table 4) and the SD around on-treatment
IOP values was assumed to be 2.47, based on the aver-
age SD across 213 study arms for which such data were
available. This SD was applied to all treatments and all
time points (other than baseline), since SD was not
found to vary between treatments or over time (except
for baseline measurements).
The percentage change in IOP was calculated for each
of the 60 000 hypothetical patients and the proportion of
simulated patients with a 20% reduction in IOP was
calculated. The results from these simulations are shown
in Table 5.
Calculating the proportion of patients with IOP
below an absolute IOP target
For each month on treatment (up to 18 months), the pro-
portion of patients with IOP levels below TARGET
mmHg was calculated in Microsoft Excel 2007 using the
formula ¼ GAMMADIST(TARGET, , , TRUE) where
 and  are given in Equation 7 above. The values shown
in Table 5 were based on the mean IOP (IOPTX,T,BL,
calculated using Equation 5; these values are shown in
Table 4) and the SD around on-treatment IOP values
was assumed to be 2.47 (the average SD across 213 study
arms reporting SD or SE).
Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 517
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

Analysis of hyperaemia-type event rates For each study j, which compares treatment k with
treatment b, the probability of hyperaemia pj,k is given by:
A second MTC was conducted to estimate the proportion   
of patients experiencing hyperaemia-type adverse events pj, k j, b if k ¼ b
logitðpj, k Þ ¼ log ¼
with each treatment. Hyperaemia-type events were those 1  pj, k j, b þ j, k, b if k 6¼ b
reported in the clinical trials as: hyperaemia, conjunctival ð8Þ
hyperaemia, conjunctivitis, red eye or follicle conjunctivi-
tis. Publications that did not report data on hyperaemia- where dj,k,b  N(db,k,  2)  N(d1,k  d1,b,  2); rj,k  Bin(pj,k, nj,k)
type adverse events were excluded from the analysis, as and rj,k is the observed number of patients with hyperaemia
were any studies that were not connected to latanoprost who were randomised to treatment k in study j; nj,k is the
(directly or indirectly) via a connected evidence network number of patients in study j randomised to treatment k;
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14

(Figure 2). Studies of any treatment duration were
included in this analysis as hyperaemia events were
assumed to occur soon after starting treatment.
The statistical methods used in this analysis were the
same as those for the efficacy MTC except that data were
analysed using WinBUGS code for random-effects MTC
of dichotomous outcomes that was adapted from code devel-
oped by Bristol University18,27 to allow for studies with up
to four arms. This code calculates relative treatment effects
in terms of odds ratios (OR). No covariates were included
in the safety analysis. Because more studies reported safety
outcomes than IOP and the authors did not restrict out-
comes to a particular time point, more data were avail-
For personal use only.
db,k is the overall log-OR of hyperaemia with treatment k
versus treatment b, where treatment k ¼ 1 is the overall
baseline treatment (latanoprost); and  2 is the between-
studies SD (heterogeneity), which was assumed to be
common to all treatments. We account for correlation
between treatment effects for studies with three/four treat-
ment arms.
Uninformative normal priors were used for all model
parameters except for the between-studies SD for which
a uniform prior (range 0–10) was used. Two chains
were run using different (arbitrarily chosen) initial
values; convergence was checked using all indicators and
was found to be adequate after a burn in of 20 000 itera-

able; it was therefore possible to calculate treatment
effects separately for individual CAIs, individual
-blockers and different pilocarpine/-blocker combina-
tions while maintaining a connected evidence network
(Figure 2). However, fixed and unfixed combinations, dif-
ferent doses and different dosing frequencies of the same
drug(s) were again assumed to be equivalent.
tions; a further 20 000 samples were used to generate
results.
Presentation and interpretation of results
All hypothesis tests were two-tailed and based on  ¼ 0.05.
Classical (frequentist) p-values and 95% confidence

