Adv Ther DOI 10.1007/s12325-014-0125-9
ORIGINAL RESEARCH
24-Hour Efficacy of Travoprost/Timolol BAK-Free Versus Latanoprost/Timolol Fixed Combinations in Patients Insufficiently Controlled with Latanoprost Anastasios G. P. Konstas • Irini C. Voudouragkaki • Kostantinos G. Boboridis Anna-Bettina Haidich Eleni Paschalinou Theodoros Giannopoulos •
•
•
•
Nikolaos D. Dragoumis • Alexandros K. Makridis • Malik Y. Kahook
To view enhanced content go to www.advancesintherapy.com Received: April 7, 2014 Ó Springer Healthcare 2014
ABSTRACT
controlled
Introduction: To compare the 24-h intraocular
monotherapy given once in the evening. Methods: The authors have conducted
pressure (IOP) control and tolerability of
prospective,
travoprost/timolol benzalkonium chloride (BAK)-free (TTFC) vs. latanoprost/timolol fixed
controlled, cross-over, comparison study. Qualified open-angle glaucoma patients who
combination preserved with BAK (LTFC) in open-angle glaucoma patients insufficiently
demonstrated a latanoprost-treated morning IOP (10:00 ± 1 h) greater than 20 mmHg on two
with
latanoprost
0.005%
observer-masked,
separate
visits
were
a
active-
randomized
for
Trial registration: ClinicalTrials.gov #NCT01779284.
3 months to receive either TTFC or LTFC. Patients were then crossed over to the
Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0125-9) contains supplementary material, which is available to authorized users.
opposite treatment for another 3 months. At the end of the latanoprost run-in and after each
A. G. P. Konstas (&) I. C. Voudouragkaki K. G. Boboridis E. Paschalinou T. Giannopoulos N. D. Dragoumis A. K. Makridis 1st University Department of Ophthalmology, Aristotle University of Thessaloniki, 1 Kyriakidi Street, 546 36 Thessaloniki, Greece e-mail: [email protected] A. G. P. Konstas K. G. Boboridis 3rd University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece A.-B. Haidich Department of Hygiene, Aristotle University of Thessaloniki, Thessaloniki, Greece M. Y. Kahook Department of Ophthalmology, University of Colorado School of Medicine, Aurora, IL, USA
3-month therapy period patients underwent 24-h IOP monitoring in the habitual position using Goldmann applanation tonometry in the sitting position during the day (10:00, 14:00, 18:00 and 22:00) and Perkins tonometry in the supine position at night (02:00 and 06:00). Selected ocular surface parameters evaluated after each therapy period.
were
Results: Forty-two open-angle glaucoma patients completed the study. The mean 24-h baseline
IOP
on
latanoprost
was
21.5 ± 1.6 mmHg. Both fixed combinations significantly reduced the IOP at each time point, for the mean, peak and fluctuation of
Adv Ther
24-h
latanoprost
efficacy of these adjunctive therapy options
monotherapy (P\0.01). When the two fixed combinations were compared directly, TTFC
IOP
compared
with
[5–7]. At present, many glaucoma patients are
provided significantly lower mean 24-h IOP (18.9 ± 2.2 mmHg) vs. LTFC (19.3 ± 2.3 mmHg) (P = 0.004) and significantly lower IOP at 18:00 (18.6 ± 2.5 vs. 19.5 ± 2.7 mmHg for LTFC) (P\0.001). Further, TTFC demonstrated significantly better tear film break-up time (5.15 vs. 4.65 s), corneal stain (1.5 vs. 1.8) and Schirmer I test (9.9 vs. 9.2 mm) compared with LTFC after 3 months of therapy (P\0.01 for all comparisons). Conclusion: The mean 24-h IOP lowering of TTFC was statistically more significant compared to LTFC in patients insufficiently controlled with latanoprost monotherapy. Measurement of ocular surface health and tear film status favored the BAK-free TTFC compared to LTFC.
being treated with latanoprost as first-line therapy. It is therefore of clinical importance to clarify which PTFC provides optimal 24-h IOP-lowering efficacy in those glaucoma patients
for
whom
monotherapy
with
latanoprost was inadequate. Glaucoma and ocular hypertension patients are often committed to lifelong pressure lowering therapies with roughly 50% of patients requiring more than one medication [8]. Chronic exposure to both active ingredient and preservatives is known to cause significant changes on the ocular surface [9, 10]. Benzalkonium chloride (BAK), a quaternary ammonium, is the most common preservative in glaucoma medications [11]. This highly effective antimicrobial agent acts as a detergent by denaturing proteins and disrupting cytoplasmic membranes. It has
Keywords: 24-h intraocular pressure (IOP) control; Benzalkonium chloride; Fixed
been convincingly demonstrated to adversely affect corneal and conjunctival epithelium [12–
combinations; Latanoprost/timolol; Ophthalmology; Polyquad; Travoprost/timolol;
15].
Polyquaternium-1
is
a
less
toxic
Ocular surface; OSD
preservative with no detergent action, which has been recently used in glaucoma topical
INTRODUCTION
medications as an alternative to BAK [16]. Recent studies have recognized a high prevalence of symptoms and signs of ocular
Fixed combinations (FCs) minimize the number of drops patients use and can enhance longterm tolerability and adherence [1–3]. Prostaglandin/timolol fixed combinations (PTFCs) are popular stepwise treatment options for glaucoma patients insufficiently controlled on prostaglandin monotherapies and requiring additional lowering of intraocular pressure (IOP) by 2–3 mmHg [2, 4, 5]. There is still uncertainty however as to the precise role and value of PTFCs in the stepwise therapy of glaucoma [2]. A 24-h IOP evaluation allows a more complete assessment of the
surface disease in chronically treated glaucoma patients [13, 17]. Topical antiglaucoma medications adversely impact tear synthesis and function, increase
film tear
osmolarity, reduce break-up time and decrease Schirmer test [11]. These ocular adverse reactions have subsequently been associated with reduced treatment tolerability and adherence, adversely impact quality of life and may ultimately elicit a more unfavorable surgical outcome [18–20]. Nevertheless, currently there is paucity of clinical evidence documenting the comparative
Adv Ther
damage upon the ocular surface of FC therapies
than 0.1 in the study eye; corneal pachymetry
with and without BAK. Published clinical
within the 550 ± 50 lm range; open anterior
studies focus mainly on the hypotensive efficacy and general safety profile without
chamber angles on gonioscopy. All patients were treated in both eyes with the same
investigating specific ocular surface parameters. Beyond efficacy however long-
therapy regimen, if medical therapy was indicated in both eyes.
term tolerability can meaningfully impact
Exclusion criteria were history of less than
long-term adherence and success of therapy [21]. The main objective of the current study
10% IOP decrease on medication, evidence
any of
IOP-lowering concurrent
was to compare the 24-h IOP-lowering efficacy and impact on the ocular surface of two popular
conjunctivitis, keratitis, or uveitis in either eye; history of inadequate adherence; intolerance,
PTFCs (travoprost/timolol FC without BAK vs.
or contraindication to either prostaglandins,
latanoprost/timolol FC containing BAK) in open-angle glaucoma patients insufficiently
b-blockers, or BAK; severe ocular surface disease, intraocular conventional or laser
controlled on latanoprost monotherapy.
surgery in the study eye; previous history of ocular trauma; use of corticosteroids (within 2 months before enrolment), history of dry eyes
METHODS
on topical artificial tear drops or active blepharitis; and use of contact lenses.
