Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20

Topical medical therapy and ocular perfusion

pressure in open angle glaucoma: a systematic
review and meta-analysis

George Rennie, Angus Wilkinson, Andrew White, Marinella Ruospo,

Armando Teixeira-Pinto & Giovanni Strippoli

To cite this article: George Rennie, Angus Wilkinson, Andrew White, Marinella Ruospo, Armando
Teixeira-Pinto & Giovanni Strippoli (2019): Topical medical therapy and ocular perfusion pressure
in open angle glaucoma: a systematic review and meta-analysis, Current Medical Research and
Opinion, DOI: 10.1080/03007995.2019.1595553

To link to this article: https://doi.org/10.1080/03007995.2019.1595553

Accepted author version posted online: 18

Mar 2019.

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Review
Topical medical therapy and ocular perfusion pressure in open angle glaucoma: a systematic
review and meta-analysis
George Rennie1, Angus Wilkinson1, Andrew White2,3, Marinella Ruospo4, Armando Teixeira-Pinto5,
Giovanni Strippoli4,5,6
1
Royal Prince Alfred Hospital, Sydney, Australia
2
Department of Ophthalmology, Westmead Hospital, Sydney, Australia
3
Save Sight Institute, Westmead Institute for Medical Research, Sydney, Australia
4
Diaverum Medical Scientific Office, Trollebergsvagen, Lund, Sweden
5
Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Australia
6
Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy

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*Corresponding author: George Rennie, Royal Prince Alfred Hospital, Sydney, Australia, 7

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Moorefields Rd Kingsgrove NSW 2208, Australia, georg.rennie@gmail.com, tel: +61422066046

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Abstract
Objective
We compared the benefits and harms of topical interventions for ocular perfusion pressure in open
angle glaucoma.

Methods
We searched the databases MEDLINE, EMBASE and CENTRAL for randomised controlled trials
comparing topical hypotensive agents in glaucoma. Of the 9 433 citations identified, 10 randomised
controlled trials were included. We summarised data using random effects meta-analysis for post
treatment mean ocular perfusion pressure and using relative risk for adverse events.

Results
10 trials (416 patients) were included. The quality of included trials was low to moderate. There was
a higher post treatment ocular perfusion pressure with bimatoprost compared to timolol (1 trial, 32
patients, mean difference -4.00mmHg, 95% confidence interval -7.01 to -0.99, p = 0.009),

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heterogeneity was not significant (I2 = 41%, Chi2 = 13.55, p = 0.09). Prostaglandins as a class had

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higher post treatment mean ocular perfusion pressure compared to alternative interventions (5
trials, 147 patients, mean difference 2.19mmHg, 95% confidence interval 0.67 to 3.70, p = 0.005),

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heterogeneity in the subgroup analysis, (I2 = 10%, Chi2 = 4.47, p = 0.35). Adverse events were found
to be significant in only one of the studies comparing latanoprost to brimonidine, relative risk 3.67

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(standard error 0.59, p 0.03).
Conclusions
We identified low to moderate quality evidence describing post intervention mean ocular perfusion
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pressure in open angle glaucoma. Bimatoprost increases mean ocular perfusion pressure when
compared to timolol. As a class, prostaglandins increase mean ocular perfusion pressure.
Prostaglandins may provide beneficial ocular perfusion pressure profiles compared to alternative
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agents.
Keywords: Glaucoma, ocular physiological phenomena, systematic review, ophthalmic solutions
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Short title: Ocular perfusion pressure: systematic review

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Introduction
Open angle glaucoma (OAG) is an optic neuropathy where there is death of retinal ganglion cells and
their axons leading to visual field loss and eventually blindness. It is currently treated by using
interventions to decrease intra-ocular pressure (IOP)[1, 2]. This treatment slows progression but
does not stop it altogether.
Ocular perfusion pressure (OPP) describes the pressure forcing blood into the eye against the
resistance of the ocular vasculature. High intra-ocular pressure increases resistance and low
systemic blood pressure decreases flow. Further, a mechanism of auto-regulation exists where by
the eye regulates blood flow under different systemic haemodynamics[3]. OPP is an indirect
measure of the vascular perfusion of the posterior ocular segment. It has been suggested that
dysfunction of the autoregulation mechanism of ocular blood flow is involved in glaucoma and this
may lead to changes in OPP [4, 5, 6]. Evidence has shown that optic nerve hypo-perfusion may
contribute to the progression of glaucoma[7, 8, 9]. Several population-based studies have revealed a
strong association between lower perfusion pressure, including mean ocular perfusion pressures
(MOPP), systolic ocular perfusion pressure (SOPP) and diastolic ocular perfusion pressure (DOPP);

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and increased prevalence of OAG in Caucasian, African, Hispanic and Asian populations[7, 10, 11, 12,
13]. In the early manifest glaucoma trial, it was also noted that patients with low systolic perfusion
pressure were more likely to progress[14].

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Systematic reviews comparing single and combination treatments in OAG and ocular hypertension
(OHT) have been published and generally show favourable outcomes for prostaglandin and beta-

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blocker therapy with regards to decreasing IOP and slowing progression of visual field loss[14, 15,
16, 17, 18]. Topical medications used currently can influence OPP primarily by decreasing IOP and to
a lesser extent some can also influence systemic blood pressure (BP) parameters[19]. There is
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evidence that topical beta-blockers specifically may exacerbate systemic nocturnal hypotension and
in these cases lead to progressive visual field damage[20, 21]. The low-pressure glaucoma study
specifically compared timolol to brimonidine and showed subjects on brimonidine showed less visual
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field progression than those randomised to timolol[21]. It has yet to be clarified whether this was
due to neuroprotective qualities of brimonidine or whether timolol may accelerate visual field loss
secondary to a theoretical decrease in OPP caused by beta blockers.
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We investigated which topical ocular hypotensive changes OPP favourably in OAG patients in order
to better understand their role in disease modification, suitability of use in a clinical setting and
potential future therapeutic applications. To our knowledge there is no systematic review comparing
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the effects of the most commonly used topical glaucoma medications on OPP.
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Methods
We reported the study according to the Preferred Reporting Items for Systematic Reviews and Meta-
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analyses (PRISMA) statement[22].

Eligibility criteria
We included randomised trials, both parallel and cross over, with a duration of a minimum of 4
weeks. Trials included patients with primary open angle glaucoma (POAG), normal tension glaucoma
(NTG), pseudo-exfoliative glaucoma (PXG) and or OHT. We included trials using topical monotherapy
for the treatment of OAG. We considered common treatments used in glaucoma, including beta
blockers, prostaglandin analogues, alpha-2 adrenergic agonists and carbonic anhydrase inhibitors.
Outcomes
The primary outcome of interest was post intervention mean ocular perfusion pressure and
secondary outcome was adverse events. We only included studies which explicitly described MOPP,
DOPP or SOPP.
Exclusion criteria were not randomised studies, those not continuing for at least 4 weeks and those
with multiple comparisons or comparing combination treatments.
Information sources
We searched the Cochrane register of controlled trials (CENTRAL), MEDLINE and EMBASE on
30/03/2018 (see online-only supplement). We only included published articles which were written in
English. No date restrictions were applied.