Latanoprost- Brimonidine-
Brimonidine Timolol
Pilocarpine-
1 2
Latanoprost- 1 Timolol
1
Dorzolamide
1 Dorzolamide-
1 3 Carteolol-
Timolol 2
Latanoprost- Pilocarpine
Latanoprost- Timolol 5 7 1
Carteolol 1
1 Control/ Placebo 2 1
Latanoprost Betaxolol
4 3
Travoprost- 1 1 2
1 10 5
Brinzolamide
Timolol 1 1
1 Brimonidine Dorzolamide
4
4 6
Travoprost- 4
Timolol
2
1 2 2
Travoprost Bimatoprost Bimatoprost-
Timolol

Figure 2. Network diagram for the mixed treatment comparison of hyperaemia-type events. Treatment network diagram: each node in the network
represents a treatment strategy and the solid lines between nodes represent pairwise comparisons for which direct (head-to-head) evidence is available from
clinical trials. The numbers indicate the number of head-to-head studies for each direct comparison. The mixed treatment comparison model was used to
evaluate all pairwise comparison in the network including indirect comparisons for which no head-to-head data are available from clinical trials.

518 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. www.cmrojournal.com ! 2010 Informa UK Ltd

intervals (CI) are presented for the results of the meta-
regression. Bayesian p-values and 95% credible intervals
(CrI) are presented for the MTC analyses. The difference
between two treatments was considered statistically signif-
icant (Bayesian p-value50.05) if the 95% CrI around the
log-OR or weighted mean difference did not include zero.
No assessment of publication bias or study quality was con-
ducted since the methods to evaluate this in MTC are still
evolving, though it was observed during the data extrac-
tion process that studies varied in quality, transparency
and extent of reporting.
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14
Results
Systematic literature search results
The preliminary searches identified 4517 potential cita-
tions for screening (4389 retrieved via the systematic
search of the literature databases plus a further 128 cita-
tions identified by hand searching; Figure 3). After two
screenings, 510 potentially relevant publications were
identified by titles and abstracts. These were further
reduced to 181 prostaglandin RCTs (282 non-
For personal use only.
prostaglandin studies and 47 secondary publications were
excluded). The full text publications for these RCTs were
reviewed to ensure the studies met with the review inclu-
sion criteria and comprehensive data extraction was con-
ducted using data from 105 RCTs. The 93 studies included
in at least one meta-analysis are listed in Appendix A.
Figure 3 shows a flow diagram of the results of the search
strategy, and the number of identified studies/citations at
each stage of the screening process.
Mixed treatment comparison on absolute IOP
MTC was used to assess the relative efficacy of the different
treatments in terms of absolute on-treatment IOP at a
single time point (3 months after start of treatment).
A total of 18 studies (including a total of 2943 patients)
were included in the MTC, since only 25% (18 out of 73)
of the studies included in the meta-regression reported
mean IOP at 3 months alongside its SD and/or SE. The
analysis converged well and the between-study SD was
0.66 (95% CrI: 0.25, 1.21), indicating some degree of het-
erogeneity between studies.
In total, results were calculated for ten treatments
(Table 2), which were all found to reduce mean IOP to
normal levels after 3 months’ treatment, from an
average of 23.54 mmHg at baseline to between 16.09
and 18.61 mmHg at 3 months (Table 2). Based on the
weighted mean differences between treatments
(Table 3), both latanoprost monotherapy and bimatoprost
monotherapy were found to produce significantly
lower on-treatment IOP than timolol (p50.05).
! 2010 Informa UK Ltd www.cmrojournal.com
Current Medical Research & Opinion Volume 26, Number 3 March 2010
However, there was no significant difference between lata-
noprost and bimatoprost (p40.05). Latanoprost com-
bined with timolol also produced a significantly lower
on-treatment IOP than latanoprost monotherapy, timolol
monotherapy, other -blocker monotherapy, CAI mono-
therapy, travoprost plus timolol, CAI plus timolol, and the
other unfixed combinations (p50.05). No other weighted
mean differences in IOP between the ten treatments eval-
uated in the MTC were statistically significant.
A sensitivity analysis including a covariate suggested
that baseline IOP had no significant effect on weighted
mean differences for each treatment compared with lata-
noprost (p40.05, results not shown).
A total of 73 studies (including 11 519 patients) were
included in the meta-regression analysis, which assessed
how on-treatment IOP levels change over time and with
variations in baseline IOP. These studies reported a total of
213 mean IOP values at time points ranging from 1 to 18
months after start of treatment. The meta-regression esti-
mated that populations with mean baseline IOP 1 mmHg
higher than average had on-treatment IOP values 0.231
(SE: 0.049) mmHg higher. The ranking of monotherapy
formulations was also similar to those from the MTC (data
not shown).
Notably, this analysis showed that mean IOP rises by an
average of 0.029 (SE: 0.038) mmHg per month after the
first month of treatment (in which a sharp fall in mean IOP
is observed), although this coefficient was not statistically
significant (p ¼ 0.4).
The time coefficient (T) and the coefficient for base-
line IOP (BaselineIOP) from the meta-regression were
used alongside the treatment effects at 3 months
(IOPTX,3mths,IOP¼23.54) that were calculated in the MTC
to calculate the mean IOP for a population of patients who
have been receiving treatment TX for T months using
Equation 4 (Table 1. The definitions of the terms used in
Equations 3 and 4 are also shown in Table 1).
The mean IOP values predicted for each treatment
(Table 4) demonstrate that the authors would expect
mean IOP to remain within the range considered normal
(10–20 mmHg4) during the first 18 months of therapy for
all treatments considered.
Using the methods described above, the percentage of
patients reaching specified treatment targets (a 20%
reduction in IOP from baseline or absolute IOP
520 mmHg) was estimated from the mean IOP values
shown in Table 3 by assuming that IOP levels follow a
gamma distribution. This demonstrates that after 3
months’ treatment, between 58 and 83% of patients
have achieved a 20% reduction in IOP and 70–93% of
patients have an absolute IOP 520 mmHg (Table 5). No
treatments other than prostaglandin monotherapy and
latanoprost/timolol enabled more than 70% of patients
to achieve a 20% reduction in IOP at 3 months.
Since these figures are derived from the mean IOP
Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 519
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

