Review Article

Effect of prostaglandin analogues on central corneal thickness in patients

with glaucoma: A systematic review and meta‑analysis with trial sequential
analysis

Rajani Kadri, Akansha Shetty, Devika Parameshwar, Ajay A Kudva, Asha Achar1, Jayaram Shetty

The objective of this meta‑analysis was to evaluate the effect of prostaglandin analogues (PGA) on central Access this article online
corneal thickness (CCT) in patients with glaucoma. Key electronic databases were searched for randomized Website:
controlled trials  (RCTs) involving the CCT effects of prostaglandin use for glaucoma. Primary outcome www.ijo.in
measures were the mean difference in the CCT measurement from baseline to the last available assessment. DOI:
Intraocular pressure and other corneal changes were recorded as secondary. Efficacy estimates were 10.4103/ijo.IJO_1971_21
measured by their weighted mean difference  (WMD) with 95% confidence intervals  (CI's) by using the PMID:
*****
random‑effects model for primary and secondary outcomes Trial sequential analysis was used to determine
if the current evidence was sufficient and conclusive. Eight RCTs met our inclusion criteria. A  total of Quick Response Code:
879  patients were included. The overall effect showed that PGA's had a significant CCT lowering effect
(WMD = −7.04, 95%CI: −10.07 to −4.00, P < 0.00001). We pooled results of 5 RCT's on Travoprost (WMD =
−10.44, 95%CI: −16.80 to −4.08, P = 0.001), seven trials on Latanoprost (WMD = −4.73, 95% CI: −9.70 to 0.25,
P = 0.06), and three trials on Bimatoprost (WMD = −11.88, 95%CI: −21.03 to −2.73, P = 0.01). The WMD across
groups in >6 months of PGA use was −11.37 (95%CI: −17.17 to −5.58, P = 0.0001), and in <6 months of PGAs
group was −8.35 (95% CI: −12.01 to −4.69, P < 0.00001), suggesting a longitudinal effect of PGAs on CCT.
In conclusion, Bimatoprost and Travoprost caused a statistically significant reduction in the thickness of
central cornea. Though only a few studies were included, the narrow confidence intervals and adequate
sample size suggest that these findings are valid.

Key words: Central corneal thickness, glaucoma, open angle, Prostaglandins, Synthetic

Glaucoma, a form of slowly progressive optic neuropathy, has authors[8,12,16] reported that a decrease in CCT in patients using
emerged as one of the leading causes of irreversible blindness either PGAs was not significantly different. No significant
worldwide.[1,2] In the management of glaucoma, intraocular difference in CCT was found in patients treated with PGA in
pressure  (IOP) remains the only modifiable risk factor, and an Italian multicenter study.[17] Arcieri et al.[13] reported that
lowering IOP has been the current goal of any therapy.[3‑5] only bimatoprost induced a statistically significant reduction
in CCT, while according to Sawada et al.[6] and Schlote et al.,[7]
Prostaglandin analogues (PGA) and prostamides have
travoprost caused maximal reduction in CCT. Bafa et al.[18]
emerged as the first line in the management of glaucoma in
in their study concluded that latanoprost and bimatoprost
the past decade.[6,7] Latanoprost (0.005%), travoprost (0.004%)
increased CCT. This fact has been supported by many studies
and tafluprost (0.0015%) are the PGAs used. Bimatoprost (0.03
that suggested that PGAs, especially latanoprost, induce
and 0.01%)[6,8] is the prostamide and unoprostone  (0.15%) is
collagen gel contraction in the corneal stroma and rounding of
the eicosanoid[9] that have been used as ocular hypotensives.
corneal cells, which increases the CCT. However, Maruyama
PGAs activate matrix metalloproteinase (MMP) in the ciliary
et al.[19] and Liu et al.[20] concluded that latanoprost reduced CCT.
bodies, cause the breakdown of extracellular matrix, and reduce
Panos et al.[21] noticed a reduction in CCT with tafluprost after
resistance to uveoscleral outflow.[9,10] Induction of MMP occurs
a year‑long therapy. Viswanathan et al.[22] and Helmy H et al.[23]
in trabecular meshwork and cornea. This has been hypothesized
concluded after 3 years of study that PGAs in monotherapy or
to be the causal factor for reduction in central corneal
in combination caused a significant corneal thinning suggesting
thickness (CCT) following the use of topical prostaglandins.[11‑13]
a long‑term effect of these medications. The effects of PGAs on
Multiple authors have reported a reduction in CCT in CCT are still uncertain.
patients under treatment with topical PGAs.[1,3,14,15] However,
the results of their studies have not been consistent. Some
This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License,
Department of Ophthalmology, A. J. Institute of Medical Sciences which allows others to remix, tweak, and build upon the work non‑commercially,
and Research Centre, Mangalore, Karnataka, 1Department of as long as appropriate credit is given and the new creations are licensed under
the identical terms.
Ophthalmology, Kanachur Institute of Medical Sciences, Mangalore,
India
For reprints contact: [email protected]
Correspondence to: Dr. Rajani Kadri, Department of Ophthalmology,
A. J. Institute of Medical Sciences and Research Centre, Mangalore, Cite this article as: Kadri R, Shetty A, Parameshwar D, Kudva AA, Achar A,
Karnataka, India. E‑mail: [email protected] Shetty J. Effect of prostaglandin analogues on central corneal thickness in
Received: 26-Jul-2021 Revision: 24-Oct-2021 patients with glaucoma: A systematic review and meta‑analysis with trial
sequential analysis. Indian J Ophthalmol 2022;70:1502-12.
Accepted: 10-Nov-2021 Published: 28-Apr-2022