Patients
Evaluation and grading of dry eye and ocular surface parameters were performed in accordance
This was a prospective, 3-month, observermasked, active-controlled, cross-over,
with the recently published guidelines and methodology proposed by the International Dry
comparative study. The trial enrolled consecutive patients at an academic glaucoma
Eye
service with early-to-moderate open-angle glaucoma (primary open-angle, exfoliative, or
Workshop
and
Meibomian
Gland
Dysfunction Workshop [22, 23]. Compliance with Ethics
pigmentary glaucoma) who were insufficiently controlled on branded latanoprost monotherapy and demonstrated a latanoprost-
All procedures followed were in accordance with the ethical standards of the responsible
treated morning (10:00 ± 1 h) IOP greater than 20 mmHg at two separate visits.
committee
on
human
experimentation
with
(institutional and national) and with the Helsinki Declaration of 1975, as revised in
latanoprost monotherapy for at least 3 months to qualify. All study patients had to be older
2000 and 2008. Informed consent was obtained from all patients for being included
than 29 years, and agreed to participate in this trial and met the inclusion and exclusion
in the study.
criteria. Enrolled patients exhibited typical
Procedures
glaucomatous disc damage and visual field loss (0.8 or better vertical cup-to-disc ratio and less
Study patients first underwent ocular surface
than 16 dB mean deviation visual field loss attributed to glaucoma); visual acuity greater
evaluation and then habitual 24-h IOP monitoring with branded latanoprost
All
patients
had
to
be
treated
Adv Ther
preserved with BAK (XalatanÒ, Pfizer, New York,
performed in the following order to evaluate
NY, USA) administered in the evening (20:00).
tear film and ocular epithelium status. Tear
Selected ocular surface signs (corneal stain, tear film break-up time, Schirmer I test) were
film break-up time (TFBUT) was recorded. A small quantity of fluorescein was instilled into
recorded prior to IOP monitoring. The same investigators measured the IOP using the same
the inferior fornix with the use of a fluorescein impregnated paper strip soaked
calibrated instruments [Goldmann and Perkins
with a drop of unpreserved normal saline.
applanation tonometers (Haag Streit USA, Mason, OH, USA)]. Patients were admitted to
After a few blinks the patient was instructed to keep the eyelids open and the interval
the hospital in the morning and IOP measurements were recorded with Goldmann
between the last complete blink and the first appearance of a dry spot, or disruption in the
applanation tonometry at 06:00, 10:00, 14:00
tear film was recorded with the use of a cobalt
and 18:00 in the seated position. The 02:00 and 06:00 h IOP measurements were performed
blue filter. A cut-off value of B5 s was required for dry eye diagnosis. The authors then
with a Perkins tonometer in the habitual supine position after waking the patient. The
conducted corneal fluorescein staining. Following the previous test, the cornea was
two night-time measurements were performed
examined for punctate epitheliopathy staining
5 min after wakening to avoid changes associated with any startle response that might
with fluorescein. The pattern and density of the spots were evaluated with the van
occur. The investigators measuring the IOP were masked from the treatment regimen. Any
Bijsterveld grading method with a range of 0–3 [24]. Finally, a Schirmer I test (without
potential side effect was recorded for each period, separately.
anesthesia) was carried out. This is an estimation of reflex tear flow stimulated by
Following the latanoprost-treated 24-h curve
the insertion of a filter paper into the
all patients were randomized for 3 months (±2 weeks) to either TTFC preserved with
conjunctival sac. The length of paper in mm soaked by tears within 5 min was recorded in
(DuoTravÒ, Alcon Fort Worth, TX, USA)
each case. A value less than 5 mm was considered pathognomonic for aqueous-
polyquaternium-1 Laboratories Inc.,
administered each evening (20:00), or LTFC
deficient dry eye.
Ò
drops preserved with BAK (Xalacom , Pfizer, New York, NY, USA) administered each evening
Statistics
(20:00). A safety visit and a morning IOP measurement (10:00 ± 1 h) were performed at
The primary efficacy endpoint of this trial was
the end of week 2. At the end of both treatment periods patients underwent ocular surface assessment and a treated 24-h curve in the
the mean 24-h IOP (the average pressure for the 6 time points). The individual time points, the peak, trough and fluctuation of 24-h IOP were
habitual position as described above.
included as secondary endpoints. A mixed model was used for the cross-over repeated
Ocular Surface Assessment
measures design to adjust for period and carryover effects. Period and sequence were included
After recording any patient reported ocular
in the model as fixed effects. Patients within a
surface symptoms, the following tests were
sequence were included in the model as a
Adv Ther
random effect. A 95% confidence interval (CI)
RESULTS
was constructed for the adjusted difference in means. An intention-to-treat approach was adopted and the subjects were analyzed
Patients
according to their randomized group. The current 24-h study had an 80% power to
Forty-two open-angle glaucoma patients (22
identify
of 44 enrolled (Fig. 1). There were 23 with primary open-angle glaucoma, 17 with
a
1.25 mmHg
difference
between
individual time points and between mean 24-h pressure readings assuming a standard deviation of 2.8 mmHg between treatments if 42 patients completed the trial. One eye was
female and 20 male) completed the study out
exfoliative glaucoma and 2 with pigmentary glaucoma. The mean age of trial participants was 65.3 years.
randomly chosen for analysis. Mean 24-h fluctuation (average of the highest time point minus the lowest time point for each individual
Intraocular Pressure
patient) as well as the mean peak and trough pressures was analyzed by a paired t test.
The mean untreated morning IOP of the study
Ocular surface signs between agents were compared with a paired t test. Adverse events were evaluated by Cochran’s Q and McNemar’s test. The Bonferroni-adjusted P values are reported to correct the analyses for multiple comparisons in secondary endpoints. All other reported P values were two tailed with P\0.05 considered
as
significant.
Analyses
were
conducted using IBM/SPSS Statistics Release (Version 20.0, IBM Corporation, Armonk, NY, USA).
cohort was 31.1 mmHg and the mean 24-h baseline IOP on latanoprost was 21.5 ± 1.6 mmHg
(Table 1).