4389 references
retrieved from the
literature databases

3751 excluded at
128 references 4517 references
first screening stage
identified by hand in the study
(1891 duplicate
searching database
citations)
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14

256 excluded at
766 potentially
second screening of
relevant references
abstracts

47 secondary 510 ocular

publications hypotensives 282 not PG
excluded from studies meeting analogue RCTs
database inclusion criteria
For personal use only.

181 PG analogue 76 studies

RCTs (228 excluded from
publications) database (third
extracted to screening of
database full-text)

32 studies
excluded from
105 studies to be
extraction (no data)
extracted

93 studies included
in meta-analyses

73 studies included
72 studies included 18 studies included
in meta-regression
in hyperaemia MTC in MTC analysis of
of IOP data at time
analysis IOP (at 3 months)
> 1 month

Figure 3. Flow diagram of the results of the search strategy and identified studies. MTC, mixed treatment comparison; IOP, intraocular pressure;
PG, prostaglandin; RCT, randomised controlled trial.

calculated in the MTC, the ranking of treatments is the
same as Table 4.
Adverse events: hyperaemia
In total, 72 studies evaluating 19 different treatments
were included in the MTC of safety outcomes. The
results of this analysis, shown in Table 6, indicate that
the probability of hyperaemia-type events while on active
treatment ranges from 14.8% (timolol) to 63.0%
(bimatoprost-timolol). Table 7 shows all statistically sig-
nificant results based on the odds ratio comparing active
treatments as estimated by the hyperaemia MTC.
Timolol monotherapy had a significantly lower odds of
hyperaemia-type events than latanoprost, bimatoprost or
travoprost (p50.05). This result is to be expected since
-blockers are more commonly associated with other
(sometimes systemic) adverse events (see Discussion).

520 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. www.cmrojournal.com ! 2010 Informa UK Ltd
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

Table 2. Mean absolute IOP at 3 months by treatment, based on the mixed treatment comparison.