© 2022 Indian Journal of Ophthalmology | Published by Wolters Kluwer - Medknow

May 2022 Kadri, et al.: Meta analysis of effect of prostaglandin analogues on central corneal thickness 1503

To the best of our knowledge, no meta‑analysis has been Exclusion criteria: Reviews, retrospective studies,
conducted to assess the effects of PGA on CCT. We aimed prospective non‑randomized studies, duplicate publications
to undertake this systematic review and meta‑analysis to and animal studies, case reports, abstracts, and reports with
summarize the existing evidence on the effects of PGAs on incomplete data were excluded.
CCT and to investigate whether long‑term topical treatment
Study selection: Three investigators (RK, AS, DP), working
with prostaglandin analogues can significantly affect the
independently, scanned all abstracts and obtained the full‑text
CCT in patients with a diagnosis of glaucoma or ocular
reports of records, which indicated or suggested that the study
hypertension (OHT) taking these medications as the first‑line
was a randomized trial evaluating prostaglandin therapy.
therapy.
After obtaining full reports of the trials, the same reviewers
Methods independently assessed eligibility from full‑text papers.

Study registration and reporting Data extraction: The same reviewers (RK, AS) conducted
data extraction independently using a standardized
The presented study has been registered at PROSPERO before
pre‑piloted form. The following information was recorded
data analysis (CRD42021241216). This meta‑analysis followed
from each study: authors of the trial, publication year, location
the current Cochrane collaboration guidelines for performing
of the study, study design  (double‑blind or single‑blind),
a meta‑analysis. Reporting followed the Preferred Reporting
parallel or cross‑over interventions, sample size, participants
Items for Systematic Reviews and Meta‑Analyses (PRISMA)
characteristics  (number, mean age, and sex), location
Statement. Ethics approval is not applicable. A comprehensive
of the trial, length of follow‑up, type of glaucoma, CCT
literature search was performed to identify the RCTs’
value from baseline to endpoint, IOP, and other corneal
investigating the effects of prostaglandins on CCT.
changes. Disagreements were resolved by discussion or
Search strategy consensus involving a third investigator. Study evaluation
We established a search strategy with title, abstract, medical included general methodological quality features assessing
subject headings [MeSH], and clinical outcomes. Text words methods of randomization, allocation concealment, use of
and medical subject headings were combined freely. We intention‑to‑treat analysis, and methods of blinding.
searched independently the following databases—PubMed, Quality assessment
Ovid Medline, Google Scholar, and Cochrane Central Register
The methodological quality of the studies was generally good.
of Controlled Trials—to identify potentially eligible studies.
We performed quality assessment of trials with the Cochrane
We used the following MeSH (medical subject headings) terms
bias risk assessment tool  (The Cochrane Collaboration) for
and keywords: Glaucoma, open angle, ocular hypertension,
RCTs. The risk of bias tool covers six domains of bias and
latanoprost, bimatoprost, travoprost, tafluprost, prostaglandin
seven items: random sequence generation  (selection bias),
analog*, central corneal thickness, and randomized controlled
allocation concealment (selection bias), blinding of participants
trials (RCTs). The commercial names Travatan, Lumigan, and
and personnel  (performance bias), blinding of outcome
Xalatan were also searched. We also contacted the authors of
assessment (detection bias), incomplete outcome date (attrition
trials for study clarifications, where required. Searches were
bias), selective reporting (reporting bias), and other bias. The
not limited by date, language, sex, or age. The bibliography of
tool involves assigning a judgment of high, low, or unclear
retrieved manuscripts and systematic reviews were searched
risk of bias for each item. Discrepancies in ratings were solved
to identify additional trials pertaining to data encompassing
by discussion between two authors. Selection bias  (biased
our primary outcome of interest. The detailed search strategy
allocation to interventions) due to inadequate generation of a
is shown in Supplementary Digital Content 1, which depicts
randomized sequence was noted in one study, and selection
the keyword‑based search for inclusion terms.
bias due to inadequate concealment of allocations prior to the
Eligibility criteria assignment was observed in a few studies.
Our search strategy followed the population, intervention, Statistical analysis
comparison, outcome, study (PICOS) design principle.
Meta‑analysis was conducted using the Review Manager (RevMan
Articles were selected based on the following criteria: 5.4.1, Cochrane Collaboration, Copenhagen, Denmark, 2014).
Population: Patients with primary open‑angle glaucoma, When data on a particular outcome were available from at least
normal‑tension glaucoma (NTG), or OHT; age >18; without sex, two studies, we combined and analyzed these data. Cochrane
region, or race restriction. Intervention and Comparison: Any Chi-square test and I2 (inconsistency) for heterogeneity were
prostaglandins, latanoprost  (0.005%), bimatoprost  (0.03%), used to assess interstudy heterogeneity. The Chi-square test
travoprost  (0.004%), tafluprost  (0.0015%), and unoprostone measures whether observed differences are compatible with
initiated at the same time. Studies evaluating a fixed combination chance alone, and I2 assesses the % of the effect variability
of prostaglandins with any other antiglaucoma medications that estimates caused by heterogeneity rather than sampling error.
met the inclusion criteria were included. Outcome: Weighted The random‑effects model was used for all analyses. For
mean difference  (WMD) in the CCT measurements from continuous variables, mean differences (MDs) were compared
baseline to the last available assessment, expressed in µm, using the inverse‑variance (I‑V) method. Subgroup analysis was
were recorded as the primary outcome. Intraocular pressure performed based on the type of prostaglandin and duration of
and other corneal changes (endothelial cell density, coefficient use. P  <  0.05 was considered statistically significant. Publication
of variation, and percentage of hexagonality) were recorded bias was checked by exploring asymmetry in funnel plots and
as secondary. Study design: Fully reported randomized trials. Egger’s regression test.[24] Additionally, a sensitivity analysis was
Crossover randomized trials were also included. conducted excluding studies of poor quality (Jadad score < 3).[25]
1504 Indian Journal of Ophthalmology Volume 70 Issue 5

