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William C. Stewart,1 Anastasios G.P. Konstas,2 Bonnie Kruft,3 Heather M. Mathis,3 and Jeanette A. Stewart1
Abstract
Purpose: To compare the change in 24-h fluctuation of the intraocular pressure (IOP) from various medical
therapies in patients with ocular hypertension, primary open-angle (POAG), or exfoliative glaucoma (XFG).
Methods: A meta-analysis of published studies that were controlled, prospective, and comparative trials. Based
on study requirements for an objective fluctuation analysis, only studies from the authors’ work met the criteria
for this analysis and contained: ≥4-week treatment period, ≥20 patients per treatment arm, and ≥6 time points
measured with Goldmann applanation over 24 h, not spaced >5 h apart. Fluctuations were defined by the mean
of the difference between the highest and lowest measured IOP for each individual patient (Σ[maximum − mini-
mum IOP]/number of patients).
Results: Thirteen articles were included evaluating 28 treatment arms in 1,017 patients. Among all individual
treatments, bimatoprost demonstrated the greatest reduction in fluctuation (P = 0.03, 3.4 mm Hg). In contrast,
2-drug therapy did not reduce fluctuations from monotherapy (P = 0.09). Among prostaglandin therapies, no sta-
tistical difference existed between evening and morning dosing (P = 0.20). In XFG, a greater reduction in fluctua-
tions was observed progressing from 1 to 2 medicines (P = 0.01), but not increasing from 2 to 3 drug therapy (P =
0.14). In general, XFG patients demonstrated a greater decrease in fluctuations than POAG patients (P = 0.003).
Conclusions: In POAG differences exist in fluctuations among monotherapy treatments with bimatoprost show-
ing the greatest effect. However, POAG patients generally demonstrate less decrease in fluctuations with treat-
ment than compared with XFG.
Introduction
1
PRN Pharmaceutical Research Network LLC, 3Charleston Research Company, LLC, North Charleston, South Carolina.
2
Glaucoma Unit, 1st University Department of Ophthalmology, AHEPA Hospital, Thessaloniki, Greece.
175
Delphi 1
Dates of starting and ending accession? Refs. 8,16–19,21,24 did not include the data
Delphi 2
Treatment allocation:
Was a method of randomization performed? Refs. 12,13,22,23 were not randomized
Was the treatment allocation blinded? Refs. 12,13,22,23 were not masked
Was the outcome accessor blinded? None
Does the analysis include an intent-to-treat None
analysis?
INTRAOCULAR PRESSURE FLUCTUATION STUDIES 177
Reduction in Treatment
Comparison Treatment fluctuation arms P value
Intraocular pressure fl uctuation, primary open-angle heterogeneity was negative among treatment arms includ-
glaucoma ing POAG patients (P = 0.6).
Among prostaglandin therapies specifically, including
The results of the meta-analysis for the IOP fluctua- monotherapy and fixed as well as unfixed combination
tions are shown in Table 3. The results demonstrated that therapies, evening and morning dosing provided statisti-
there was a statistical difference in the reduction of fluc- cally equivalent changes in fluctuations from prior therapy
tuations from no treatment among all individual mono- (P = 0.20, Table 4).
therapy treatments with bimatoprost demonstrating the
greatest reduction of all 4 treatments compared together Intraocular pressure fl uctuation, exfoliation glaucoma
(P = 0.03). In contrast, there was no further decrease in
fluctuations with 2-drug treatment from monotherapy The results including exfoliative patients are seen
(P = 1.0). In addition, there was no statistical difference in in Table 5. Adding a second medicine to monotherapy
the change in fluctuations between monotherapy among decreased fluctuations from monotherapy (P = 0.01) but a
fixed and unfixed combinations (P = 0.5). The test for further reduction was not noted by adding a third medicine
(P = 0.014). The reduction in fluctuations with monotherapy may not allow for a further decrease in fluctuation. However,
was not evaluable because only one study was available to additional medications beyond 2-drug therapy (which was
evaluate this therapeutic step. evaluated partially in only one of the included studies in
In addition, for all studies adding a medicine in exfolia- this analysis) might conceivably further lower fluctuation
tive patients demonstrated statistically greater reduction in beyond the level of monotherapy, but this needs further
fluctuations versus in POAG (P = 0.003). The test for het- study.17
erogeneity was negative among exfoliative treatment arms In contrast, POAG patients generally demonstrated
(P = 0.3). less reduction in fluctuations than exfoliation patients.
Further, adding a second medicine to monotherapy in
XFG decreased fluctuations from monotherapy but a fur-
Discussion ther reduction was not noted by adding a third medicine.