Treatment Mean absolute IOP at 3 months (mmHg) No. of trial arms (No. patients)
Mean SE Lower 95% CrI Upper 95% CrI

Latanoprost-timolol 16.09* 0.53 15.03 17.14 4 (368)

Bimatoprost 16.97 0.51 15.95 17.99 3 (188)
Latanoprost 17.42 0.10 17.22 17.62 15 (1015)
Travoprost 17.44 0.73 15.98 18.91 1 (138)
CAI-timolol 17.76 0.63 16.54 19.03 3 (261)
CAI 17.94 0.50 16.95 18.92 3 (124)
Other -blocker 18.06 0.70 16.68 19.44 2 (54)
Timolol 18.38* 0.34 17.7 19.05 6 (536)
Travoprost-timolol 18.60 1.08 16.48 20.64 1 (100)
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14

Other unfixed combinationy 18.61 0.65 17.29 19.87 3 (159)

The mean baseline IOP across all trials included in the MTC was 23.54 mmHg.
*Statistically significant difference in mean IOP compared with latanoprost (p50.05) given that the 95% CrI around the weighted mean difference for the treatment
in question versus latanoprost did not include 0.
yPooled result for timolol and pilocarpine, travoprost and brinzolamide, carteolol and pilocarpine.
CAI, carbonic anhydrase inhibitor; CrI, credible (Bayesian probability) interval; IOP, intraocular pressure; SE, standard error.

Table 3. Weighted mean difference in absolute IOP at 3 months by treatment, based on the mixed treatment comparison. Statistically significant results*.

Treatment comparison Weighted mean difference in IOP for A vs. B

A B Mean SE Lower 95% CrI Upper 95% CrI

Latanoprost-timolol Travoprost-timolol 2.51 1.17 4.83 0.12

For personal use only.

Latanoprost-timolol Other unfixed combinationy 2.52 0.85 4.19 0.82

Latanoprost-timolol Timolol 2.29 0.59 3.46 1.11
Latanoprost-timolol Other -blocker 1.98 0.89 3.75 0.23
Latanoprost-timolol CAI 1.85 0.74 3.31 0.39
Latanoprost-timolol CAI-timolol 1.67 0.53 2.74 0.66
Bimatoprost Timolol 1.41 0.60 2.61 0.20
Latanoprost-timolol Latanoprost 1.33 0.54 2.42 0.27
Latanoprost Timolol 0.96 0.35 1.65 0.25

*For comparisons of treatment A versus treatment B, a weighted mean difference below 0 indicates that the absolute on-treatment IOP is lower for treatment A than
for treatment B. Statistical significance was inferred in all cases where the 95% CrI around the weighted mean difference for the treatment in question versus the
comparator arm did not include 0. Values are based on a population with a mean baseline IOP of 23.54 mmHg.
yPooled result for three unfixed combinations: timolol and pilocarpine, travoprost and brinzolamide, carteolol and pilocarpine.
CAI, carbonic anhydrase inhibitor; CrI, credible (Bayesian probability) interval; IOP, intraocular pressure; SE, standard error.

Table 4. Predicted mean IOP for each treatment at different time points, calculated using Equation 3*.

Treatment Predicted mean IOP values (mmHg)

Month 1 Month 2 Month 3 Month 6 Month 12 Month 18

Latanoprost-timolol 16.19 16.22 16.25 16.34 16.52 16.70

Bimatoprost 17.07 17.10 17.13 17.22 17.40 17.58
Latanoprost 17.52 17.55 17.58 17.67 17.85 18.03
Travoprost 17.54 17.57 17.60 17.69 17.87 18.05
CAI-timolol 17.86 17.89 17.92 18.01 18.19 18.37
CAI 18.04 18.07 18.10 18.19 18.37 18.55
Other -blocker 18.16 18.19 18.22 18.31 18.49 18.67
Timolol 18.48 18.51 18.54 18.63 18.81 18.99
Travoprost-timolol 18.70 18.73 18.76 18.85 19.03 19.21

*Predicted values were based on a mean baseline IOP of 23.54 mmHg based on the average of the baseline IOP values across the 213 measurements of mean IOP
included in the meta-regression analysis.
CAI, carbonic anhydrase inhibitor; IOP, intraocular pressure.

However, latanoprost monotherapy had a significantly monotherapy was found to have significantly higher
lower odds of hyperaemia-type events than travoprost, odds of hyperaemia-type events than brimonidine, dorzo-
bimatoprost, travoprost with timolol, and bimatoprost lamide, dorzolamide-timolol, latanoprost, latanoprost-
with timolol (p50.05). Furthermore, bimatoprost timolol, timolol, and timolol-pilocarpine.