Trial sequential analysis

Trial Sequential Analysis Viewer [TSA software (version 0.9.5.10
Beta)] was used to calculate the required information size (RIS)
for meta‑analysis and evaluate treatment benefits based on the
sample sizes. The risk of type I error was set at 5% with a power
of 80%, the variance was calculated from the data obtained from
the included trials, and the relative risk reduction was set at
20%.[26] When cumulative Z-curves crossed sequential monitoring
boundaries, a sufficient level of evidence was obtained for the
intervention. When Z-curves did not cross the boundaries, the
conclusions for the intervention were not justified.[27]
Grading of Recommendations Assessment, Development,
and Evaluation (GRADE)
The certainty of the evidence was summarized using the
GRADE evidence[28] approach for individual outcomes. The
strength of recommendations reduces the potential to facilitate
critical appraisal and improve communication of judgments.
GRADEpro GDT (GRADEpro Guideline Development
Tool  [Software], McMaster University, 2020  [developed by
Evidence Prime, Inc] was used to facilitate the development
of evidence summaries and recommendations.

Results
Characteristics of trials
The process for literature search and study selection is
outlined in Fig. 1. The literature search identified 68 potentially
relevant manuscripts based on the abstract. Ten randomized
trials that evaluated the effect of prostaglandin on CCT and
met our inclusion criteria were considered for analysis. Two
RCTs[18,29] were excluded as relevant data could not be retrieved.
Finally, we included eight trials reporting 879 patients in the
analysis.[3,6,8,9,13,14,16,30]
Two crossover trials[6,13] were included in our analysis. Arcieri
et al.[13] described a 4‑week washout between each regimen of
medications. However, in a study by Sawada et al.,[6] as there was
no wash‑out period between the drugs, only the first period data
were considered for analysis to avoid the carryover effect. Seven
studies on latanoprost, five on travoprost, three on bimatoprost,
and one on any PGA were included. Two studies[3,30] evaluated
the effects of a fixed combination of latanoprost with other
antiglaucoma (netarsudil and timolol) medications. Five studies
had three intervention arms. Three studies had two intervention
arms. The trial duration ranged from 1 month to 3.8 years. The
range of the mean age was 38.69–77.7 years. According to the
type of glaucoma, 33 subjects had POAG, 462 had OHT, and 15
had other types of glaucoma. In three studies, though data on
the type of glaucoma were not presented, they included POAG
or OHT patients. The characteristics of the eligible studies
including Jadad scores are summarized in Table 1.
Efficacy analysis
The overall effect, expressed as µm, showed that prostaglandins Figure 1: Flow diagram for selection of eligible studies in the meta-
had a significant CCT lowering effect  (WMD = −7.04, 95% analysis
CI: −10.07 to −4.00, P < 0.00001), heterogeneity: Chi² = 11.72,
df = 15 (P = 0.70), and I² = 0% [Fig. 2]. TSA suggested that accrued boundary, indicating that current evidence was sufficient to
information size (n  =  879) was more than RIS (n  =  669). The reach a firm conclusion [Fig. 3].
cumulative Z‑curve (blue line) with quadratic indications of
each trial surpassed the traditional boundary (etched lines) for Primary outcome
statistical significance during the inclusion of the trial. Further To effectively compare the effects of prostaglandin on CCT, we
cumulative Z‑curve crossed the trial sequential monitoring adopted subgroup analysis according to the type and period
May 2022 Kadri, et al.: Meta analysis of effect of prostaglandin analogues on central corneal thickness 1505