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Study selection
Two investigators (GR and AW) assessed study titles and abstracts. We obtained and reviewed the

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full text of all eligible articles. We discussed any disagreements with an arbitrator (GS).
Data collection

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Two investigators (GR and AW) used pre-designed data-extraction forms to collect data from
suitable trials. Forms contained study design; duration; details on randomisation and blinding;
financial disclosure; number of participants; age; diagnosis; intervention; IOP; systemic BP
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measurements including systolic blood pressure (SBP) and diastolic blood pressure (DBP); OPP;
DOPP; SOPP and adverse events.
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Risk of bias in included studies

We used the Cochrane risk of bias tool to assess the methodology and outcomes of included studies
(The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials).
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Result analysis
We used RevMan 5.3 software for the analysis. Weighted mean difference (MD) of the post
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intervention MOPP was calculated for the primary outcome. For studies reporting diastolic ocular
perfusion pressure as the outcome of interest, we calculated mean ocular perfusion pressure
according to the formula 2/3 (1/3 x systolic blood pressure + 2/3 x diastolic blood pressure) –
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IOP[23]. Standard deviation (SD) was derived from standard error (SE) when required using the
formula SD = SE x √n, where n is the number of participants.
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Heterogeneity was considered significant where I2 > 50%. We combined the results of the included
studies using the random effects model to pool the data. A p value of <0.05 was considered
significant. We used relative risk and SE for dichotomous data.
Subgroup analysis was performed a priori according to intervention type and class, and type of
glaucoma. We intended to assess publication bias by means of a funnel plot but did not given the
small number of studies included.
Results
Characteristics of trials
We screened 9,433 unique records from the 3 databases searched. We reviewed 17 full text articles
and 10 were eligible randomised trials and were included in our study[24, 25, 26, 27, 28, 29, 30, 31,
32, 33] (Figure 1). The included trials enrolled a total of 416 patients, each study including between
20 and 140 patients, median of 32 and interquartile range 24 to 41. Median follow up time was 8
weeks, interquartile range 4 to 10 weeks. Five (50%) studies included NTG patients[24, 26, 28, 29,
32, 33] while 3 (33%) included POAG or OHT patients[25, 27, 30] and 1 (10%) study included POAG
patients only[31]. Eight interventions were described in the included studies. Five studies (50%) used
latanoprost, 4 (40%) timolol, 3 (30%) brimonidine, 2 (20%) studies each included bimatoprost and
dorzolamide, while 1 (10%) study included timogel, tafluprost and travaprost. 5 studies included in
the review reported patients taking systemic medication for cardiovascular disease, while 3 did not
and the remaining 2 did not report this detail. The characteristics of the populations and
interventions in the included studies are summarised in Table 1. [Figure 1 and Table 1 near here]

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Additionally, 1 study measured IOP 10 times per day [33], 1 study 9 times daily [29], 1 7 times daily

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[32], 3 studies 6 times daily [24, 30, 31], 1 study 3 times daily and the remaining 3 did not specify
[25, 26, 27]. Of the studies reporting multiple measurements, 5 measured IOP and BP during the

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waking hours only [24, 28, 29, 32, 33], while 2 measured IOP over 24 hours [30, 31].
Risk of bias

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The overall quality of the trials was low to moderate, where 7 of 10 included studies had at least one
Cochrane domain assessed as being at high risk of bias (Figure 2). The studies performed well in the
domains of attrition or incomplete outcome data (1 of the 10 included studies assessed as high risk
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of bias) and selective reporting (1 study assessed at high risk and another of having an unclear risk of
bias). The included studies performed poorly in the domains of selection, performance and detection
bias where all of the included studies in the first two domains and 6 of 10 included studies in the
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latter domain were assessed to have uncertain or high risk of bias. Liu ‘02 and Oddone ‘15 were the
only two studies to report a method of random sequence production[28, 30]. No included study
described an allocation concealment method. Quaranta ’08, Oddone ’15 and Fuchsjager-mayrl ’05,
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or 3 of 10 included studies, were the only studies to blind participants[25, 30, 32] while Liu ‘02
masked observers but not the dosing coordinator[28] and Harris ’03 described single blinding but did
not describe whether this refers to participants or observers[26]. Most studies declared no financial
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interest (7 of 10), and one did not report on one (Costagliola et al), while Oddone ‘15 and
Fuchsjager-mayrl ‘05 (2 of 10) declared a potential financial interest[25, 30]. Shin ‘14 and Oddone
‘15 included sample size calculations[30, 33] while Quaranta ’08 included power and effect size
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calculations for the given number of subjects included[32]. Sensitivity analysis was not performed
given the included studies did not differ significantly in terms of quality. [Figure 2 near here]
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Efficacy of topical treatment on post intervention mean ocular perfusion pressure

There was a significant increase in post intervention mean ocular perfusion pressure with
bimatoprost compared to timolol (1 trial, 32 participants, mean difference -4.00mmHg, 95%
confidence interval -7.01 to -0.99, p = 0.009[30]) (Figure 3). There was no significant increase in post
treatment MOPP with timolol compared to timogel (1 trial, with 28 patients and showed a mean
difference of 0.00mmHg, 95% confidence interval -5.39 to 5.39[31]). There was no significant
difference in MOPP at the end of treatment with comparisons of prostaglandins, bimatoprost
compared to latanoprost had a mean difference of 0.00mmHg (1 trial, 40 patients, 95% confidence
interval -4.06 to 4.06)[32], while travaprost compared to tafluprost showed a non-significant mean
difference of 1.40mmHg (1 trial, 41 patients, 95% confidence interval -0.66 to 3.46)[33]. There was
no significant increase in post intervention MOPP with twice daily versus three times daily dosing of
brimonidine (1 trial, 20 patients, mean difference -1.50mmHg, 95% confidence interval -6.12 to
3.12[29]). There was no significant heterogeneity across comparisons (I2 = 41%, Chi2 = 13.55, p =
0.09).
In the subgroup analysis according to glaucoma subtypes we found no significant difference in post
intervention MOPP among studies for primary open angle glaucoma or ocular hypertension analysis
(4 trials, 238 patients, and had a mean difference of -0.75mmHg, 95% confidence interval -3.14 to
1.63) (Figure 4). There was no significant difference in post treatment MOPP among studies in the
normal tension glaucoma analysis (6 trials, 178 patients and a mean difference of -0.98mmHg, 95%
confidence interval -2.87 to 0.91) (Figure 4). There was no significant heterogeneity in the subgroup
analysis by glaucoma subtype (I2 = 36%, Chi2 = 7.77, p = 0.17). In the subgroup analysis according to
treatment types we did not find a significant difference between interventions (see Figure 5).
Analysis according to treatment class showed prostaglandins significantly increased MOPP when
compared to other treatment classes (5 trials, 147 patients, mean difference 2.19mmHg, 95%
confidence interval 0.67 to 3.70, p = 0.005) (Figure 6). Significant heterogeneity was shown in the
subgroup analysis by treatment class (Chi2 = 11.61, df = 3, p = 0.009, I2 = 74.2%). It is unclear why

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there is significant heterogeneity in this subgroup analysis given the subgroup analysis by treatment