! 2010 Informa UK Ltd www.cmrojournal.com Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 521
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

Discussion IOP 520 mmHg. It would be necessary to treat 7–10

The analysis suggests that latanoprost and bimatoprost are
significantly more effective than timolol in terms of mean
on-treatment IOP (p50.05), although there were no sig-
nificant differences between latanoprost and bimatoprost
(p40.05). Travoprost was found to produce a mean IOP
that is lower than timolol, although the difference was not
statistically significant. After 3 months’ treatment,
58–83% of patients will have achieved a 20% reduction
in IOP and 70–93% of patients will have an absolute
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14
patients with prostaglandin monotherapy in place of timo-
lol to get an additional patient with IOP520 mmHg. The
results suggest that the treatments considered in this ana-
lysis enable most patients to reach conservative IOP tar-
gets, although some treatments (notably -blockers and
CAIs) may not induce sufficient IOP lowering (e.g., main-
taining IOP 518 mmHg) to meet more aggressive targets.
The risk of hyperaemia varied considerably between
active treatments, ranging from 14.75% (timolol) to
63.03% (bimatoprost and timolol). It is known that adher-

ence with topical hypotensives is low17, and it is likely that

Table 5. Percentage of patients reaching treatment target at 3 months for adherence will be reduced further for treatments with a
each treatment, based on the mean IOP estimated in MTC IOP analysis. high incidence of adverse events; in one observational
study of pharmacy claims data, 37% of patients who expe-
Percentage of patients NNT rienced hyperaemia due to topical prostaglandin treatment
expected to meet 520 mmHg
IOP target after vs. timolol stopped or switched their treatment36. Timolol monother-
3 months’ therapy apy has significantly lower odds of hyperaemia-type events
20% Absolute than latanoprost, bimatoprost or travoprost. However lata-
reduction IOP520 mmHg noprost and bimatoprost were found to be significantly
Latanoprost-timolol 82.95 92.81 5.1 more effective than timolol. Latanoprost has significantly
Bimatoprost 75.22 87.44 7.0 lower odds of hyperaemia-type events than either travo-
Latanoprost 70.88 83.69 9.5 prost or bimatoprost; there will be one additional hyper-
Travoprost 70.50 83.51 9.7
For personal use only.

CAI-timolol 67.32 80.36 13.9 aemia event for every 5.5 patients treated with latanoprost
CAI 65.51 78.42 19.1 (rather than no treatment), compared with one additional
Other -blocker 64.10 77.06 25.7 hyperaemia event in every 1.9 and 2.4 patients treated
Timolol 60.18 73.18 –
Travoprost-timolol 58.06 70.30 – with either bimatoprost or travoprost, respectively.
This analysis therefore demonstrates that out of all the
CAI, carbonic anhydrase inhibitor; IOP, intraocular pressure; NNT, number
needed to treat (i.e. the number of patients who would need to receive the
prostaglandins, latanoprost achieves a good balance
treatment in question instead of timolol in order to see one additional patient between tolerability and IOP reduction. It should be
with absolute IOP520 mmHg at 3 months). noted that the safety MTC focussed on one type of

Table 6. Probability of hyperaemia-type event by treatment (in descending order of risk).

Treatment Proportion of patients experiencing hyperaemia No. of trial arms NNH vs.
(No. patients) placebo
Mean SE 95% CrI
Lower Upper