Figure 2: Forest plot of central corneal thickness (µm) following treatment with prostaglandin analogue. The individual trials mean difference
and confidence intervals are shown. The overall effects for each prostaglandin analogue and differences between subgroups are shown. The
95% CIs are shown as lines for individual studies and as diamonds for pooled estimates. SD, standard deviation; CI, confidence interval; CCT,
central corneal thickness; PGA‑ Prostaglandin analogues

Table 1: Characteristics of the included studies

Study Region Center Design POAG/OHT/ Mean Sex Drug used No. of eyes Duration Jadad
Others Age (M/F) included (months) score
Sawada et al. 2012[6] Japan Single RCT/DB/C 42/0/0 53.2±11.8 23/19 LAT, TRAVO 42 11 5
Zhong et al. 201[9] China Single RCT/DB 56/13/6 51±12.3 35/34 LAT, TRAVO, 69 2.5‑52 4
BIMAT
Hatanaka et al. Brazil Single RCT/DB NP 68.5±9.2 NP LAT, TRAVO, 73 2 3
2009[8] BIMAT
Lass et al. 2001[30] USA Multicenter RCT/DB 226/134/9 61±12 183/186 LAT, TIM 369 12 5
Arcieri et al. 2008[13] Brazil Single RCT/DB/C 17/17/0 57.8±9.6 14/20 LAT, TRAVO, 34 1 5
BIMAT
Wisely et al. 2020[3] USA Multicenter RCT/DB NP 63.6±11.2 156/259 LAT, NET 415 3 5
Stefan et al. 2007[16] Romania Single RCT/DB NP NP NP TRAVO, LAT 52 3 2
Brandt et al. 2008[14] USA Multicenter RCT 0/298/0 59.8±8.8 NP Any PGA 298 31 1
POAG, primary open‑angle glaucoma; OHT, ocular hypertension; RCT, randomized controlled trials; DB, double‑blind; C, cross over; LAT, latanoprost;
TRAVO, travoprost; BIM, bimatoprost; TIM, timolol; NET, netarsudil; NP, not provided; PGA, prostaglandin analogue
1506 Indian Journal of Ophthalmology Volume 70 Issue 5

the drug was used. The results showed that bimatoprost indicates that the meta‑analysis was underpowered to reach
had a significant CCT lowering effect (WMD = −11.88, 95% a conclusion [Fig. 6b].
CI: −21.03 to −2.73, P = 0.01) followed by travoprost (WMD =
Secondary outcome
−10.44, 95% CI: −16.80 to −4.08, P = 0.001). Least affection was
by latanoprost (WMD = −4.73, 95% CI: −9.70 to 0.25, P = 0.06). Of the seven studies included in the meta‑analysis, two
Two studies[3,24] evaluated the effect of fixed combinations of reported additional corneal effects and two reported intraocular
latanoprost with netarsudil and timolol. Pooled data analysis pressure (IOP) changes. Wisely et al.[3] presented the baseline to
of these two studies demonstrated an insignificant reduction 3‑month specular microscopy data in their study. Changes from
baseline to month 3 in corneal endothelial cell density (ECD),
in CCT (WMD = −3.38, 95% CI: −10.51 to 3.74, P = 0.35) [Fig. 4].
coefficient of variation  (CV), and % of hexagonal cells were
We pooled seven, six, and three trials assessing latanoprost,
clinically insignificant in all the groups studied. The results
travoprost, and bimatoprost, respectively, in the  <6‑month
of two RCTs[3,30] of this meta‑analysis reporting ECD for
post‑treatment [Fig. 5a] and a total of five trials in the >6‑month
latanoprost failed to demonstrate any effect on corneal
post‑treatment [Fig. 6a] analysis. The WMD across groups in
endothelium (WMD = 4.57, 95% CI: −51.86 to 61, P = 0.87) [Fig. 7].
the >6‑month prostaglandin use was −11.37 (95% CI: −17.17
The data on IOP change from baseline of two crossover studies
to  −5.58), which was greater than that in the  <6  months
demonstrated a significant reduction of IOP by PGA (WMD =
treatment with prostaglandins (WMD = −8.35, 95% CI: −12.01
−4.67, 95% CI: −6.65 to −2.69, P < 0.0001) [Fig. 8]. Arcieri et al.[13]
to −4.69), suggesting a longitudinal effect of prostaglandins studied the blood–aqueous barrier in patients on PGA by using
on CCT. TSA suggested that accrued information size  (n  a laser flare meter and found no significant differences in the
=  418) in the  <6‑month PGA treatment group was more mean flare measurements (P > 0.069). Two trials[6,30] reported
than that in RIS  (n  =  339), and the cumulative Z-curve conjunctival hyperemia and conjunctival irritation as the most
crossed the trial sequential monitoring boundary, indicating common adverse event respectively.
that current evidence was sufficient to reach a firm
conclusion [Fig. 5b] In the >6‑month PGA treatment group, Sensitivity analysis
the Z-curve did not intersect any TSA boundaries, which To investigate the influence of one study on the overall WMD, a
sensitivity analysis (data not shown) was performed excluding
studies of poor quality (Jadad score <3).[8,14,16] Sensitivity analysis
with these studies removed in the analysis, at a time showed
that the corresponding global estimation was not changed.
Publication Bias
This analysis had statistically significant coefficients (Omnibus
P  <  0.001, test for heterogeneity P =  0.700). Egger’s test was
not significant (P = 0.642), indicating a low risk of publication
bias (Supplementary Digital Content 2).
Risk of bias summary and graph
Risk of bias summary and graph are presented
in (Supplementary Digital Content 3). Selection bias (biased
allocation to interventions) due to inadequate generation of a
randomized sequence was noted in one study,[14] and selection
bias due to inadequate concealment of allocations prior to the
assignment was observed in a few studies.[3,8,9,14,16]