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type did not yield significant subgroup heterogeneity (Chi2 = 11.20, df = 5, p = 0.05, I2 = 55.4%) and
the populations in both analyses included similar variations of IOP, BP, glaucoma subtypes and

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systemic medication for cardio-vascular disease. [Figures 3,4,5 and 6 near here]

Adverse events
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We found a significant difference between treatment groups for adverse events when looking at
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crude event data in the study of Liu ’02, where the risk of an adverse event was higher with
Latanoprost compared to Brimonidine (27 patients, RR of 3.67, SE 0.59, p = 0.03), see Table 2[28].
The most common side effect reported in this study for Latanoprost was conjunctival
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hyperaemia[28]. [Table 2 near here]

Discussion
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We performed a systematic review analysing the post intervention MOPP change comparing
commonly used ocular hypotensive agents (OHA) in open angle glaucoma (OAG). There were a small
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number of studies of poor or uncertain quality included in this review limiting our ability to draw
conclusions with great certainty.
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Among included trials, Oddone provided the only significant difference between intervention types,
where bimatoprost resulted in a higher post intervention mean ocular perfusion pressure than
timolol[30](Figure 3). This study included POAG and OHT subjects. This may be due to the superior
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ocular hypotensive effect of bimatoprost relative to timolol or its favourable systemic

haemodynamic effects, i.e. no change or an increase in systemic haemodynamics. There is some
evidence of the superior ocular hypotensive effect of prostaglandins as a class when compared to
beta-blockers and evidence suggesting the ocular hypotensive superiority of bimatoprost within its
class [17, 34, 35, 36, 37, 38, 39]. In the Oddone study, bimatoprost significantly decreased IOP
relative to timolol[30]. A meta-analysis showed that bimatoprost resulted in the greatest reduction
in IOP fluctuations which may suggest that consistency in an ocular hypotensive effect may be
necessary in improving ocular perfusion pressure[40]. A retrospective case series of prostaglandin
non-responders in a normal tension glaucoma population showed significantly lower non response
rates in bimatoprost compared to latanoprost, travaprost and tafluprost[41]. This suggests that
there may be unique effects of bimatoprost on aqueous flow which increase efficacy, decreased IOP
fluctuations and decrease the rate of non-responders.
It is also possible that bimatoprost increases OPP more than timolol secondary to favourable
systemic BP effects. In the Oddone study, timolol significantly decreased SBP and DBP relative to
baseline; where bimatoprost did not have this effect[30]. A randomised controlled trial showed
single use bimatoprost and travaprost did not significantly reduce blood pressure; while another RCT
comparing bimatoprost to fixed combination of latanoprost and timolol showed significant increase
in systolic BP and systolic OPP for the bimatoprost group (with similar IOP reduction between the
two groups) [42, 43]. There are variable reports on the systemic haemodynamic effects of topical
beta blockers, where some evidence points to no systemic hypotensive effects while others support
the contrary[20, 44, 45, 46, 47, 48, 49]. The evidence would suggest that bimatoprost either has no
or increased effect on systemic BP while timolol has no or a systemic hypotensive effect. Another
meta-analysis on the twenty-four hour effect of timolol showed no difference between pre and post
treatment ocular perfusion pressure[50]. In the Oddone study the systolic perfusion pressure was
lower with timolol and unchanged with bimatoprost, while the diastolic perfusion pressure was
higher with bimatoprost and unchanged with timolol[30]. This suggests that a favourable post
intervention OPP is subject to significant IOP decrease without causing systemic hypotensive effects
and a significant favourable change of OPP compared to baseline. Our findings suggest that relative

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to timolol, prostaglandin analogues such as bimatoprost have a more favourable ocular and systemic

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pressure profile leading to an increased OPP. There was only one comparison between bimatoprost
and timolol in our review and the generalisability of this conclusion is limited.

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It is unclear which parameter, if any, is critical in determining the OPP superiority of one agent over
another, i.e. IOP or systemic haemodynamics relative to baseline or to each other or OPP relative to
baseline. This is an area which requires further investigation.

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It would be reasonable to expect the difference in post intervention MOPP found between
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bimatoprost and timolol to be mirrored in the subgroup analysis by treatment types (discrete type of
intervention vs other). Generally, systematic reviews have not consistently yielded a single superior
ocular hypotensive agent[17, 18, 34, 35, 51, 52]. As discussed above, topical timolol may have an
inferior hypotensive effect relative to prostaglandins and it may or may not decrease systemic BP
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parameters. It may therefore be expected to perform poorly relative to comparators. We found no

significant difference in MOPP between timolol vs other treatments. The superiority of bimatoprost
was not replicated in the subgroup analysis by treatment type (Figure 2). However, limitations in our
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subgroup analysis are that some intervention types yielded a small number of included studies, e.g.
the bimatoprost sub-group included 2 studies. Also, some comparisons within the subgroups were
with different formulations of the intervention, e.g. timolol vs timogel, and interventions of the
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same class, e.g. bimatoprost vs latanoprost. These factors would limit the validity of this analysis.
Subgroup analysis by treatment class yielded significant increase in post intervention mean ocular
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perfusion pressure for prostaglandins (Figure 4). This is likely secondary to the superior ocular
hypotensive effect of prostaglandin analogues relative to timolol[17, 34, 39, 51]; the more stable IOP
profiles produced by prostaglandin analogues relative to ocular hypotensives targeting aqueous
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production[53]; and the potential systemic hypotensive effect of beta blockers[20, 44, 45, 46, 47, 48,
49]. In two included and two excluded studies timolol was found to decrease systemic blood
pressure[24, 30, 54, 55]. In line with available evidence, all our included studies and four RCTs
excluded from our review showed prostaglandins were not found to significantly change BP[24, 25,
26, 27, 28, 29, 30, 31, 32, 33, 37, 54, 55, 56, 57]. We did not find evidence of systemic BP effects of
carbonic anhydrase inhibitors but did find one excluded RCT which showed a systemic hypotensive
effect with an alpha agonist, brimonidine[55]. Also, the subgroup analysis by treatment type or
treatment class did not show that timolol or beta-blockers decrease ocular perfusion pressure. This
suggests that the association of visual field progression and beta-blocker induced nocturnal
hypotension found in the literature may be mediated by other means other than a decrease in
measured OPP[20, 21]. Randomised controlled trials examining measured OPP and associated
parameters with visual field progression may help clarify this association.
Among included RCTs and four excluded RCTs prostaglandins were found to significantly increase
post treatment MOPP relative to timolol in three studies and relative to brimonidine in one
study[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 54, 55, 56, 57]. Our review suggests, that prostaglandins
as a class have favourable IOP and systemic BP profiles which lead to increased OPP relative to
betablockers, carbonic anhydrase inhibitors and alpha agonists. It is uncertain what the clinical effect
of a mean increase of 2.19mmHg in MOPP may hold and this is an area which requires further
investigation. This also suggests that despite the lack of a clear benefit of a single agent in the
treatment of glaucoma based on IOP, prostaglandin analogues should be used first line given a
potential benefit in terms of OPP.
Subgroup analysis by glaucoma subtype, POAG and/or OHT or NTG did not show a significant
difference in MOPP between interventions (eFigure 1). Systematic reviews comparing ocular
hypotensive effectiveness in POAG populations generally support that prostaglandins are more
effective than others, while a systematic review in an NTG population showed equal efficacy
between prostaglandins and timolol[16, 17, 34, 39, 51]. Another metanalysis showed that POAG
subjects fared prognostically better with ocular hypotensives while NTG subjects did not[58]. A