The reduction in fluctuations with monotherapy was not
Despite the recent interest in evaluation of the 24-h IOP
evaluable because only one study was available to evalu-
curve, the amount of available data that links fluctuation of
ate this therapeutic step. However, the decrease in fluc-
this measure to progression is limited. Three lines of evidence
tuations with monotherapy was significant in the original
can be used to assert the importance of IOP fluctuation. First,
article.13
in a retrospective, 5-year outcomes study, Konstas, Stewart
The finding of a greater reduction in fluctuation in exfo-
and colleagues showed that fluctuation of the daytime IOP
liative, than in POAG patients, was not a surprise because
was an independent risk factor for glaucomatous progres-
previous studies have noted that this form of glaucoma,
sion.15 However, not all studies by these authors have dem-
as in our own studies, demonstrates higher untreated and
onstrated such a finding.16 Second, the Advanced Glaucoma
treated pressures and fluctuations.13,27 This higher pressure
Intervention Study investigators noted patients with peak
most likely results from greater outflow obstruction owing
pressures of ≤18 mm Hg, associated with a mean pressure
to the exfoliation material within the trabecular mesh-
of 12.8 mm Hg, had very little evidence of progression over 5
work.27 Further, these patients may require more therapy to
years.2 In addition, the Early Manifest Glaucoma Trial study,
control the mean IOP than patients with POAG.13,27 Possibly,
as well as an additional study by Bengtsson and Heijl, has
the higher non-treated fluctuations in XFG allowed for the
showed that there was no association with fluctuation and
greater statistical reduction with additional drug therapy
progression over time.3,4 Third, in a 24-h, prospective study
not observed in POAG that is generally associated with the
Asrani and coworkers showed that patients who had 24-h
lower fluctuations.
IOPs taken in the clinic or at home over 5 days had elevated
This study suggests that in POAG differences exist in
fluctuations as an independent risk factor for progression.6
fluctuations among monotherapy treatments with bimato-
In addition, even if fluctuations are important several
prost showing the greatest effect. However, POAG patients
other problems exist before using this parameter in rou-
demonstrate generally less decrease in fluctuations with
tine practice, first, we do not yet understand which times
treatment than in exfoliation glaucoma.
during the 24-h day are necessary to measure the IOP to ac-
Monotherapy reduces fluctuations from no treatment
curately assess this parameter. Possibly, in the future, sur-
with bimatoprost showing the greatest effect. However,
rogate times points during the day could be described that
these patients demonstrate generally less decrease in fluc-
reflect pressures found at night so that physicians in routine
tuation with treatment than in treated XFG.
clinical practice could assess this parameter. Second, a clin-
This meta-analysis did not evaluate all monother-
ically measurable target pressure, for fluctuation, in a sim-
apy and fixed combination therapies available. In addi-
ilar fashion as for mean pressures to prevent glaucomatous
tion, the number of XFG patients evaluated was limited.
progression needs to be identified and last, no method cur-
Consequently, a number of useful comparisons were not
rently is available that guarantees an accurate pressure read-
able to be performed in this meta-analysis. In addition, this
ing during the nighttime when the patient usually is supine,
analysis did not include only randomized studies that might
and asleep.
have led to differences in baseline values between trials.
The purpose of this study was to compare the change in
Consequently other factors may have influenced the extent
fluctuation of various medical therapies by a meta-analysis
of pressure reductions apart from the medicine that were
of studies that contained an evaluation of 24-h fluctuation
not apparent by our results. Further, fluctuations still need
of the IOP in patients with ocular hypertension or primary
to be assessed in the supine position as well as their extent
open-angle glaucoma or XFG.
based on the mean level of IOP. In addition, the fluctuation of
This meta-analysis showed of all monotherapies evalu-
the IOP as an independent risk factor needs to be confirmed.
ated, bimatoprost, followed by travoprost, demonstrated to
Additionally, target pressures for fluctuation that assist in
be the 2 most effective medicines in reducing the fluctuations
preventing glaucomatous progression, and daytime time
among all monotherapies compared together. This finding is
points that simulate 24-h fluctuations, need to be described
not surprising since several prior trials indicate they may be
to make using this parameter practical in routine clinical
the most effective monotherapy agents available, although
practice.
this finding is not consistent.25–27
In contrast, there was no further decrease in fluctua-
tions with 2 or more drug treatments from monotherapy.
Author Disclosure Statement
In addition, there was no statistical difference in the change
in fluctuations from monotherapy among various fixed and The authors have no competing interests to declare. This
unfixed combinations. This finding indicates that adding a meta-analysis was not supported by any public or private
second medicine, either as a fixed or unfixed combination, funding agency.
180 STEWART ET AL.
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Received: November 10, 2009
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Accepted: February 9, 2010
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15. Konstas, A.G., Maltezos, A.C., Gandi, S., et al. Comparison of Address correspondence to:
24-hour intraocular pressure reduction with two dosing regi- Dr. William C. Stewart
mens of latanoprost and timolol maleate in patients with pri- 6296 Rivers Avenue
mary open-angle glaucoma. Am. J. Ophthalmol. 128:15 –20, 1999. Suite 309
16. Konstas, A.G., Nakos, E., Tersis, I., et al. A comparison of once- North Charleston, SC 29406
daily morning vs evening dosing of concomitant latanoprost/
timolol. Am. J. Ophthalmol. 133:753 –757, 2002. E-mail: info@prnorb.com