Figure  3: Trial sequential analysis (TSA) of the studies included in GRADE evidence
the meta-analysis demonstrated the required information size (RIS) The relevant summary results are presented in Table  2
to be 669 with “GRADE” evidence. The certainty of the evidence

Figure  4: Forest plot of central corneal thickness  (µm) following treatment with a fixed combination of latanoprost with other antiglaucoma
medications. The individual trials mean differences and 95% CIs are shown. The overall effects for each prostaglandin analogue are shown. The
95% CIs are shown as lines for individual studies and as diamonds for pooled estimates. SD, standard deviation; CI, confidence interval; CCT,
central corneal thickness; PGA, Prostaglandin analogues
May 2022 Kadri, et al.: Meta analysis of effect of prostaglandin analogues on central corneal thickness 1507

b
Figure 5: (a) Forest plot of central corneal thickness (µm) following treatment with prostaglandin analogues for <6 months. The individual trials
mean differences and 95% CIs are shown. The overall effects for each prostaglandin analogues are shown. The 95% CIs are shown as lines for
individual studies and as diamonds for pooled estimates. SD, standard deviation; CI, confidence interval; CCT, central corneal thickness; PGA,
Prostaglandin analogs. (b) Trial sequential analysis (TSA) of <6 months of prostaglandin analogues treatment subgroup demonstrated required
information size (RIS) to be 339

was summarized as “moderate” for the outcome of CCT following treatment with PGA due to “serious imprecision.”
following treatment with a fixed combination of latanoprost For the rest of the studied outcomes, the certainty of the
with other antiglaucoma medications and corneal ECD evidence was described as “high,” with a few methodological
1508 Indian Journal of Ophthalmology Volume 70 Issue 5

b
Figure 6: (a) Forest plot of central corneal thickness (µm) following treatment with prostaglandin analogues for >6 months. The individual trials
mean differences and 95% CIs are shown. The overall effects for each prostaglandin analog are shown. The 95% CIs are shown as lines for
individual studies and as diamonds for pooled estimates. SD, standard deviation; CI, confidence interval; CCT, central corneal thickness; PGA,
Prostaglandin analogues. (b) Trial sequential analysis (TSA) of > 6 months of prostaglandin analogue treatment subgroup demonstrated required
information size (RIS) to be 490

issues (inadequate randomization and inadequate allocation topical therapy with prostaglandin analogues for glaucoma.
concealment) in a few studies. According to our results, bimatoprost  (0.03%) once daily
caused a significant reduction in CCT, closely followed by
Discussion travoprost. Latanoprost caused a reduction of corneal thickness
Our meta‑analysis of eight RCTs involving 879  patients that was statistically not significant. Further, our analysis
indicated a significant reduction in the CCT following showed travoprost to cause maximal, statistically significant
May 2022 Kadri, et al.: Meta analysis of effect of prostaglandin analogues on central corneal thickness 1509

Figure 7: Forest plot of corneal endothelial cell density (cells/mm3) following treatment with prostaglandin analogues. The individual trials mean
differences and 95% CIs are shown. The 95% CIs are shown as lines for individual studies and as diamonds for pooled estimates. SD‑standard
deviation; CI‑ confidence interval; CECD‑ corneal endothelial cell density; PGA‑ Prostaglandin analogues