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prospective clinical study of POAG and NTG showed that topical beta blockers were associated with

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systemic hypotension at night and that this was associated with VF deterioration in the NTG
population[20]. Among all included and four excluded studies significant treatment differences in

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post intervention OPP and systemic hypotensive effects were noted in both NTG and POAG
subjects[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 54, 55, 56, 57]. It is unclear whether ocular
hypotensives provide a significant decrease in IOP or systemic BP parameters preferentially across

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glaucoma subtypes. If the vascular hypothesis to the aetiology of NTG were correct and optic nerve
damage occurred with hypoperfusion it would be expected that ocular hypotensives which
significantly decrease IOP and do not compromise systemic BP would result in more favourable OPP.
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Conversely, given the trend evident from current literature that timolol decreases IOP less than
prostaglandins while possibly causing systemic hypotension, it may be expected that timolol would
fare worse than comparators when measuring OPP in the normal tension glaucoma population. Our
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findings suggest that current ocular hypotensives do not effect OPP significantly differently between
NTG and POAG populations.
There was no topical agent which produced consistently greater adverse events and only one
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comparison between Latanoprost and Brimonidine showed a significant difference, in favour of

Brimonidine (Table 2). Generally, most literature reports variable adverse events outcomes when
comparing prostaglandins to other treatments and favourable outcomes when comparing
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latanoprost to other prostaglandins[51, 52, 59, 60, 61] .

The strength of our study is that we performed an extensive and robust review of available literature
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and synthesised the data in order to clarify the effect of commonly used interventions in OAG on
OPP. We used single comparison trials to provide greater clarity in intervention outcomes through
simpler data interpretation. Weaknesses in our study include using a small number of studies in
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total, a small number of studies per comparison and including trials only published in the English
language. We did not include studies which did not specifically measure ocular perfusion pressure,
although they did provide intra ocular perfusion pressure and haemodynamic information from
which to extrapolate ocular perfusion pressure. The reason for this is that extrapolating ocular
perfusion data would introduce greater uncertainty into the calculations of mean ocular perfusion
pressure. Also, we could not be sure under such circumstances that IOP and BP were measured at
the same time. Extrapolating mean ocular perfusion pressure was required for 3 of the studies,
Quaranta ‘08, Quaranta ‘12 and Oddone ‘15, as the outcome of interest reported in these studies
was DOPP. Small number of studies included. Small number of studies per intervention comparison.
Further, we included studies in which some of the populations were taking medication for
cardiovascular disease and some did not, and it is conceivable that ocular hypotensives may change
IOP, BP and OPP differently in those that take systemic medication for cardiovascular disease versus
those who do not.
In conclusion we found few relevant studies of low to moderate quality. We found that bimatoprost
significantly increased MOPP relative to timolol and that as a class, prostaglandins significantly
increased MOPP relative to other interventions. Current ocular hypotensive interventions do not
appear to preferentially increase MOPP in NTG or POAG. Further research is required in order to
clarify which component parameters of ocular perfusion pressure, i.e. IOP or systemic BP, yield the
greatest influence on measured OPP. Our findings support the use of prostaglandin analogues, and
specifically bimatoprost, as first line agents in OAG secondary to their potential positive effect on
OPP.

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Transparency

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Declaration of funding

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This paper was not funded.

Declaration of financial/other relationships

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The authors on this manuscript have no relevant financial or other relationships to disclose.
A peer reviewer of this manuscript declares receiving unrestricted research fund from Senju
Pharmaceutical, a distributor of bimatoprost in Japan. Peer reviewers on this manuscript have no
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other relevant financial or other relationships to disclose.

Acknowledgements
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The authors acknowledge Ruth Mitchell for assistance in developing the search strategies
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References
1. Anderson DR, Drance SM, Schulzer M. Comparison of glaucomatous progression between
untreated patients with normal-tension glaucoma and patients with therapeutically reduced
intraocular pressures. American Journal of Ophthalmology. 1998 October;126(4):487-497.
doi: http://dx.doi.org/10.1016/S0002-9394%2898%2900223-2. PubMed PMID: 28475912.
2. Gaasterland DE, Ederer F, Beck A, et al. The Advanced Glaucoma Intervention Study (AGIS):
7. The relationship between control of intraocular pressure and visual field deterioration.
American Journal of Ophthalmology. 2000 October;130(4):429-440. doi:
http://dx.doi.org/10.1016/S0002-9394%2800%2900538-9. PubMed PMID: 30759196.
3. Riva CE, Hero M, Titze P, et al. Autoregulation of human optic nerve head blood flow in
response to acute changes in ocular perfusion pressure. Graefes Arch Clin Exp Ophthalmol.
1997 Oct;235(10):618-26. PubMed PMID: 9349945; eng.
4. Harris A, Rechtman E, Siesky B, et al. The role of optic nerve blood flow in the pathogenesis
of glaucoma [Review]. Ophthalmology Clinics of North America. 2005 September;18(3):345-
353. doi: http://dx.doi.org/10.1016/j.ohc.2005.04.001. PubMed PMID: 41073860.

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5. Nicolela MT. Clinical clues of vascular dysregulation and its association with glaucoma. Can J

ip
Ophthalmol. 2008 Jun;43(3):337-41. doi: 10.3129/i08-063. PubMed PMID: 18493274; eng.
6. Plange N, Kaup M, Remky A, et al. Prolonged retinal arteriovenous passage time is correlated

cr
to ocular perfusion pressure in normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol.
2008 Aug;246(8):1147-52. doi: 10.1007/s00417-008-0807-6. PubMed PMID: 18386036; eng.
7. Bonomi L, Marchini G, Marraffa M, et al. Vascular risk factors for primary open angle

8.
PMID: 10889099; eng.
us
glaucoma: the Egna-Neumarkt Study. Ophthalmology. 2000 Jul;107(7):1287-93. PubMed

Leske MC. Ocular perfusion pressure and glaucoma: Clinical trial and epidemiologic findings
an
[Review]. Current Opinion in Ophthalmology. 2009 March;20(2):73-78. doi:
http://dx.doi.org/10.1097/ICU.0b013e32831eef82. PubMed PMID: 354355304.
9. Xu L, Wang YX, Jonas JB. Ocular perfusion pressure and glaucoma: the Beijing Eye Study. Eye
M

(Lond). 2009 Mar;23(3):734-6. doi: 10.1038/eye.2008.342. PubMed PMID: 18989341; eng.

10. Zheng Y, Wong TY, Mitchell P, et al. Distribution of ocular perfusion pressure and its
relationship with open-angle glaucoma: the singapore malay eye study. Invest Ophthalmol
Vis Sci. 2010 Jul;51(7):3399-404. doi: 10.1167/iovs.09-4867. PubMed PMID: 20164462; eng.
ed

11. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-
angle glaucoma. A population-based assessment. Arch Ophthalmol. 1995 Feb;113(2):216-21.
PubMed PMID: 7864755; eng.
pt

12. Quigley HA, West SK, Rodriguez J, et al. The prevalence of glaucoma in a population-based
study of Hispanic subjects: Proyecto VER. Arch Ophthalmol. 2001 Dec;119(12):1819-26.
ce

PubMed PMID: 11735794; eng.