Placebo/vehicle only 5.61 3.84 1.08 15.40 4 (101) –

Timolol 14.75 2.95 9.63 21.18 27 (1977) 10.9
Dorzolamide 21.64 8.84 8.02 42.38 3 (227) 6.2
Brimonidine 21.65 6.39 11.02 35.71 7 (554) 6.2
Timolol-pilocarpine 21.66 9.08 7.91 43.00 3 (200) 6.2
Dorzolamide-timolol 23.28 5.16 14.28 34.38 13 (1063) 5.7
Latanoprost 23.68 1.14 21.47 25.91 43 (3426) 5.5
Latanoprost-timolol 27.91 5.50 18.04 39.61 27 (2048) 4.5
Betaxolol 29.60 15.57 6.69 65.77 1 (34) 4.2
Brimonidine-timolol 37.25 15.89 11.15 70.91 2 (198) 3.2
Travoprost-brinzolamide 40.22 16.77 11.78 74.93 2 (117) 2.9
Latanoprost-carteolol 43.66 26.92 3.31 93.14 1 (64) 2.6
Travoprost 46.62 11.54 24.86 69.32 10 (1193) 2.4
Latanoprost-dorzolamide 50.23 19.31 14.68 86.00 3 (133) 2.2
Travoprost-timolol 50.97 8.43 34.67 67.53 10 (1193) 2.2
Carteolol-pilocarpine 53.77 22.29 11.99 91.53 1 (26) 2.1
Latanoprost-brimonidine 54.40 19.76 16.51 89.03 2 (69) 2.0
Bimatoprost 58.59 6.77 44.87 71.19 19 (1959) 1.9
Bimatoprost-timolol 63.03 16.96 26.39 90.50 2 (267) 1.7

Crl; credible interval; NNH, number needed to harm (i.e. the number of patients who would need to receive the treatment in question in order to see
one additional case of hyperaemia-type events over and above those that would be seen with placebo); SE, standard error.

522 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. www.cmrojournal.com ! 2010 Informa UK Ltd
 Current Medical Research & Opinion Volume 26, Number 3 March 2010

side-effect, hyperaemia, which is common across all topi-
cal hypotensives. In doing so we have ignored other
adverse events, including many that occur more frequently
with other drug classes compared to prostaglandins. Other
than hyperaemia, the most common adverse events occur-
ring in trials meeting the systematic review inclusion cri-
teria were: allergic reaction, corneal punctate erosions,
superficial punctate keratitis/epitheliopathy, exudates,
eyelid swelling/blepharitis, burning/stinging, irritation/
foreign body sensation, itching/pruritis, dry eye, eye dis-
comfort/pain, blurred vision, visual disturbance/reduced
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14
patients with a history of asthma or obstructive airways
disease, bradycardia, heart block or uncontrolled heart
failure42. It is reasonable to assume that the side-effects
associated with CAIs and -blockers would also affect
compliance14–16 and may be more frequent or troublesome
to patients than hyperaemia.
Applications
The authors present an innovative and flexible way of
using heterogeneous trial data to calculate figures that

acuity, visual field changes, pupil contraction/miosis,
photophobia, purities and taste perversion, headache, eye-
lash growth, eyelid pigmentation and iris pigmentation.
Though the authors have not conducted a formal meta-
analyses of these events to date, -blockers and CAIs were
observed to have different safety profiles from prostaglan-
dins. Stinging/burning/itching are common with CAIs and
occur more commonly with dorzolamide than with pros-
taglandins. More serious systemic effects associated with
topical -blockers such as timolol are widely documented
and include fainting, cardiac arrhythmia and other adverse
cardiovascular effects such as bradycardia and decompen-
For personal use only.
are directly relevant to clinical practice. Equation 4 may
be used to predict the mean IOP that different patient
populations are likely to achieve after different lengths
of time on treatment. However, the meta-regression is
based only on IOP measurements taken between 1 and
18 months after the start of treatment and its validity
has not been evaluated at time points outside this range.
In particular, this equation is unlikely to produce valid
predictions of IOP during the first month of treatment,
in which IOP falls rapidly. Furthermore, Equation 4 is
based on population averages, rather than outcomes for
individual patients and is therefore not necessarily a

sated congestive heart failure, worsening of heart block, valid prediction tool for individual patients. Since the sys-
bronchospasm-related events, and central nervous system tematic review identified no studies quantifying the corre-
effects37–41; -blockers are therefore contraindicated in lation between baseline and on-treatment IOP at the level

Table 7. Odds ratio of hyperaemia by treatment comparison, based on the mixed treatment comparison analysis: Statistically significant
results*.