Figure 8: Forest plot of intraocular pressure change (mm Hg) following treatment with prostaglandin analogues. The individual trials mean
differences and 95% CIs are shown. The overall effects for each prostaglandin analogues are shown. The 95% CIs are shown as lines for
individual studies and as diamonds for pooled estimates. SD, standard deviation; CI, confidence interval; IOP, Intraocular pressure; PGA,
Prostaglandin analogues

reduction in the corneal thickness when used as monotherapy Schlote et al. [7] performed a study over  12  months of
for glaucoma for <6 months. Both bimatoprost and travoprost travoprost treatment and showed a nonlinear CCT reduction
equally reduced the corneal thickness beyond 6‑month therapy. that mainly occurred within the first 6  months of treatment
but continued less intensively during the next 6  months. In
In our meta‑analysis, we observed an overall decrease of
a 4‑year retrospective study by Maruyama et al.,[19] the mean
7–10 µm in CCT following PGAs treatment. Arcieri et al.[13]
CCT significantly decreased in the first 2 years of latanoprost
in their study confirmed that topical bimatoprost induced
treatment; however, no significant difference was found
a statistically significant decrease in CCT, an effect they did
between the mean CCT at midpoint and that at final follow‑up;
not observe with latanoprost and travoprost. However, they
only about 10 µm of CCT decrease was observed during the
observed that the change induced by bimatoprost was clinically
4‑year follow‑up period, and IOP values were unaffected.
small  (1%), insufficient to promote significant changes in
Though our research on PGAs treatment for > 6‑month showed
IOP measurements with Goldmann applanation tonometry.
an increased thinning of cornea compared to short‑duration
Doughty and Zaman et al.[31] conducted a meta‑analysis on
treatment of these medications, suggesting a longitudinal effect
human corneal thickness and its impact on IOP measures,
of PGAs on CCT, the small sample size and high heterogeneity
and demonstrated that relationships between IOP and CCT
involving this outcome  (>6  months) in our meta‑analysis
measures could be different in different ethnic groups and
suggest that these results should be considered with caution.
acute and chronic (glaucoma) disease. They concluded that in
eyes with glaucoma, a 10% difference in CCT would result in All studies included in this analysis were randomized
a 2.5 ± 1.1 mm Hg difference in IOP measures by applanation trials, which largely reduced confounders. There were three
tonometry. However, as the corneal stromal matrix architecture multicenter studies[3,14,30] included in our analysis performed
is changed by PGA, the potential influence of CCT on IOP and in multiple countries. Studies included did not differ in the
use of IOP correction formula[31,32] in these cases may not be concentration of the drug, frequency of dosing of medications,
accurate.[12,33,34] or measurement of CCT. In all the studies, included drug
1510 Indian Journal of Ophthalmology Volume 70 Issue 5

was instilled once a day. An average of five consecutive CCT

Quality of
evidence
(GRADE)

Moderate

Moderate
readings using ultrasonic pachymeter was taken for analysis

⨁⨁⨁◯

⨁⨁⨁◯
⨁⨁⨁⨁

⨁⨁⨁⨁

⨁⨁⨁⨁

CCT: central corneal thickness: IOP: intraocular pressure; GRADE, Grading of Recommendations Assessment Development and Evaluation; CI, Confidence interval; MD, Mean difference: aMethodology issues in
in all the included studies. Intraoperator and interoperator

⨁⨁⨁
High

High

High

High
of CCT were thus taken care of.[35] To avoid the effects of the
diurnal variation of CCT,[36] all the measurements were carried

<0.00001

<0.00001

<0.00001
out between 9 AM and 11 AM in two studies.[6,9] However,
overall

0.0001
effect
P for

0.35

0.87
the time of measurement of CCT was not mentioned in the
remaining studies. There was no significant heterogeneity in
our analysis. Further, the confidence intervals of the pooled

[−17.17, −5.58]
results were narrow, suggesting that our data are sufficient to
−7.04 [−10.07,

−3.38 [−10.51,

−8.35 [−12.01,

−4.67 [−6.65,
4.57 [−51.86,
difference

reach a conclusion about this outcome. These factors make the

(95%CI)

−11.37
−4.00]

−4.69]

−2.69]
61.00]
Mean

3.74]

results of our analysis more convincing.