13. Leske MC, Connell AM, Wu SY, et al. Risk factors for open-angle glaucoma. The Barbados Eye
Study. Arch Ophthalmol. 1995 Jul;113(7):918-24. PubMed PMID: 7605285; eng.
Ac

14. Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early manifest
glaucoma trial. Ophthalmology. 2007 Nov;114(11):1965-72. doi:
10.1016/j.ophtha.2007.03.016. PubMed PMID: 17628686; eng.
15. Aptel F, Cucherat M, Denis P. Efficacy and tolerability of prostaglandin-timolol fixed
combinations: a meta-analysis of randomized clinical trials (Provisional abstract). European
Journal of Ophthalmology. 2011 [cited 5-18 p.]. http://cochranelibrary-
wiley.com/o/cochrane/cldare/articles/DARE-12011007605/frame.html
16. Cheng J, Cai J, Wei R. Meta-analysis of medical intervention for normal tension glaucoma
(Structured abstract). Ophthalmology. 2009 [cited 1243-1249 p.]. http://cochranelibrary-
wiley.com/o/cochrane/cldare/articles/DARE-12009106796/frame.html
17. Orme M, Collins S, Dakin H, et al. Mixed treatment comparison and meta-regression of the
efficacy and safety of prostaglandin analogues and comparators for primary open-angle
 glaucoma and ocular hypertension. Current Medical Research and Opinion. 2010
March;26(3):511-528. doi: http://dx.doi.org/10.1185/03007990903498786. PubMed PMID:
358318078.
18. Vass C, Hirn C, Sycha T, et al. Medical interventions for primary open angle glaucoma and
ocular hypertension. Cochrane Database of Systematic Reviews. 2007 [cited.
DOI:10.1002/14651858.CD003167.pub3 http://cochranelibrary-
wiley.com/doi/10.1002/14651858.CD003167.pub3/abstract
19. Detry-Morel M. Side effects of glaucoma medications. Bull Soc Belge Ophtalmol. 2006
(299):27-40. PubMed PMID: 16681086; eng.
20. Hayreh SS, Podhajsky P, Zimmerman MB. Beta-blocker eyedrops and nocturnal arterial
hypotension. Am J Ophthalmol. 1999 Sep;128(3):301-9. PubMed PMID: 10511024; eng.
21. Krupin T, Liebmann JM, Greenfield DS, et al. A randomized trial of brimonidine versus timolol
in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. Am
J Ophthalmol. 2011 Apr;151(4):671-81. doi: 10.1016/j.ajo.2010.09.026. PubMed PMID:
21257146; eng.
22. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and

t
meta-analyses: the PRISMA statement. International journal of surgery (London, England).

ip
2010;8(5):336-41. doi: 10.1016/j.ijsu.2010.02.007. PubMed PMID: 20171303; eng.
23. Costa VP, Harris A, Anderson D, et al. Ocular perfusion pressure in glaucoma. Acta

cr
Ophthalmol. 2014 Jun;92(4):e252-66. doi: 10.1111/aos.12298. PubMed PMID: 24238296;
eng.

us
24. Costagliola C, Parmeggiani F, Virgili G, et al. Circadian changes of intraocular pressure and
ocular perfusion pressure after timolol or latanoprost in Caucasians with normal-tension
glaucoma. Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
an
[Graefe's archive for clinical and experimental ophthalmology]. 2008 [cited 389-396 p.].
DOI:10.1007/s00417-007-0704-4 Comparative Study; Randomized Controlled Trial available
at http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/146/CN-
00706146/frame.html PubMed Central; PMCID: PMCPubmed 18004586.
M

25. Fuchsjäger-Mayrl G, Wally B, Rainer G, et al. Effect of dorzolamide and timolol on ocular
blood flow in patients with primary open angle glaucoma and ocular hypertension. British
journal of ophthalmology. 2005 [cited 1293-1297 p.]. DOI:10.1136/bjo.2005.067637 Clinical
ed

Trial; Comparative Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
available at http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/336/CN-
00530336/frame.html PubMed Central; PMCID: PMCPubmed 16170119.
pt

26. Harris A, Migliardi R, Rechtman E, et al. Comparative analysis of the effects of dorzolamide
and latanoprost on ocular hemodynamics in normal tension glaucoma patients. European
journal of ophthalmology. 2003 [cited 24-31 p.]. Clinical Trial; Comparative Study;
ce

Randomized Controlled Trial; Research Support, Non-U.S. Gov't available at

http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/863/CN-
00435863/frame.html PubMed Central; PMCID: PMCPubmed 12635671.
Ac

27. Inan U, Ermis S, Yücel A, et al. The effects of latanoprost and brimonidine on blood flow
velocity of the retrobulbar vessels: a 3-month clinical trial. Acta ophthalmologica
scandinavica. 2003 [cited 155-160 p.]. Clinical Trial; Randomized Controlled Trial available at
http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/520/CN-
00437520/frame.html PubMed Central; PMCID: PMCPubmed 12752054.
28. Liu C, Ko Y, Cheng C, et al. Changes in intraocular pressure and ocular perfusion pressure
after latanoprost 0.005% or brimonidine tartrate 0.2% in normal-tension glaucoma patients.
Ophthalmology. 2002 [cited 2241-2247 p.]. Clinical Trial; Comparative Study; Evaluation
Studies; Randomized Controlled Trial available at http://cochranelibrary-
wiley.com/o/cochrane/clcentral/articles/997/CN-00411997/frame.html PubMed Central;
PMCID: PMCPubmed 12466165.
29. Liu CJL, Cheng CY, Ko YC, et al. Diurnal intraocular pressure and blood pressure with two
dosing regimens of brimonidine in normal tension glaucoma. Journal of the Chinese Medical
Association. 2004 September;67(9):465-471. PubMed PMID: 39549413.
30. Oddone F, Rossetti L, Tanga L, et al. Effects of topical bimatoprost 0.01% and timolol 0.5% on
circadian IOP, blood pressure and perfusion pressure in patients with glaucoma or ocular
hypertension: A randomized, double masked, placebo-controlled clinical trial. PLoS ONE.
2015 20 Oct;10 (10) (no pagination)(e0140601). doi:
http://dx.doi.org/10.1371/journal.pone.0140601. PubMed PMID: 607132843.
31. Quaranta L, Katsanos A, Floriani I, et al. Circadian intraocular pressure and blood pressure
reduction with timolol 0.5% solution and timogel 0.1% in patients with primary open-angle
glaucoma. Journal of clinical pharmacology. 2012 [cited 1552-1557 p.].
DOI:10.1177/0091270011420254 Clinical Trial; Randomized Controlled Trial available at
http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/952/CN-
00881952/frame.html PubMed Central; PMCID: PMCPubmed 22110164.
32. Quaranta L, Miglior S, Floriani I, et al. Effects of the timolol-dorzolamide fixed combination
and latanoprost on circadian diastolic ocular perfusion pressure in glaucoma. Investigative