Both
FCs
significantly reduced the IOP at each time point, for the mean 24-h IOP, peak 24-h IOP and 24-h fluctuation of IOP compared with latanoprost monotherapy (P\0.01) (Table 1; Figs. 2, 3). Specifically, LTFC further reduced the mean 24-h IOP by 2.2 mmHg, whereas TTFC further reduced 24-h IOP by 2.6 mmHg. The difference in mean incremental IOP reduction from latanoprost baseline between the two FCs was significant (P = 0.004). When the two FCs were compared directly, TTFC provided significantly
lower
mean
24-h
IOP
(18.9 ± 2.2 mmHg) compared with LTFC (19.3 ± 2.3 mmHg) (P = 0.004) and significantly lower IOP at 18:00 (18.6 ± 2.5 mmHg) vs. LTFC (19.5 ± 2.7 mmHg) (P\0.001) (Table 2). Test for carry-over effect (P = 0.526) and period effect (P = 0.245) was not significant. Ocular Surface Assessment Fig. 1 Flow chart of the study. BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/ timolol fixed combination preserved with BAK, OS ocular surface evaluation, TTFC travoprost/timolol fixed combination without benzalkonium chloride (BAK)
All three ocular surface signs investigated were significantly worse with LTFC compared with latanoprost monotherapy (P B 0.001), whereas
Adv Ther
Table 1 Statistical comparison in efficacy between latanoprost and TTFC (IOP values in mmHg) Comparison time
Latanoprost (mmHg)
TTFC BAK-free (mmHg)
P value
06:00
21.6
19.1
\0.001*
10:00
22.7
19.6
\0.001*
14:00
21.7
19.1
\0.001*
18:00
21.5
18.6
\0.001*
22:00
20.9
18.5
\0.001*
02:00
20.3
18.5
\0.001
Mean 24-h IOP
21.5
18.9
\0.001
Minimum 24-h
19.8
17.5
\0.001*
Peak 24-h
23.3
20.5
0.323
24-h fluctuation
3.52
2.98
0.014
BAK benzalkonium chloride, IOP intraocular pressure, TTFC BAK travoprost/timolol fixed combination without BAK * Bonferroni-adjusted P values
Fig. 2 IOP control with latanoprost vs. TTFC over 24 h (IOP values in mmHg). BAK benzalkonium chloride, IOP intraocular pressure, TTFC travoprost/timolol fixed combination without benzalkonium chloride (BAK) TTFC demonstrated significantly more corneal staining than latanoprost (1.53 vs. 1.3) (P = 0.005), but no difference for the other two signs of tear film break-up time and Schirmer I test. When the two FCs were compared directly, TTFC demonstrated significantly better corneal staining (1.53 vs. 1.78), TFBUT (5.15 vs. 4.65), and Schirmer I test (9.95 vs. 9.23) compared with LTFC (P\0.003
Fig. 3 24-h IOP efficacy with LTFC vs. TTFC (IOP values in mmHg). BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/ timolol fixed combination without BAK These findings indicate that both FCs impact the corneal epithelium more than latanoprost monotherapy, with the TTFC without BAK causing
the
least
epithelial
damage.
In
addition, LTFC worsened the quality and quantity of tear film compared to latanoprost alone, whereas TTFC was comparable to latanoprost monotherapy and significantly
for all comparisons) at the end of treatment
superior to LTFC on tear film changes possibly due to the milder effect of polyquaternium-1
period (Fig. 4; Table 3).
compared to BAK.
Adv Ther
Table 2 Statistical comparison in efficacy between TTFC and LTFC (IOP values in mmHg) Comparison time
LTFC (mmHg)
TTFC BAK-free (mmHg)
06:00
19.6
19.1
0.176*
10:00
19.4
19.6
1.000*
14:00
19.3
19.1
0.657*
18:00
19.5
18.6
\0.001*
22:00
19.1
18.5
0.084*
02:00
18.7
18.5
1.000*
Mean 24-h IOP
19.3
18.9
0.004
Minimum 24-h
17.7
17.5
0.229
Peak 24-h
20.7
20.5
0.323
24-h fluctuation
3.02
P value
2.98
0.809
BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/timolol fixed combination without BAK * Bonferroni-adjusted P values
DISCUSSION To the best of the authors’ knowledge this study is the first 24-h comparison between LTFC preserved with BAK and TTFC preserved with polyquaternium-1. Previous studies have demonstrated that a 24-h IOP evaluation Fig. 4 Ocular surface parameters with LTFC vs. TTFC. BAK benzalkonium chloride, BUT break-up time, LTFC latanoprost/timolol fixed combination preserved with BAK, Stain corneal fluorescein staining, TTFC travoprost/timolol fixed combination without BAK
Adverse Events
allows a more complete assessment of the true efficacy of available therapy options [25, 26]. There is limited published evidence evaluating the complete diurnal–nocturnal efficacy of PTFCs beyond 2–3 time points during the daytime [1, 2]. Although PTFCs in regulatory trials have demonstrated greater daytime efficacy
than
each
of
their
individual
All three treatments were well tolerated. Patients reported significantly more stinging
components, the enhanced IOP reduction has been less than was originally anticipated [2].
with LTFC (19%) compared with latanoprost
This may be due, at least in part, to the potency of prostaglandin analogs, when used as
(4.8%) (P = 0.031). When the two FC therapies were compared directly the frequency of ocular or systemic adverse effects did not differ significantly between them (P[0.05).
monotherapy, and the use of timolol only once daily in PTFCs. Importantly, previously published comparisons have generally
Adv Ther
Table 3 Statistical comparison in ocular surface signs between LTFC and TTFC Comparison
LTFC
TTFC BAK-free
P value
BUT (s)
4.65
5.15
\0.001
Corneal stain (van Bijsterveld score)
1.78
1.53
0.003
Schirmer test (mm)
9.23
9.95
\0.001
BAK benzalkonium chloride, BUT break-up time, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/timolol fixed combination without BAK demonstrated greater efficacy for all PTFCs
topical antiglaucoma medications and their
compared with their constituents over 24 h [27–30].
prostaglandin
preservatives [31]. In this study, both PTFCs provided significant
A previous comparative 24-h study between
incremental 24-h IOP lowering compared with
BAK-containing TTFC and LTFC in exfoliative glaucoma patients demonstrated superior 24-h
branded latanoprost monotherapy in openangle glaucoma patients who needed further
efficacy for the TTFC containing BAK [6, 7]. It should be noted, however, that a number of
IOP reduction. There was a clinically meaningful and statistically significant 24-h IOP separation
parameters
administration,
between the two PTFCs (LTFC 2.2 mmHg and
methodology of IOP evaluation, baseline IOP, etc.) influence 24-h comparisons. To remove
TTFC 2.6 mmHg) and latanoprost. Thus, the present investigation corroborates previous
possible ambiguity with the new BAK-free formulation of the TTFC it was considered
evidence suggesting PTFCs can provide an additional 2–3 mmHg of IOP lowering [5, 27–
important to assess the therapeutic efficacy of
30]. It is worth noting that, in this trial, TTFC
this new formulation vs. LTFC preserved with BAK throughout the 24-h period. To better
without BAK provided significantly better 24-h efficacy than LTFC preserved with BAK. Hence,
reflect clinical practice worldwide, the authors have included in the present trial open-angle
the findings of this study consolidate evidence from a previous trial with exfoliative glaucoma
glaucoma patients insufficiently controlled on
patients, which also demonstrated superiority
latanoprost latanoprost
monotherapy. Currently, (branded or generic) is the
over 24 h for TTFC vs. LTFC, both preserved with BAK [6, 7].
commonest initial monotherapy selected by physicians in many countries.
There is convincing evidence in vitro and on animal models [12, 32, 33] demonstrating the
Similarly, the authors believe the current study is also the first to combine 24-h efficacy
milder profile of polyquaternium-1 compared to BAK on the ocular surface. In addition, there is
evaluation and ocular surface health metrics.
some clinical evidence that travoprost BAK-free
Another novelty of the present study is the inclusion of an easy-to-perform clinical
formulation preserved with polyquaternium-1 is equally efficient and safe compared to BAK-
evaluation of three selected ocular surface signs. These signs are seen as a credible
preserved travoprost [34]. In the same vein, clinical evidence suggests that TTFC preserved
surrogate of ocular surface health and can be
with polyquaternium-1 has comparable IOP-
used in clinical practice to detect and quantify epithelial and tear film alterations caused by
lowering effect and better safety profile than BAK-containing TTFC [35].