Meda et al.[4] reported a positive correlation between CCT,
corneal hysteresis (CH), and corneal resistance factor (CRF).
An increase in these parameters following cessation of chronic
patients
No. of

use of PGA and a subsequent reduction following reinitiation

879

237

418

461

264

144 of the medication was observed in their study. Though

long‑term treatment with PGA is associated with a small
Imprecision

but significant thinning of the cornea, its clinical relevance

Not serious

Not serious

Not serious

Not serious

on IOP measurements needs to be considered in glaucoma

Seriousb

Seriousb

practice. Study of corneal biomechanics  (CH) has provoked

much interest in recent years for its implication in glaucoma,
although the exact relationship between CH and glaucoma
Indirectness

is yet to be understood. Corneal hysteresis has recently been

Not serious

Not serious

Not serious

Not serious

Not serious

Not serious

claimed to be more strongly associated with diagnosis of

glaucoma, risk of progression, and effectiveness of glaucoma
treatment than CCT itself.[37] However, there is a paucity of
data exploring the effects of prostaglandins on IOP, corneal
hysteresis, and CCT simultaneously. Though knowledge of
Inconsistency

corneal hysteresis may allow us to treat each eye as a unique

Not serious

Not serious

Not serious

Not serious

Not serious

Not serious

entity; its clinical adoption may be slower than pachymetry

owing to the relative inexpensiveness, portability, and easy
availability of pachymetry devices.
Limitations
Serious,a
Seriousa

Seriousa

Seriousa
Risk of

serious

serious

Publication bias cannot be ruled out from the subgroup analysis

bias

Not

Not

because of the small number of studies in the subgroups. We

included data only from full-paper publications; data from
Randomized

Randomized

Randomized

Randomized

Randomized

Randomized

abstracts and international meetings were not included.

Further, only published trials with available data were analyzed
design
Study

in our study; therefore, the inclusion of unpublished data

trials

trials

trials

trials

trials

trials

could influence our conclusions. We excluded a trial by Bafa

et al.[18] as relevant study data could not be retrieved. This
Table 2: Summary results with GRADE of evidence

studies

trial, in contrast to the studies included, reported an increase in

No. of

16

14

corneal thickness in patients on latanoprost; as such, inclusion

2

of this study may have affected the overall outcome. Pooled

data in the subgroup (>6 months) analyses were based on only
with other group of antiglaucoma medications

a few trials. Further, TSA suggested that accrued information

CCT following treatment with prostaglandion

size (n = 461) in >6-month PGA treatment group was less than

combination of prostaglandion analogues

CCT following treatment with PGA for <6

CCT following treatment with PGA for >6

that in RIS (n = 490), indicating that current evidence was

CECD following treatment with PGA

insufficient to reach a firm conclusion; thus, more research

some studies; bWide confidence interval
CCT following treatment with fixed

IOP following treatment with PGA

would be needed on the available evidence derived. Though

most of the trials recruited newly diagnosed glaucoma patients
or considered a 4-week washout for PGA and beta-blockers
before the baseline reading was taken, in the study by Lass
et al.,[30] during the 3-week run-in period, all the subjects were
treated with timolol 0.5% one drop once daily. Though timolol
was chosen because of its long track record of corneal safety,
reversible increase in CCT following administration of timolol
analogues
Outcome

as reported by Grueb et al.[38] could have influenced their results.

months

months

They also recruited three patients with pigmentary glaucoma in

their study. This prompted us to perform a sensitivity analysis
May 2022 Kadri, et al.: Meta analysis of effect of prostaglandin analogues on central corneal thickness 1511

by excluding this study. No significant change in the overall 11. Harasymowycz  PJ, Papamatheakis  DG, Ennis  M, Brady  M,
result (WMD = −7.04, 95% CI: −10.23 to −3.85) was observed. Gordon  KD. Travoprost central corneal thickness study group.
Relationship between travoprost and central corneal thickness
Conclusion in ocular hypertension and open‑angle glaucoma. Cornea
2007;26:34‑41.
In conclusion, bimatoprost (0.03%) and travoprost cause a small, 12. Sen E, Nalcacioglu P, Yazici A, Aksakal FN, Altinok A, Tuna T,
statistically significant reduction in the thickness of the central et al. Comparison of the effects of latanoprost and bimatoprost on
cornea. As these drugs may significantly confound the routine central corneal thickness. J Glaucoma 2008;17:398‑402.
IOP measurement despite modest changes in CCT, longitudinal 13. Arcieri ES, Pierre Filho PT, Wakamatsu TH, Costa VP. The effects of
CCT variation that may arise throughout the follow‑up period prostaglandin analogues on the blood aqueous barrier and corneal
of glaucoma patients treated with PGA, a proper IOP target thickness of phakic patients with primary open‑angle glaucoma
attainment mandate performing pachymetry more than once and ocular hypertension. Eye (Lond) 2008;22:179‑83.
by ophthalmologists in a glaucoma patient’s lifetime. 14. Brandt JD, Gordon MO, Beiser JA, Lin SC, Alexander MY, Kass MA,
et al. Changes in central corneal thickness over time: The ocular
Acknowledgements hypertension treatment study. Ophthalmology 2008;115:1550‑6.
We would like to express our deep and sincere gratitude to 15. Viestenz A, Martus P, Schlötzer‑Schrehardt U, Langenbucher A,
our research guide/mentor/teacher Dr. Thrivikrama P. Tantry, Mardin  CY. Einfluss von ProstaglandinF  [Impact of
Professor, Department of Anaesthesiology, A. J. Institue prostaglandin‑F  (2 alpha)‑analogues and carbonic anhydrase
of Medical Sciences and Research Centre, Mangalore, for inhibitors on central corneal thickness ‑‑ A cross‑sectional study
providing invaluable guidance throughout this research work, on 403 eyes]. Klin Monbl Augenheilkd 2004;221:753‑6.
and, in whose absence we would not have been able to conduct 16. Stefan  C, Dumitrica  DM, Tebeanu  E, Nae  I, Sapundgieva  A,
our meta‑analysis. Dragomir L. Sanalogii de prostaglandină şi grosimea corneeană
centrală [Prostaglandin analogues and central corneal thickness].
Financial support and sponsorship Oftalmologia 2007;51:95‑9.
Nil. 17. Iester  M, Telani  S, Brusini  P, Rolle  T, Fogagnolo  P, Martini  E,
et al. Central corneal thickness and glaucoma treatment: An
Conflicts of interest Italian multicenter cross‑sectional study. J Ocul Pharmacol Ther
There are no conflicts of interest. 2013;29:469‑73.
18. Bafa M, Georgopoulos G, Mihas C, Stavrakas P, Papaconstantinou D,
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Supplementary Digital Content 1
The Search Strategy. The search terms were used to search databases of PUBMED, OVID MEDLINE, CCRCT, and Google
Scholar (modified to suit each specific database with abstract, keywords, and text with the removal of duplicates)
The Search Strategy