t
Ophthalmology and Visual Science. 2008 October;49(10):4226-4231. doi:

ip
http://dx.doi.org/10.1167/iovs.08-1744. PubMed PMID: 355371697.
33. Shin J, Lee JW, Choi BS, et al. The circadian changes of intraocular pressure and ocular

cr
perfusion pressure after tafluprost compared with travoprost in normal tension glaucoma.
Journal of Ocular Pharmacology and Therapeutics. 2014 01 Dec;30(10):803-809. doi:

us
http://dx.doi.org/10.1089/jop.2014.0034. PubMed PMID: 600727002.
34. Lin L, Zhao Y, Chew P, et al. Comparative efficacy and tolerability of topical prostaglandin
analogues for primary open-angle glaucoma and ocular hypertension (Provisional abstract).
an
Database of Abstracts of Reviews of Effects. 2014 [cited 1585-1593 p.].
http://cochranelibrary-wiley.com/o/cochrane/cldare/articles/DARE-
12014055457/frame.html
35. Denis P, Lafuma A, Khoshnood B, et al. A meta-analysis of topical prostaglandin analogues
M

intra-ocular pressure lowering in glaucoma therapy. Current Medical Research and Opinion.
2007 March;23(3):601-608. doi: http://dx.doi.org/10.1185/030079907X178720. PubMed
PMID: 46456908.
ed

36. Kawaguchi I, Higashide T, Ohkubo S, et al. Comparison of efficacy of four prostaglandin

analogues by bilateral treatment in healthy subjects. Jpn J Ophthalmol. 2012 Jul;56(4):346-
53. doi: 10.1007/s10384-012-0155-2. PubMed PMID: 22669351; eng.
pt

37. Mishra D, Sinha BP, Kumar MS. Comparing the efficacy of latanoprost (0.005%), bimatoprost
(0.03%), travoprost (0.004%), and timolol (0.5%) in the treatment of primary open angle
glaucoma. Korean J Ophthalmol. 2014 Oct;28(5):399-407. doi: 10.3341/kjo.2014.28.5.399.
ce

PubMed PMID: 25276082; PubMed Central PMCID: PMCPMC4179117. eng.

38. Stalmans I, Oddone F, Cordeiro MF, et al. Comparison of preservative-free latanoprost and
preservative-free bimatoprost in a multicenter, randomized, investigator-masked cross-over
Ac

clinical trial, the SPORT trial. Graefes Arch Clin Exp Ophthalmol. 2016 Jun;254(6):1151-8. doi:
10.1007/s00417-016-3299-9. PubMed PMID: 26907933; eng.
39. Li T, Lindsley K, Rouse B, et al. Comparative Effectiveness of First-Line Medications for
Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis.
Ophthalmology. 2016 Jan;123(1):129-40. doi: 10.1016/j.ophtha.2015.09.005. PubMed PMID:
26526633; PubMed Central PMCID: PMCPMC4695285. eng.
40. Stewart WC, Konstas AG, Kruft B, et al. Meta-analysis of 24-h intraocular pressure
fluctuation studies and the efficacy of glaucoma medicines. J Ocul Pharmacol Ther. 2010
Apr;26(2):175-80. doi: 10.1089/jop.2009.0124. PubMed PMID: 20334538; eng.
41. Inoue K, Setogawa A, Tomita G. Nonresponders to Prostaglandin Analogs Among Normal-
Tension Glaucoma Patients. J Ocul Pharmacol Ther. 2016 Mar;32(2):90-6. doi:
10.1089/jop.2015.0086. PubMed PMID: 26624245; eng.
42. Rossetti L, Sacchi M, Karabatsas CH, et al. Comparison of the effects of bimatoprost and a
fixed combination of latanoprost and timolol on 24-hour blood and ocular perfusion
pressures: the results of a randomized trial. BMC Ophthalmol. 2015 Jan 22;15:7. doi:
10.1186/1471-2415-15-7. PubMed PMID: 25613811; PubMed Central PMCID:
PMCPMC4320581. eng.
43. Inan UU, Ermis SS, Orman A, et al. The comparative cardiovascular, pulmonary, ocular blood
flow, and ocular hypotensive effects of topical travoprost, bimatoprost, brimonidine, and
betaxolol. Journal of Ocular Pharmacology and Therapeutics. 2004 August;20(4):293-310.
doi: http://dx.doi.org/10.1089/1080768041725344. PubMed PMID: 39108894.
44. Arend O, Harris A, Arend S, et al. The acute effect of topical beta-adrenoreceptor blocking
agents on retinal and optic nerve head circulation. Acta ophthalmologica Scandinavica. 1998
Feb;76(1):43-9. PubMed PMID: 9541433; eng.
45. Uusitalo H, Nino J, Tahvanainen K, et al. Efficacy and systemic side-effects of topical 0.5%

t
timolol aqueous solution and 0.1% timolol hydrogel. Acta Ophthalmol Scand. 2005

ip
Dec;83(6):723-8. doi: 10.1111/j.1600-0420.2005.00562.x. PubMed PMID: 16396651; eng.
46. Dickstein K, Aarsland T. Comparison of the effects of aqueous and gellan ophthalmic timolol

cr
on peak exercise performance in middle-aged men. Am J Ophthalmol. 1996 Apr;121(4):367-
71. PubMed PMID: 8604729; eng.

us
47. Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5%
timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002 Jun;240(6):430-5. doi:
10.1007/s00417-002-0462-2. PubMed PMID: 12107508; eng.
an
48. Stewart WC, Stewart JA, Crockett S, et al. Comparison of the cardiovascular effects of
unoprostone 0.15%, timolol 0.5% and placebo in healthy adults during exercise using a
treadmill test. Acta Ophthalmologica Scandinavica. 2002 Jun;80(3):272-276. doi:
10.1034/j.1600-0420.2002.800308.x. PubMed PMID: WOS:000176204600008.
M

49. Nieminen T, Uusitalo H, Turjanmaa V, et al. Association between low plasma levels of
ophthalmic timolol and haemodynamics in glaucoma patients. Eur J Clin Pharmacol. 2005
Jul;61(5-6):369-74. doi: 10.1007/s00228-005-0945-2. PubMed PMID: 15912390; eng.
ed

50. Lee PW, Doyle A, Stewart JA, et al. Meta-analysis of timolol on diurnal and nighttime
intraocular pressure and blood pressure. Eur J Ophthalmol. 2010 Nov-Dec;20(6):1035-41.
PubMed PMID: 20491052; eng.
pt

51. Daka Q, Trkulja V. Efficacy and tolerability of mono-compound topical treatments for
reduction of intraocular pressure in patients with primary open angle glaucoma or ocular
hypertension: an overview of reviews. Croatian medical journal. 2014 Oct;55(5):468-80.
ce

PubMed PMID: 25358880; PubMed Central PMCID: PMCPMC4228301. eng.