(time
of
Adv Ther
A key consideration beyond efficacy for the
IOP monitoring. The three ocular surface
success of combined therapy is long-term
parameters employed in the present study are
tolerability. Long-term tolerability may influence the rate of adherence, persistence
easy and relatively simple to perform in daily practice. The authors deliberately did not assess
and ultimately, the long-term efficacy and success of combined therapy. It is therefore
the more sensitive conjunctival epithelium changes with the use of lissamine green
important to consider the long-term ocular
staining in order to avoid detection of earlier,
surface health when selecting initial and combined antiglaucoma therapy. In this study
milder changes and rather focus on the more established corneal epithelial changes. In the
the authors compared three commonly used baseline ocular surface parameters (tear film
future, it may be best to first evaluate patient symptoms with a validated questionnaire (e.g.,
break-up time, corneal stain and Schirmer
Ocular Surface Disease Index), then assess the
I test). TTFC without BAK exhibited more corneal stain than latanoprost monotherapy,
tear film quality and quantity, carry out an osmolarity measurement and finally investigate
but there was no difference on the tear film parameters despite the addition of timolol,
the ocular surface damage with lissamine green and fluorescein staining. This should be
which has been demonstrated to adversely
followed by an examination of meibomian
affect ocular surface and break-up time, as it happened with LTFC where all three ocular
gland morphology and function [22, 23]. This approach may improve the awareness and
surface parameters were worse than those with latanoprost. When the two FCs were compared
understanding of all adverse effects induced by glaucoma medications upon the ocular surface
directly, TTFC demonstrated better TFBUT, corneal stain and Schirmer I test values than
and may clarify better its correlation with longterm tolerability and adherence. Newer metrics
LTFC possibly due to elimination of BAK and
that can objectively assess the tear film and
the milder effect of polyquaternium-1 on the ocular surface and tear film. This is also
perform in vivo imaging of the epithelium might be of use in future studies once
highlighted by the superior tolerability profile of TTFC preserved with polyquaternium-1 when
validated in human trials [15, 36]. This trial did not evaluate the long-term 24-h
compared with BAK-preserved TTFC [35]. It is
efficacy of TTFC without BAK
logical to assume that while short-term tolerability with latanoprost and the LTFC
containing BAK, or its individual components. This study also did not compare the TTFC
may be superior the long-term tolerability and ocular surface health between these
without BAK to travoprost without BAK, or to other fixed combinations. It should be noted
medications and travoprost/TTFC may differ
that
because latanoprost and LTFC contain the highest concentration of BAK (0.02%), whereas
between medications there might be a difference between what is statistically
travoprost and TTFC now contain the preservative polyquaternium-1. This
significant and what is clinically significant. As with all similar studies, it remains unclear if the
hypothesis requires further verification.
detected IOP and ocular surface differences are
This trial further supports the need to routinely assess ocular surface and tear film
clinically significant. Nevertheless, a 24-h efficacy difference may be of greater value
parameters in glaucoma patients in addition to
than a difference based on a single, or even a
when
evaluating
efficacy
vs. LTFC
differences
Adv Ther
few IOP readings. More information is needed
consulting support from Allergan and Thea. MY
on the specific role of 24-h parameters (e.g.,
Kahook has received research support from Alcon, Allergan, Bausch & Lomb and
peak 24-h IOP) upon glaucoma progression [30]. In addition, the use of three different metrics
consulting support from Alcon, Allergan, and
for evaluation of the ocular surface bolsters the findings and lends credence to the likelihood of
Aerie. He is stock shareholder in Shape Ophthalmics, Shape Tech, and Clarvista. IC
clinical
Voudouragkaki, E Paschalinou, AB Haidich, T Giannopoulos, ND Dragoumis and AK Makridis
significance.
Evaluation
with
questionnaires that focus on patient report outcomes should be performed in future studies as an additional metric that would be of value. More research is needed to further
declare no conflicts of interest.
clarify the best FC therapy and to delineate the
Compliance with ethics guidelines. All procedures followed were in accordance with
optimal stepwise therapy to treat ocular hypertension and open-angle glaucoma.
the ethical standards of committee on human
the responsible experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Informed consent was
CONCLUSION The present investigation established that in open-angle glaucoma patients insufficiently controlled
on
branded
latanoprost
obtained from all patients for being included in the study.
TTFC
without BAK provided superior 24-h efficacy compared with LTFC containing BAK. This
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ACKNOWLEDGMENTS This study was supported in part by Alcon (Alcon Laboratories Inc., Fort Worth, Texas, USA). All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Conflict of interest. AG Konstas has received research support from Alcon, Allergan and consulting support from Alcon, Allergan, Merck and Santen. KG Boboridis has received
Adv Ther
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Konstas AG, Haidich AB, Rossetti L, Webers C. Prostaglandin-timolol fixed combinations efficacy: myth or reality? Eur J Ophthalmol. 2012;22:1–4. Kass MA, Heuer DK, Higginbotham EJ, et al. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120: 701–13. Ammar DA, Kahook MY. Effects of benzalkonium chloride- or polyquad-preserved fixed combination glaucoma medications on human trabecular meshwork cells. Mol Vis. 2011;17:1806–13.
10. Baudouin C, Labbe A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–34. 11. Freeman PD, Kahook MY. Preservatives in topical ophthalmic medications: historical and clinical perspectives. Expert Rev Ophthalmol. 2009;4: 59–64. 12. Ammar DA, Noecker RJ, Kahook MY. Effects of benzalkonium chloride- and polyquad-preserved combination glaucoma medications on cultured human ocular surface cells. Adv Ther. 2011;28: 501–10. 13. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29:618–21. 14. Horsley MB, Kahook MY. Effects of prostaglandin analog therapy on the ocular surface of glaucoma patients. Clin Ophthalmol. 2009;3:291–5. 15. Liang H, Brignole-Baudouin F, Riancho L, et al. Reduced in vivo ocular surface toxicity with polyquad-preserved travoprost versus benzalkonium-preserved travoprost or latanoprost ophthalmic solutions. Ophth Res. 2012;48:89–101. 16. Rolando M, Crider JY, Kahook MY. Ophthalmic preservatives: focus on polyquaternium-1. Expert Opin Drug Deliv. 2011;8:1425–38. 17. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350–5. 18. Boimer C, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. J Glaucoma. 2013;22:730–5.