OVID- MEDLINE search

Search No Query Results
1 prostaglandin.mp. [mp=ti, ab, tx, ct] 85,516
2 analog*.mp. [mp=ti, ab, tx, ct] 566,902
3 travoprost.mp. [mp=ti, ab, tx, ct] 1,096
4 latanoprost.mp. [mp=ti, ab, tx, ct] 3,233
5 bimatoprost.mp. [mp=ti, ab, tx, ct] 1,318
6 lumigan.mp. [mp=ti, ab, tx, ct] 323
7 travatan.mp. [mp=ti, ab, tx, ct] 318
8 xalatan.mp. [mp=ti, ab, tx, ct] 671
9 central.mp. [mp=ti, ab, tx, ct] 1,526,176
10 cornea*.mp. [mp=ti, ab, tx, ct] 119,471
11 thickness.mp. [mp=ti, ab, tx, ct] 484,186
12 1 and 2 19,126
13 3 or 4 or 5 or 6 or 7 or 8 4,143
14 random*.mp. [mp=ti, ab, tx, ct] 2,082,342
15 9 or 10 or 11 1,912,362
16 12 and 13 and 14 and 15 554
17 tafluprost.mp. [mp=ti, ab, tx, ct] 235
18 unoprostone.mp. [mp=ti, ab, tx, ct] 235
19 13 or 17 or 18 4,245
20 12 and 14 and 15 and 19 563

Pubmed search

Search number Search Details Results

23 20 AND 22 230
22 Randomize * 12,88,985
20 18 AND 19 1,500
19 12 OR 13 OR 14 15,87,363
18 16 OR 17 26,024
17 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 10 OR 11 2,905
16 1 AND 2 24,506
14 “thick”[All Fields] OR “thickness”[All Fields] OR “thicknesses”[All Fields] 3,07,344
13 “cornea*”[All Fields] 1,23,552
12 “central”[All Fields] OR “centrally”[All Fields] OR “centrals”[All Fields] 12,01,476
11 “tafluprost”[Supplementary Concept] OR “tafluprost”[All Fields] 245
10 “unoprostone”[All Fields] 194
8 “travoprost”[MeSH Terms] OR “travoprost”[All Fields] OR “travatan”[All Fields] 728
7 “bimatoprost”[MeSH Terms] OR “bimatoprost”[All Fields] OR “lumigan”[All Fields] 839
6 “latanoprost”[MeSH Terms] OR “latanoprost”[All Fields] OR “xalatan”[All Fields] 2,067
5 “bimatoprost”[MeSH Terms] OR “bimatoprost”[All Fields] 832
4 “latanoprost”[MeSH Terms] OR “latanoprost”[All Fields] 2,050
3 “travoprost”[MeSH Terms] OR “travoprost”[All Fields] 718
2 “analog*”[All Fields] 10,32,092
1 “prostaglandin * [All Fields] 1,49,924
Supplementary Digital Content 2: Publication Bias. The Funnel
Plots for CCT following PGA treatment. Regression test for Funnel
plot asymmetry (Egger’s test). P values were >0.05
 a

b
Supplementary Digital Content 3: Risk of Bias Summary (a) and Graph (b)