52. Raber S, Mandema JW, Li H, et al. A model-based dose-response meta-analysis of ocular
hypotensive agents as a drug development tool to evaluate new therapies in glaucoma. J
Ac

Ocul Pharmacol Ther. 2015 May;31(4):189-97. doi: 10.1089/jop.2014.0106. PubMed PMID:

25714918; eng.
53. Sit AJ. Intraocular pressure variations: causes and clinical significance. Can J Ophthalmol.
2014 Dec;49(6):484-8. doi: 10.1016/j.jcjo.2014.07.008. PubMed PMID: 25433736; eng.
54. Drance SM, Crichton A, Mills RP. Comparison of the effect of latanoprost 0.005% and timolol
0.5% on the calculated ocular perfusion pressure in patients with normal-tension glaucoma.
Am J Ophthalmol. 1998 May;125(5):585-92. PubMed PMID: 9625541; eng.
55. Quaranta L, Gandolfo F, Turano R, et al. Effects of topical hypotensive drugs on circadian
IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with
glaucoma. Invest Ophthalmol Vis Sci. 2006 Jul;47(7):2917-23. doi: 10.1167/iovs.05-1253.
PubMed PMID: 16799034; eng.
56. Arend O, Harris A, Wolter P, et al. Evaluation of retinal haemodynamics and retinal function
after application of dorzolamide, timolol and latanoprost in newly diagnosed open-angle
glaucoma patients. Acta Ophthalmol Scand. 2003 Oct;81(5):474-9. PubMed PMID:
14510794; eng.
57. Nicolela MT, Buckley AR, Walman BE, et al. A comparative study of the effects of timolol and
latanoprost on blood flow velocity of the retrobulbar vessels. Am J Ophthalmol. 1996
Dec;122(6):784-9. PubMed PMID: 8956632; eng.
58. Maier PC, Funk J, Schwarzer G, et al. Treatment of ocular hypertension and open angle
glaucoma: meta-analysis of randomised controlled trials. BMJ (Clinical research ed). 2005 Jul
16;331(7509):134. doi: 10.1136/bmj.38506.594977.E0. PubMed PMID: 15994659; PubMed
Central PMCID: PMCPMC558697. eng.
59. Orme M, Collins S, Dakin H, et al. Mixed treatment comparison and meta-regression of the
efficacy and safety of prostaglandin analogues and comparators for primary open-angle
glaucoma and ocular hypertension. Current medical research and opinion. 2010
Mar;26(3):511-28. doi: 10.1185/03007990903498786. PubMed PMID: 20014995; eng.
60. Honrubia F, Garcia-Sanchez J, Polo V, et al. Conjunctival hyperaemia with the use of

t
latanoprost versus other prostaglandin analogues in patients with ocular hypertension or

ip
glaucoma: a meta-analysis of randomised clinical trials. The British journal of ophthalmology.
2009 Mar;93(3):316-21. doi: 10.1136/bjo.2007.135111. PubMed PMID: 19019922; PubMed

cr
Central PMCID: PMCPMC2639645. eng.
61. Vass C, Hirn C, Sycha T, et al. Medical interventions for primary open angle glaucoma and

us
ocular hypertension. The Cochrane database of systematic reviews. 2007 Oct
17(4):Cd003167. doi: 10.1002/14651858.CD003167.pub3. PubMed PMID: 17943780; eng.
an
M
ed
pt
ce
Ac
Table and figure legends
Figure 1 Flow chart showing the identification and selection of randomised controlled trials included
in the review.
Figure 2 Cochrane risk of bias assessment tool for included studies.
Figure 3 Comparison of post intervention mean ocular perfusion pressure (MOPP) among included
studies. SD = standard deviation, IV = inverse variance, 95% CI = 95% confidence interval
Figure 4 Subgroup analysis by glaucoma type comparing post intervention mean ocular perfusion
pressure (MOPP) among included studies. NTG = normal tension glaucoma, POAG = primary open
angle glaucoma, OHT = ocular hypertension, SD = standard deviation, IV = inverse variance, 95% CI =
95% confidence interval
Figure 5 Subgroup analysis by intervention type comparing post intervention mean ocular perfusion
pressure (MOPP) among included studies. SD = standard deviation, IV = inverse variance, 95% CI =
95% confidence interval

t
ip
Figure 6 Subgroup analysis by intervention class comparing post intervention mean ocular perfusion
pressure (MOPP) among included studies. SD = standard deviation, IV = inverse variance, 95% CI =

cr
95% confidence interval
Table 1 Characteristics of included randomised clinical trials

us
Table 2 Relative Risk and Standard Error of adverse events by Trial included. Statistically significant
result (p<0.05) marked by *. (NR – not reported)
an
M
ed
pt
ce
Ac
Appendices
Appendix 1
MedLine Ovid Search Strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 pragmatic clinical trial.pt.
4 randomized.ab.
5 placebo.ab.
6 drug therapy.fs.
7 randomly.ab.

t
8 trial.ab.

ip
9 groups.ab.

cr
10 Cross-over Studies/
11 (crossover or cross-over).tw.
12
13
or/1-11
animals/ not (humans/ and animals/)
us
an
14 12 not 13
15 Ocular Hypertension/
M

16 Glaucoma/
17 Glaucoma, Open Angle/
ed

18 Low Tension Glaucoma/

19 Exfoliation Syndrome/
pt

20 glaucoma.tw.
ce

21 POAG.tw.
22 ocular hypertension.tw.
Ac

23 exfoliat* syndrome*.tw.
24 (((increas$ or elevat$ or high$) adj3 (ocular or intra-ocular)) and pressure).tw.
25 pseudoexfoliat* syndrome.tw.
26 or/15-25
27 and/14,26
28 exp Adrenergic beta-Antagonists/
29 (beta adj3 antagonis*).tw.
30 (beta adj3 block*).tw.
31 timolol*.tw.
32 metipranolol*.tw.
33 carteolol*.tw.
34 levobunolol*.tw.
35 betaxolol*.tw.
36 levobetaxolol*.tw.
37 exp Carbonic Anhydrase Inhibitors/
38 (carbonic anhydrase adj2 inhibitor*).tw.
39 brinzolamide*.tw.

t
40 dorzolamide*.tw.

ip
41 exp Prostaglandins, Synthetic/

cr
42 (prostaglandin* adj2 analog*).tw.
43 latanoprost*.tw.
44
45
travoprost*.tw.
bimatoprost*.tw.
us
an
46 unoprostone*.tw.
47 tafluprost*.tw.
M

48 exp Adrenergic alpha-2 Receptor Agonists/

49 (alpha* adj4 agonist*).tw.
ed

50 brimonidine*.tw.
51 or/28-50
pt

52 and/27,51
ce
Ac
Appendix 2
Embase search strategy
1 randomized controlled trial/
2 randomization/
3 double blind procedure/
4 single blind procedure/
5 triple blind procedure/
6 controlled clinical trial/
7 exp clinical trials/
8 placebo/

t
9 crossover procedure/

ip
10 random*.tw.

cr
11 trial.ti.
12 ((singl* or doubl* or tripl* or trebl*) adj (blind* or mask*)).tw.
13
14
(crossover or cross over).tw.
placebo*.tw.
us
an
15 factorial.tw.
16 (allocat* or assign*).tw.
M