19. Broadway D, Hitchings R, Grierson I. Topical antiglaucomatous therapy: adverse effects on the conjunctiva and implications for filtration surgery. J Glaucoma. 1995;4:136. 20. Broadway DC, Chang LP. Trabeculectomy, risk factors for failure and the preoperative state of the conjunctiva. J Glaucoma. 2001;10:237–49. 21. Zimmerman TJ, Hahn SR, Gelb L, et al. The impact of ocular adverse effects in patients treated with topical prostaglandin analogs: changes in prescription patterns and patient persistence. J Ocular Pharmacol Ther. 2009;25:145–52. 22. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf 2007;5:75–92. 23. Schaumberg DA, Nichols JJ, Papas EB, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for MGD. Invest Ophthalmol Vis Sci. 2011;52:1994–2005. 24. van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol. 1969;82:10–4. 25. Konstas AG, Quaranta L, Katsanos A, et al. Twentyfour hour efficacy with preservative free tafluprost compared with latanoprost in patients with primary open angle glaucoma or ocular hypertension. Br J Ophthalmol. 2013;97:1510–5. 26. Quaranta L, Katsanos A, Russo A, et al. 24-hour intraocular pressure and ocular perfusion pressure in glaucoma. Surv Ophthalmol. 2013;58:26–41. 27. Konstas AG, Boboridis K, Tzetzi D, et al. Twentyfour-hour control with latanoprost-timolol-fixed combination therapy vs latanoprost therapy. Arch Ophthalmol. 2005;123:898–902. 28. Konstas AG, Hollo G, Mikropoulos D, et al. Twentyfour-hour intraocular pressure control with bimatoprost and the bimatoprost/timolol fixed combination administered in the morning, or evening in exfoliative glaucoma. Br J Ophthalmol. 2010;94:209–13. 29. Konstas AG, Mikropoulos D, Haidich AB, et al. Twenty-four-hour intraocular pressure control with the travoprost/timolol maleate fixed combination compared with travoprost when both are dosed in the evening in primary open-angle glaucoma. Br J Ophthalmol. 2009;93:481–5. 30. Konstas AG, Quaranta L, Mikropoulos DG, et al. Peak intraocular pressure and glaucomatous
Adv Ther
progression in primary open-angle glaucoma. J Ocul Pharmacol Ther. 2012;28:26–32. 31. Research in dry eye: report of the research subcommittee of the international dry eye workshop (2007). Ocul Surf 2007;5:179–93. 32. Labbe A, Pauly A, Liang H, et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocular Pharmacol Ther. 2006;22:267–78. 33. Liang H, Brignole-Baudouin F, Pauly A, et al. Polyquad-preserved travoprost/timolol, benzalkonium chloride (BAK)-preserved travoprost/ timolol, and latanoprost/timolol in fixed combinations: a rabbit ocular surface study. Adv Ther. 2011;28:311–25.
34. Gandolfi S, Paredes T, Goldberg I, et al. Comparison of a travoprost BAK-free formulation preserved with polyquaternium-1 with BAK-preserved travoprost in ocular hypertension or open-angle glaucoma. Eur J Ophthalmol. 2012;22:34–44. 35. Kitazawa Y, Smith P, Sasaki N, et al. Travoprost 0.004 %/timolol 0.5 %-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy. Eye. 2011;25:1161–9. 36. Martone G, Frezzotti P, Tosi GM, et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol. 2009;147:725 e1–735 e1.
ORIGINAL RESEARCH
24-Hour Efficacy of Travoprost/Timolol BAK-Free Versus Latanoprost/Timolol Fixed Combinations in Patients Insufficiently Controlled with Latanoprost Anastasios G. P. Konstas • Irini C. Voudouragkaki • Kostantinos G. Boboridis Anna-Bettina Haidich Eleni Paschalinou Theodoros Giannopoulos •
•
•
•
Nikolaos D. Dragoumis • Alexandros K. Makridis • Malik Y. Kahook
To view enhanced content go to www.advancesintherapy.com Received: April 7, 2014 Ó Springer Healthcare 2014
ABSTRACT
controlled
Introduction: To compare the 24-h intraocular
monotherapy given once in the evening. Methods: The authors have conducted
pressure (IOP) control and tolerability of
prospective,
travoprost/timolol benzalkonium chloride (BAK)-free (TTFC) vs. latanoprost/timolol fixed
controlled, cross-over, comparison study. Qualified open-angle glaucoma patients who
combination preserved with BAK (LTFC) in open-angle glaucoma patients insufficiently
demonstrated a latanoprost-treated morning IOP (10:00 ± 1 h) greater than 20 mmHg on two
with
latanoprost
0.005%
observer-masked,
separate
visits
were
a
active-
randomized
for
Trial registration: ClinicalTrials.gov #NCT01779284.
3 months to receive either TTFC or LTFC. Patients were then crossed over to the
Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0125-9) contains supplementary material, which is available to authorized users.
opposite treatment for another 3 months. At the end of the latanoprost run-in and after each
A. G. P. Konstas (&) I. C. Voudouragkaki K. G. Boboridis E. Paschalinou T. Giannopoulos N. D. Dragoumis A. K. Makridis 1st University Department of Ophthalmology, Aristotle University of Thessaloniki, 1 Kyriakidi Street, 546 36 Thessaloniki, Greece e-mail: [email protected] A. G. P. Konstas K. G. Boboridis 3rd University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece A.-B. Haidich Department of Hygiene, Aristotle University of Thessaloniki, Thessaloniki, Greece M. Y. Kahook Department of Ophthalmology, University of Colorado School of Medicine, Aurora, IL, USA
3-month therapy period patients underwent 24-h IOP monitoring in the habitual position using Goldmann applanation tonometry in the sitting position during the day (10:00, 14:00, 18:00 and 22:00) and Perkins tonometry in the supine position at night (02:00 and 06:00). Selected ocular surface parameters evaluated after each therapy period.
were
Results: Forty-two open-angle glaucoma patients completed the study. The mean 24-h baseline
IOP
on
latanoprost
was
21.5 ± 1.6 mmHg. Both fixed combinations significantly reduced the IOP at each time point, for the mean, peak and fluctuation of
Adv Ther
24-h
latanoprost
efficacy of these adjunctive therapy options
monotherapy (P\0.01). When the two fixed combinations were compared directly, TTFC
IOP
compared
with
[5–7]. At present, many glaucoma patients are
provided significantly lower mean 24-h IOP (18.9 ± 2.2 mmHg) vs. LTFC (19.3 ± 2.3 mmHg) (P = 0.004) and significantly lower IOP at 18:00 (18.6 ± 2.5 vs. 19.5 ± 2.7 mmHg for LTFC) (P\0.001). Further, TTFC demonstrated significantly better tear film break-up time (5.15 vs. 4.65 s), corneal stain (1.5 vs. 1.8) and Schirmer I test (9.9 vs. 9.2 mm) compared with LTFC after 3 months of therapy (P\0.01 for all comparisons). Conclusion: The mean 24-h IOP lowering of TTFC was statistically more significant compared to LTFC in patients insufficiently controlled with latanoprost monotherapy. Measurement of ocular surface health and tear film status favored the BAK-free TTFC compared to LTFC.
being treated with latanoprost as first-line therapy. It is therefore of clinical importance to clarify which PTFC provides optimal 24-h IOP-lowering efficacy in those glaucoma patients
for
whom
monotherapy
with
latanoprost was inadequate. Glaucoma and ocular hypertension patients are often committed to lifelong pressure lowering therapies with roughly 50% of patients requiring more than one medication [8]. Chronic exposure to both active ingredient and preservatives is known to cause significant changes on the ocular surface [9, 10]. Benzalkonium chloride (BAK), a quaternary ammonium, is the most common preservative in glaucoma medications [11]. This highly effective antimicrobial agent acts as a detergent by denaturing proteins and disrupting cytoplasmic membranes. It has
Keywords: 24-h intraocular pressure (IOP) control; Benzalkonium chloride; Fixed
been convincingly demonstrated to adversely affect corneal and conjunctival epithelium [12–
combinations; Latanoprost/timolol; Ophthalmology; Polyquad; Travoprost/timolol;
15].