Treatment Comparator Odds ratio of SE 95% CrI

hyperaemia
Lower Upper

Timolol Bimatoprost-timolol 0.06 0.06 0.02 0.48

Dorzolamide Bimatoprost-timolol 0.08 0.06 0.02 0.96
Timolol-pilocarpine Bimatoprost-timolol 0.09 0.07 0.02 0.98
Timolol Latanoprost-brimonidine 0.09 0.07 0.02 0.88
Brimonidine Bimatoprost-timolol 0.09 0.08 0.02 0.86
Dorzolamide-timolol Bimatoprost-timolol 0.11 0.11 0.03 0.86
Timolol Bimatoprost 0.11 0.33 0.06 0.23
Latanoprost Bimatoprost-timolol 0.12 0.12 0.03 0.87
Timolol Travoprost-timolol 0.15 0.42 0.08 0.32
Timolol Travoprost 0.18 0.37 0.08 0.47
Latanoprost Bimatoprost 0.21 0.70 0.12 0.38
Brimonidine Bimatoprost 0.21 0.11 0.07 0.48
Timolol-pilocarpine Bimatoprost 0.22 0.14 0.05 0.59
Dorzolamide Bimatoprost 0.22 0.15 0.05 0.59
Dorzolamide-timolol Bimatoprost 0.22 0.08 0.10 0.41
Latanoprost-timolol Bimatoprost 0.25 0.66 0.13 0.54
Dorzolamide-timolol Travoprost-timolol 0.26 0.55 0.12 0.67
Latanoprost Travoprost-timolol 0.28 0.76 0.15 0.59
Brimonidine Travoprost-timolol 0.29 0.16 0.09 0.69
Timolol-pilocarpine Travoprost-timolol 0.30 0.21 0.07 0.85
Dorzolamide Travoprost-timolol 0.30 0.22 0.07 0.85
Latanoprost Travoprost 0.32 0.60 0.14 0.94
Latanoprost-timolol Travoprost-timolol 0.34 0.79 0.16 0.80
Timolol Latanoprost-timolol 0.47 0.15 0.24 0.83
Timolol Latanoprost 0.56 0.14 0.34 0.88

*For comparisons of treatment A versus treatment B, an odds ratio below 1 indicates that the odds of hyperaemia occurring is lower for treatment A
compared with treatment B. Statistical significance was inferred in all cases where the 95% CrI around the odds ratio for the treatment A compared
with treatment B did not include 1.
CrI, credible (Bayesian probability) interval; IOP, intraocular pressure; SE, standard error.