17 or/1-16
18 animal.mp.
ed

19 human/
20 18 and 19
pt

21 18 not 20
ce

22 17 not 21
23 Glaucoma/
Ac

24 Glaucomatous Optic Neuropathy/

25 Intraocular Hypertension/
26 Low Tension Glaucoma/
27 Open Angle Glaucoma/
28 Primary Glaucoma/
29 secondary Glaucoma/
30 glaucoma.tw.
31 POAG.tw.
32 ocular hypertension.tw.
33 exfoliat* syndrome*.tw.
34 pseudoexfoliat* syndrome*.tw.
35 (((increas$ or elevat$ or high$) adj3 (ocular or intra-ocular)) and pressure).tw.
36 or/23-35
37 exp Beta Adrenergic Receptor Blocking Agent/
38 (beta adj3 antagonis*).tw.
39 (beta adj3 block*).tw.
40 timolol*.tw.

t
41 metipranolol*.tw.

ip
42 carteolol*.tw.

cr
43 levobunolol*.tw.
44 betaxolol*.tw.
45
46
levobetaxolol*.tw.
exp Carbonate Dehydratase Inhibitor/
us
an
47 (carbon* adj3 (anhydrase or dehydratase) adj3 inhibitor*).tw.
48 brinzolamide*.tw.
M

49 dorzolamide*.tw.
50 exp Prostaglandin/
ed

51 latanoprost*.tw.
52 travoprost*.tw.
pt

53 bimatoprost*.tw.
ce

54 unoprostone*.tw.
55 tafluprost*.tw.
Ac

56 (prostaglandin* adj2 analog*).tw.

57 alpha 2 Adrenergic Receptor Stimulating Agent/
58 Brimonidine/
59 brimonidine*.tw.
60 (alpha adj4 agonist*).tw.
61 or/37-60
62 and/22,36,61
Appendix 3
Central search strategy (results)
1 glaucoma:ti,ab,kw
2 "glaucomatous optic neuropathy":ti,ab,kw
3 "ocular hypertension":ti,ab,kw
4 (("intra-ocular" or intraocular) next hypertension):ti,ab,kw
5 (exfoliat* next syndrome*):ti,ab,kw
6 (pseudoexfoliat* next syndrome*):ti,ab,kw
7 (((increas* or elevat* or high*) near/3 (ocular or intraocular or intra-ocular)) and

t
pressure):ti,ab,kw

ip
8 POAG:ti,ab,kw

cr
9 {or #1-#8}
10 MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees
11
12
(beta near/3 antagonis*):ti,ab,kw
(beta near/3 block*):ti,ab,kw us
an
13 timolol*:ti,ab,kw
14 metipranolol*:ti,ab,kw
M

15 carteolol*:ti,ab,kw
16 levobunolol*:ti,ab,kw
ed

17 betaxolol*:ti,ab,kw
18 levobetaxolol*:ti,ab,kw
pt

19 (carbon* near/3 (anhydrase or dehydratase) near/3 inhibitor*):ti,ab,kw

20 brinzolamide*:ti,ab,kw
ce

21 dorzolamide*:ti,ab,kw
22 MeSH descriptor: [Prostaglandins, Synthetic] explode all trees
Ac

23 prostaglandin*:kw
24 (prostaglandin* near/2 analog*):ti,ab,kw
25 latanoprost*:ti,ab,kw
26 travoprost*:ti,ab,kw
27 bimatoprost*:ti,ab,kw
28 unoprostone*:ti,ab,kw
29 tafluprost*:ti,ab,kw
30 MeSH descriptor: [Adrenergic alpha-2 Receptor Agonists] explode all trees
31 "alpha 2 adrenergic receptor stimulating agent":ti,ab,kw
32 (alpha near agonist*):ti,ab,kw
33 brimonidine*:ti,ab,kw
34 {or #10-#33}
35 {and #9, #34}

t
ip
cr
us
an
M
ed
pt
ce
Ac
 Tables

Trial Intervent Mean Diagnosis Systemic Baseline Baseline Baseline Follow Sample
ion Age medicati intra- systolic diastolic up size
(years; Primary Ocular Normal on for ocular blood blood (weeks (number
standar open hypert tension cardiova pressure pressure pressure ) )
d angle ension glaucom scular (standard (standard (standard
deviati glaucom a disease deviation deviation deviation)
on) a ) )
Quaran Bimatopr 56 (8)  No 15.5 (2.4) 126.2 75.1 8 40
ta 2008 ost vs (7.1) (5.5)
Latanopr
ost
Liu Brimonid 65 (12)  Yes 15.2 (2.4) 125.8 74.0 4 27
2002 ine vs (13.6) (4.2)
Latanopr
ost

t
Costagli Timolol 67 (4)  No 17.8 (2.8) 122.3 74.5 4 30

ip
ola vs (6.5) (5.9)
2008 Latanopr

cr
ost
Quaran Timolol 62 (10)  No 23.1 (0.6) 126.7 75.8 8 28
ta 2012 vs (7.9) (5.9)

us
Timogel
Oddon Timolol 61 (11)   Yes 20.3 (3.8) 129.8 79.5 8 32
e 2015 vs (5.3) (2.9)
Bimatopr
an
ost
Shin Taflupros 43 (13)  Yes 16.8 (2.0) 119.3 77.6 8 41
2014 t vs (7.5) (6.4)
M

Travapro
st
Inan Brimonid 62 (14)   Yes 23.1 (3.7) 127.5 79.5 12 38
2003 ine vs (12.2) (8.1)
ed

Latanopr
ost
Fuchsja Timolol 62 (19)   Not 22.9 (4.8) 141.9 75.3 24 140
ger- vs Reported (23.8) (15.6
pt

mayrl Dorzola )
2005 mide
ce

Harris Latanopr -  Not 15 (2) 123.5 77 4 20

2003 ost vs Reported (27) (17)
Dorzola
mide
Ac

Liu Brimonid 59 (15)  Yes 14.3 (3.2) 115.8 71.9 4 20

2004 ine twice (18.6) (13.4
daily vs )
thrice
daily

Table 1 Characteristics of included randomised clinical trials

STUDY Intervention Intervention 2 Relative Risk Standard Error P value
1 Crude Event
Crude Event Rate
Rate
COSTAGLIOLA 0/30 0/30 - - -
08 Timolol Latanoprost
INAN 15 3/30 0/30 7.00 1.49 0.19
Latanoprost Brimonidine
LIU 02 11/27 3/27 3.67 0.59 0.03*
Latanoprost Brimonidine
ODDONE 15 3/32 4/32 0.75 0.72 0.69
Timolol Bimatoprost
QUARANTA 33/200 43/200 0.77 0.21 0.20
08 Latanoprost Bimatoprost
QUARANTA 34/140 24/140 1.42 0.24 0.14

t
12 Timolol Timogel

ip
SHIN 14 31/41 35/41 0.89 0.11 0.27
Tafluprost Travaprost

cr
FUCHSJAGER- NR NR NR NR NR
MAYRL 05 Timolol Dorzolamide

us
HARRIS 03 NR NR NR NR NR
Dorzolamide Latanoprost
LIU 04 0/20 0/20 - - -
an
Brimonidine Brimonidine
TDS BD
M

Table 2 Relative Risk and Standard Error of adverse events by Trial included. Statistically significant
result (p<0.05) marked by *. (NR – not reported)
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