Polyquaternium-1
is
a
less
toxic
Ocular surface; OSD
preservative with no detergent action, which has been recently used in glaucoma topical
INTRODUCTION
medications as an alternative to BAK [16]. Recent studies have recognized a high prevalence of symptoms and signs of ocular
Fixed combinations (FCs) minimize the number of drops patients use and can enhance longterm tolerability and adherence [1–3]. Prostaglandin/timolol fixed combinations (PTFCs) are popular stepwise treatment options for glaucoma patients insufficiently controlled on prostaglandin monotherapies and requiring additional lowering of intraocular pressure (IOP) by 2–3 mmHg [2, 4, 5]. There is still uncertainty however as to the precise role and value of PTFCs in the stepwise therapy of glaucoma [2]. A 24-h IOP evaluation allows a more complete assessment of the
surface disease in chronically treated glaucoma patients [13, 17]. Topical antiglaucoma medications adversely impact tear synthesis and function, increase
film tear
osmolarity, reduce break-up time and decrease Schirmer test [11]. These ocular adverse reactions have subsequently been associated with reduced treatment tolerability and adherence, adversely impact quality of life and may ultimately elicit a more unfavorable surgical outcome [18–20]. Nevertheless, currently there is paucity of clinical evidence documenting the comparative
Adv Ther
damage upon the ocular surface of FC therapies
than 0.1 in the study eye; corneal pachymetry
with and without BAK. Published clinical
within the 550 ± 50 lm range; open anterior
studies focus mainly on the hypotensive efficacy and general safety profile without
chamber angles on gonioscopy. All patients were treated in both eyes with the same
investigating specific ocular surface parameters. Beyond efficacy however long-
therapy regimen, if medical therapy was indicated in both eyes.
term tolerability can meaningfully impact
Exclusion criteria were history of less than
long-term adherence and success of therapy [21]. The main objective of the current study
10% IOP decrease on medication, evidence
any of
IOP-lowering concurrent
was to compare the 24-h IOP-lowering efficacy and impact on the ocular surface of two popular
conjunctivitis, keratitis, or uveitis in either eye; history of inadequate adherence; intolerance,
PTFCs (travoprost/timolol FC without BAK vs.
or contraindication to either prostaglandins,
latanoprost/timolol FC containing BAK) in open-angle glaucoma patients insufficiently
b-blockers, or BAK; severe ocular surface disease, intraocular conventional or laser
controlled on latanoprost monotherapy.
surgery in the study eye; previous history of ocular trauma; use of corticosteroids (within 2 months before enrolment), history of dry eyes
METHODS
on topical artificial tear drops or active blepharitis; and use of contact lenses.
Patients
Evaluation and grading of dry eye and ocular surface parameters were performed in accordance
This was a prospective, 3-month, observermasked, active-controlled, cross-over,
with the recently published guidelines and methodology proposed by the International Dry
comparative study. The trial enrolled consecutive patients at an academic glaucoma
Eye
service with early-to-moderate open-angle glaucoma (primary open-angle, exfoliative, or
Workshop
and
Meibomian
Gland
Dysfunction Workshop [22, 23]. Compliance with Ethics
pigmentary glaucoma) who were insufficiently controlled on branded latanoprost monotherapy and demonstrated a latanoprost-
All procedures followed were in accordance with the ethical standards of the responsible
treated morning (10:00 ± 1 h) IOP greater than 20 mmHg at two separate visits.
committee
on
human
experimentation
with
(institutional and national) and with the Helsinki Declaration of 1975, as revised in
latanoprost monotherapy for at least 3 months to qualify. All study patients had to be older
2000 and 2008. Informed consent was obtained from all patients for being included
than 29 years, and agreed to participate in this trial and met the inclusion and exclusion
in the study.
criteria. Enrolled patients exhibited typical
Procedures
glaucomatous disc damage and visual field loss (0.8 or better vertical cup-to-disc ratio and less
Study patients first underwent ocular surface
than 16 dB mean deviation visual field loss attributed to glaucoma); visual acuity greater
evaluation and then habitual 24-h IOP monitoring with branded latanoprost
All
patients
had
to
be
treated
Adv Ther
preserved with BAK (XalatanÒ, Pfizer, New York,
performed in the following order to evaluate
NY, USA) administered in the evening (20:00).
tear film and ocular epithelium status. Tear
Selected ocular surface signs (corneal stain, tear film break-up time, Schirmer I test) were
film break-up time (TFBUT) was recorded. A small quantity of fluorescein was instilled into
recorded prior to IOP monitoring. The same investigators measured the IOP using the same
the inferior fornix with the use of a fluorescein impregnated paper strip soaked
calibrated instruments [Goldmann and Perkins
with a drop of unpreserved normal saline.
applanation tonometers (Haag Streit USA, Mason, OH, USA)]. Patients were admitted to
After a few blinks the patient was instructed to keep the eyelids open and the interval
the hospital in the morning and IOP measurements were recorded with Goldmann
between the last complete blink and the first appearance of a dry spot, or disruption in the
applanation tonometry at 06:00, 10:00, 14:00
tear film was recorded with the use of a cobalt
and 18:00 in the seated position. The 02:00 and 06:00 h IOP measurements were performed
blue filter. A cut-off value of B5 s was required for dry eye diagnosis. The authors then
with a Perkins tonometer in the habitual supine position after waking the patient. The
conducted corneal fluorescein staining. Following the previous test, the cornea was
two night-time measurements were performed
examined for punctate epitheliopathy staining
5 min after wakening to avoid changes associated with any startle response that might
with fluorescein. The pattern and density of the spots were evaluated with the van
occur. The investigators measuring the IOP were masked from the treatment regimen. Any
Bijsterveld grading method with a range of 0–3 [24]. Finally, a Schirmer I test (without
potential side effect was recorded for each period, separately.
anesthesia) was carried out. This is an estimation of reflex tear flow stimulated by
Following the latanoprost-treated 24-h curve
the insertion of a filter paper into the
all patients were randomized for 3 months (±2 weeks) to either TTFC preserved with
conjunctival sac. The length of paper in mm soaked by tears within 5 min was recorded in
(DuoTravÒ, Alcon Fort Worth, TX, USA)
each case. A value less than 5 mm was considered pathognomonic for aqueous-
polyquaternium-1 Laboratories Inc.,
administered each evening (20:00), or LTFC
deficient dry eye.