! 2010 Informa UK Ltd www.cmrojournal.com Mixed treatment comparison of prostaglandin analogues for POAG Orme et al. 523
 Current Medical Research & Opinion Volume 26, Number 3 March 2010
of individual patients, the predictions of the proportion of
patients with a 20% reduction in IOP assumes no corre-
lation; this may mean that the study over- or under-
estimates the proportion of patients meeting this target.
The results of this meta-analysis have been used in a
decision-analytic model assessing the cost effectiveness of
topical ocular hypotensives commonly used in the UK32
that took account of differences in: drug costs; the inci-
dence of hyperaemia and its impact on compliance; and
the probability of meeting IOP targets and the impact that
this will have on the risk of glaucoma.
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14
Strengths and limitations of the review
and analyses
This study is the first MTC of glaucoma trials. MTC
ensures that all available evidence is used in the analysis:
including indirect evidence as well as head-to-head trials.
It also estimates relative treatment effects based on the
differences between groups randomised to different treat-
ments, thereby minimising the potential for bias and the
effect of unknown confounding variables. Furthermore,
sensitivity analyses demonstrated that controlling for a
For personal use only.
known covariate (baseline IOP) had no effect on results.
However, within these analyses it was not practical to
control for other potential confounding factors, such as
whether or not patients had previously received or failed
drug therapy, the dose and frequency of administration or
the time of day at which IOP was measured or the drug was
administered.
Although meta-regression on the individual arms of
different trials would not be an appropriate method for
estimating treatment effects as it ignores randomisation,
it provided a simple, practical method of quantifying the
rate at which IOP changes over time. This analysis sug-
gested that mean IOP increases by 0.03 mmHg every
month between 1 and 18 months after start of treatment,
although this effect was not statistically significant
(p ¼ 0.4). Furthermore, this analysis assumes that the
rate at which IOP increases is the same for all treatments.
Though a gradual rise in IOP has been observed in
long-term observational studies of latanoprost7,30, tachy-
phylaxis is primarily associated with timolol and is not
known to be an issue with prostaglandins43–45. By assum-
ing that the rate of IOP increase is constant across treat-
ments, the analysis may therefore underestimate the
efficacy of prostaglandins.
Around 50% (88/181) of trials identified in the system-
atic review could be not included in any of the
meta-analyses because of short follow-up (less than 1
month on-treatment), not reporting hyperaemia outcomes
or the appropriate IOP measure, or having incomplete
reporting of study characteristics and outcome measures.
Out of 181 studies meeting the systematic review inclusion
524 Mixed treatment comparison of prostaglandin analogues for POAG Orme et al.
criteria, 10% (18/181) were used in the efficacy MTC,
40% (73/181) in the meta-regression and 40% (72/181)
in the safety MTC (Appendix A). Furthermore, the sys-
tematic review included only trials with a prostaglandin
arm. As many studies on other drug classes were omitted
from the analysis, the results for these drugs should be
interpreted cautiously. It is likely that including studies
without prostaglandin arms would have increased the pre-
cision with which the efficacy of non-prostaglandin treat-
ments was estimated. Since techniques to assess
publication bias within MTC are still under development,
it was not possible to assess publication bias within the
dataset. Furthermore, there were too few studies to accu-
rately estimate treatment effects separately for each dose of
each treatment or for specific CAIs or -blockers other
than timolol. Consequently, different doses and/or treat-
ments in a class were analysed as though they were a single
treatment. This is likely to have increased heterogeneity
and reduced the accuracy with which treatment effects and
coefficients were estimated.
As with any form of meta-analysis, the results are sub-
ject to a number of key assumptions, in particular that the
clinical trials and intervention groupings are sufficiently
similar to be compared. One key assumption is that differ-
ent dosing regimens are pooled in the analysis. However, it
is not clear if dosing a patient in the morning has a differ-
ent effect to dosing a patient in the evening, or whether
the efficacy would be different if the daily dose is the same
but eye drops are administered more frequently. One could
consider an analysis of the different drug groupings, with
the daily dose and timing of doses/number of doses per day
as covariates and consider time that the IOP outcome was
measured.
The authors plan to conduct further research to address
these issues by developing new MTC techniques to
account for repeated IOP measurements and a wider
range of confounding factors using a more comprehensive
set of RCTs.
Conclusion
This analysis suggests that latanoprost and bimatoprost
produce a statistically significant reduction in IOP com-
pared with timolol, but are associated with a higher risk of
hyperaemia. Out of all the prostaglandins, latanoprost may
achieve a good balance between tolerability and IOP effi-
cacy. Methods to predict the probability of achieving IOP
treatment targets or experiencing hyperaemia-type adverse
events were developed. Though the methodology
described in this paper has some limitations, analyses are
based on a large systematic review, controlled for key con-
founding variables and preserved randomisation when esti-
mating treatment effects. The study’s methodology
therefore reduces bias and it is an objective application
www.cmrojournal.com ! 2010 Informa UK Ltd

of the clinical evidence base. Furthermore, the outputs of
the analysis relate to clinically meaningful targets and are
therefore of practical use when comparing different ocular
hypotensives.
Transparency
Declaration of funding
This research was funded by Pfizer Ltd, Walton on the Hill,
Surrey, UK.
Curr Med Res Opin Downloaded from informahealthcare.com by University of California San Francisco on 12/19/14
Declaration of financial/other relationships
S.K. and J.L. have disclosed that they are employees of Pfizer.
M.O., H.D. and S.C. have disclosed that they have undertaken
paid consultancy work on behalf of Pfizer.
Some peer reviewers receive honoraria from CMRO for their
review work. The peer reviewers of this paper have disclosed that
they have no relevant financial relationships.
Acknowledgement
The authors thank Nicky Welton for her advice on the
WinBUGS code and also thank the Abacus systematic review/
data extraction team for their involvement in the project.
For personal use only.
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