Ò
drops preserved with BAK (Xalacom , Pfizer, New York, NY, USA) administered each evening
Statistics
(20:00). A safety visit and a morning IOP measurement (10:00 ± 1 h) were performed at
The primary efficacy endpoint of this trial was
the end of week 2. At the end of both treatment periods patients underwent ocular surface assessment and a treated 24-h curve in the
the mean 24-h IOP (the average pressure for the 6 time points). The individual time points, the peak, trough and fluctuation of 24-h IOP were
habitual position as described above.
included as secondary endpoints. A mixed model was used for the cross-over repeated
Ocular Surface Assessment
measures design to adjust for period and carryover effects. Period and sequence were included
After recording any patient reported ocular
in the model as fixed effects. Patients within a
surface symptoms, the following tests were
sequence were included in the model as a
Adv Ther
random effect. A 95% confidence interval (CI)
RESULTS
was constructed for the adjusted difference in means. An intention-to-treat approach was adopted and the subjects were analyzed
Patients
according to their randomized group. The current 24-h study had an 80% power to
Forty-two open-angle glaucoma patients (22
identify
of 44 enrolled (Fig. 1). There were 23 with primary open-angle glaucoma, 17 with
a
1.25 mmHg
difference
between
individual time points and between mean 24-h pressure readings assuming a standard deviation of 2.8 mmHg between treatments if 42 patients completed the trial. One eye was
female and 20 male) completed the study out
exfoliative glaucoma and 2 with pigmentary glaucoma. The mean age of trial participants was 65.3 years.
randomly chosen for analysis. Mean 24-h fluctuation (average of the highest time point minus the lowest time point for each individual
Intraocular Pressure
patient) as well as the mean peak and trough pressures was analyzed by a paired t test.
The mean untreated morning IOP of the study
Ocular surface signs between agents were compared with a paired t test. Adverse events were evaluated by Cochran’s Q and McNemar’s test. The Bonferroni-adjusted P values are reported to correct the analyses for multiple comparisons in secondary endpoints. All other reported P values were two tailed with P\0.05 considered
as
significant.
Analyses
were
conducted using IBM/SPSS Statistics Release (Version 20.0, IBM Corporation, Armonk, NY, USA).
cohort was 31.1 mmHg and the mean 24-h baseline IOP on latanoprost was 21.5 ± 1.6 mmHg
(Table 1).
Both
FCs
significantly reduced the IOP at each time point, for the mean 24-h IOP, peak 24-h IOP and 24-h fluctuation of IOP compared with latanoprost monotherapy (P\0.01) (Table 1; Figs. 2, 3). Specifically, LTFC further reduced the mean 24-h IOP by 2.2 mmHg, whereas TTFC further reduced 24-h IOP by 2.6 mmHg. The difference in mean incremental IOP reduction from latanoprost baseline between the two FCs was significant (P = 0.004). When the two FCs were compared directly, TTFC provided significantly
lower
mean
24-h
IOP
(18.9 ± 2.2 mmHg) compared with LTFC (19.3 ± 2.3 mmHg) (P = 0.004) and significantly lower IOP at 18:00 (18.6 ± 2.5 mmHg) vs. LTFC (19.5 ± 2.7 mmHg) (P\0.001) (Table 2). Test for carry-over effect (P = 0.526) and period effect (P = 0.245) was not significant. Ocular Surface Assessment Fig. 1 Flow chart of the study. BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/ timolol fixed combination preserved with BAK, OS ocular surface evaluation, TTFC travoprost/timolol fixed combination without benzalkonium chloride (BAK)
All three ocular surface signs investigated were significantly worse with LTFC compared with latanoprost monotherapy (P B 0.001), whereas
Adv Ther
Table 1 Statistical comparison in efficacy between latanoprost and TTFC (IOP values in mmHg) Comparison time
Latanoprost (mmHg)
TTFC BAK-free (mmHg)
P value
06:00
21.6
19.1
\0.001*
10:00
22.7
19.6
\0.001*
14:00
21.7
19.1
\0.001*
18:00
21.5
18.6
\0.001*
22:00
20.9
18.5
\0.001*
02:00
20.3
18.5
\0.001
Mean 24-h IOP
21.5
18.9
\0.001
Minimum 24-h
19.8
17.5
\0.001*
Peak 24-h
23.3
20.5
0.323
24-h fluctuation
3.52
2.98
0.014
BAK benzalkonium chloride, IOP intraocular pressure, TTFC BAK travoprost/timolol fixed combination without BAK * Bonferroni-adjusted P values
Fig. 2 IOP control with latanoprost vs. TTFC over 24 h (IOP values in mmHg). BAK benzalkonium chloride, IOP intraocular pressure, TTFC travoprost/timolol fixed combination without benzalkonium chloride (BAK) TTFC demonstrated significantly more corneal staining than latanoprost (1.53 vs. 1.3) (P = 0.005), but no difference for the other two signs of tear film break-up time and Schirmer I test. When the two FCs were compared directly, TTFC demonstrated significantly better corneal staining (1.53 vs. 1.78), TFBUT (5.15 vs. 4.65), and Schirmer I test (9.95 vs. 9.23) compared with LTFC (P\0.003
Fig. 3 24-h IOP efficacy with LTFC vs. TTFC (IOP values in mmHg). BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/ timolol fixed combination without BAK These findings indicate that both FCs impact the corneal epithelium more than latanoprost monotherapy, with the TTFC without BAK causing
the
least
epithelial
damage.
In
addition, LTFC worsened the quality and quantity of tear film compared to latanoprost alone, whereas TTFC was comparable to latanoprost monotherapy and significantly
for all comparisons) at the end of treatment
superior to LTFC on tear film changes possibly due to the milder effect of polyquaternium-1
period (Fig. 4; Table 3).
compared to BAK.
Adv Ther
Table 2 Statistical comparison in efficacy between TTFC and LTFC (IOP values in mmHg) Comparison time
LTFC (mmHg)
TTFC BAK-free (mmHg)
06:00
19.6
19.1
0.176*
10:00
19.4
19.6
1.000*
14:00
19.3
19.1
0.657*
18:00
19.5
18.6
\0.001*
22:00
19.1
18.5
0.084*
02:00
18.7
18.5
1.000*
Mean 24-h IOP
19.3
18.9
0.004
Minimum 24-h
17.7
17.5
0.229
Peak 24-h
20.7
20.5
0.323
24-h fluctuation
3.02
P value
2.98
0.809
BAK benzalkonium chloride, IOP intraocular pressure, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/timolol fixed combination without BAK * Bonferroni-adjusted P values
DISCUSSION To the best of the authors’ knowledge this study is the first 24-h comparison between LTFC preserved with BAK and TTFC preserved with polyquaternium-1. Previous studies have demonstrated that a 24-h IOP evaluation Fig. 4 Ocular surface parameters with LTFC vs. TTFC. BAK benzalkonium chloride, BUT break-up time, LTFC latanoprost/timolol fixed combination preserved with BAK, Stain corneal fluorescein staining, TTFC travoprost/timolol fixed combination without BAK
Adverse Events
allows a more complete assessment of the true efficacy of available therapy options [25, 26]. There is limited published evidence evaluating the complete diurnal–nocturnal efficacy of PTFCs beyond 2–3 time points during the daytime [1, 2]. Although PTFCs in regulatory trials have demonstrated greater daytime efficacy
than
each
of
their
individual
All three treatments were well tolerated. Patients reported significantly more stinging
components, the enhanced IOP reduction has been less than was originally anticipated [2].
with LTFC (19%) compared with latanoprost
This may be due, at least in part, to the potency of prostaglandin analogs, when used as
(4.8%) (P = 0.031). When the two FC therapies were compared directly the frequency of ocular or systemic adverse effects did not differ significantly between them (P[0.05).
monotherapy, and the use of timolol only once daily in PTFCs. Importantly, previously published comparisons have generally
Adv Ther
Table 3 Statistical comparison in ocular surface signs between LTFC and TTFC Comparison
LTFC
TTFC BAK-free
P value
BUT (s)
4.65
5.15
\0.001
Corneal stain (van Bijsterveld score)
1.78
1.53
0.003
Schirmer test (mm)
9.23
9.95
\0.001
BAK benzalkonium chloride, BUT break-up time, LTFC latanoprost/timolol fixed combination preserved with BAK, TTFC travoprost/timolol fixed combination without BAK demonstrated greater efficacy for all PTFCs
topical antiglaucoma medications and their
compared with their constituents over 24 h [27–30].
prostaglandin
preservatives [31]. In this study, both PTFCs provided significant
A previous comparative 24-h study between
incremental 24-h IOP lowering compared with
BAK-containing TTFC and LTFC in exfoliative glaucoma patients demonstrated superior 24-h
branded latanoprost monotherapy in openangle glaucoma patients who needed further
efficacy for the TTFC containing BAK [6, 7]. It should be noted, however, that a number of
IOP reduction. There was a clinically meaningful and statistically significant 24-h IOP separation
parameters
administration,
between the two PTFCs (LTFC 2.2 mmHg and
methodology of IOP evaluation, baseline IOP, etc.) influence 24-h comparisons. To remove
TTFC 2.6 mmHg) and latanoprost. Thus, the present investigation corroborates previous
possible ambiguity with the new BAK-free formulation of the TTFC it was considered
evidence suggesting PTFCs can provide an additional 2–3 mmHg of IOP lowering [5, 27–
important to assess the therapeutic efficacy of
30]. It is worth noting that, in this trial, TTFC
this new formulation vs. LTFC preserved with BAK throughout the 24-h period. To better
without BAK provided significantly better 24-h efficacy than LTFC preserved with BAK. Hence,
reflect clinical practice worldwide, the authors have included in the present trial open-angle
the findings of this study consolidate evidence from a previous trial with exfoliative glaucoma
glaucoma patients insufficiently controlled on
patients, which also demonstrated superiority
latanoprost latanoprost
monotherapy. Currently, (branded or generic) is the
over 24 h for TTFC vs. LTFC, both preserved with BAK [6, 7].
commonest initial monotherapy selected by physicians in many countries.
There is convincing evidence in vitro and on animal models [12, 32, 33] demonstrating the
Similarly, the authors believe the current study is also the first to combine 24-h efficacy
milder profile of polyquaternium-1 compared to BAK on the ocular surface. In addition, there is
evaluation and ocular surface health metrics.
some clinical evidence that travoprost BAK-free
Another novelty of the present study is the inclusion of an easy-to-perform clinical
formulation preserved with polyquaternium-1 is equally efficient and safe compared to BAK-
evaluation of three selected ocular surface signs. These signs are seen as a credible
preserved travoprost [34]. In the same vein, clinical evidence suggests that TTFC preserved
surrogate of ocular surface health and can be
with polyquaternium-1 has comparable IOP-
used in clinical practice to detect and quantify epithelial and tear film alterations caused by
lowering effect and better safety profile than BAK-containing TTFC [35].
(time
of
Adv Ther
A key consideration beyond efficacy for the
IOP monitoring. The three ocular surface
success of combined therapy is long-term
parameters employed in the present study are
tolerability. Long-term tolerability may influence the rate of adherence, persistence
easy and relatively simple to perform in daily practice. The authors deliberately did not assess
and ultimately, the long-term efficacy and success of combined therapy. It is therefore
the more sensitive conjunctival epithelium changes with the use of lissamine green
important to consider the long-term ocular
staining in order to avoid detection of earlier,
surface health when selecting initial and combined antiglaucoma therapy. In this study
milder changes and rather focus on the more established corneal epithelial changes. In the
the authors compared three commonly used baseline ocular surface parameters (tear film
future, it may be best to first evaluate patient symptoms with a validated questionnaire (e.g.,
break-up time, corneal stain and Schirmer
Ocular Surface Disease Index), then assess the
I test). TTFC without BAK exhibited more corneal stain than latanoprost monotherapy,
tear film quality and quantity, carry out an osmolarity measurement and finally investigate
but there was no difference on the tear film parameters despite the addition of timolol,
the ocular surface damage with lissamine green and fluorescein staining. This should be
which has been demonstrated to adversely
followed by an examination of meibomian
affect ocular surface and break-up time, as it happened with LTFC where all three ocular
gland morphology and function [22, 23]. This approach may improve the awareness and
surface parameters were worse than those with latanoprost. When the two FCs were compared
understanding of all adverse effects induced by glaucoma medications upon the ocular surface
directly, TTFC demonstrated better TFBUT, corneal stain and Schirmer I test values than
and may clarify better its correlation with longterm tolerability and adherence. Newer metrics
LTFC possibly due to elimination of BAK and
that can objectively assess the tear film and
the milder effect of polyquaternium-1 on the ocular surface and tear film. This is also
perform in vivo imaging of the epithelium might be of use in future studies once
highlighted by the superior tolerability profile of TTFC preserved with polyquaternium-1 when
validated in human trials [15, 36]. This trial did not evaluate the long-term 24-h
compared with BAK-preserved TTFC [35]. It is
efficacy of TTFC without BAK
logical to assume that while short-term tolerability with latanoprost and the LTFC
containing BAK, or its individual components. This study also did not compare the TTFC
may be superior the long-term tolerability and ocular surface health between these
without BAK to travoprost without BAK, or to other fixed combinations. It should be noted
medications and travoprost/TTFC may differ
that
because latanoprost and LTFC contain the highest concentration of BAK (0.02%), whereas
between medications there might be a difference between what is statistically
travoprost and TTFC now contain the preservative polyquaternium-1. This
significant and what is clinically significant. As with all similar studies, it remains unclear if the
hypothesis requires further verification.
detected IOP and ocular surface differences are
This trial further supports the need to routinely assess ocular surface and tear film
clinically significant. Nevertheless, a 24-h efficacy difference may be of greater value
parameters in glaucoma patients in addition to
than a difference based on a single, or even a
when
evaluating
efficacy
vs. LTFC
differences
Adv Ther
few IOP readings. More information is needed
consulting support from Allergan and Thea. MY
on the specific role of 24-h parameters (e.g.,
Kahook has received research support from Alcon, Allergan, Bausch & Lomb and
peak 24-h IOP) upon glaucoma progression [30]. In addition, the use of three different metrics
consulting support from Alcon, Allergan, and
for evaluation of the ocular surface bolsters the findings and lends credence to the likelihood of
Aerie. He is stock shareholder in Shape Ophthalmics, Shape Tech, and Clarvista. IC
clinical
Voudouragkaki, E Paschalinou, AB Haidich, T Giannopoulos, ND Dragoumis and AK Makridis
significance.
Evaluation
with
questionnaires that focus on patient report outcomes should be performed in future studies as an additional metric that would be of value. More research is needed to further
declare no conflicts of interest.
clarify the best FC therapy and to delineate the
Compliance with ethics guidelines. All procedures followed were in accordance with
optimal stepwise therapy to treat ocular hypertension and open-angle glaucoma.
the ethical standards of committee on human
the responsible experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and 2008. Informed consent was
CONCLUSION The present investigation established that in open-angle glaucoma patients insufficiently controlled
on
branded
latanoprost
obtained from all patients for being included in the study.
TTFC
without BAK provided superior 24-h efficacy compared with LTFC containing BAK. This
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