Clinical science
`
`1Glaucoma Unit, 1st University
`Department of Ophthalmology,
`Aristotle University, AHEPA
`Hospital, Thessaloniki, Greece
`2Centre for the Study of
`Glaucoma, University of
`Brescia, Brescia, Italy
`3Ophthalmology Department,
`University of Ioannina,
`Ioannina, Greece
`4Department of Ophthalmology
`and Visual Science, Yale Eye
`Center, Yale University School
`of Medicine, New Haven,
`Connecticut, USA
`5IRCCS Istituto di Ricerche
`Farmacologiche Mario Negri,
`Milan, Italy
`6Department of Hygiene,
`Aristotle University,
`Thessaloniki, Greece
`
`Correspondence to
`Professor A G P Konstas,
`Glaucoma Unit, 1st University
`Department of Ophthalmology,
`Aristotle University, AHEPA
`Hospital, 1 Kyriakidi Street,
`Thessaloniki 546 36, Greece;
`konstas@med.auth.gr
`
`Received 24 December 2012
`Revised 12 March 2013
`Accepted 7 April 2013
`Published Online First
`16 May 2013
`
`▸ http://dx.doi.org/10.1136/
`bjophthalmol-2013-303528
`
`To cite: Konstas AGP,
`Quaranta L, Katsanos A,
`et al. Br J Ophthalmol
`2013;97:1510–1515.
`
`Twenty-four hour efficacy with preservative free
`tafluprost compared with latanoprost in patients
`with primary open angle glaucoma or ocular
`hypertension
`Anastasios G P Konstas,1 Luciano Quaranta,2 Andreas Katsanos,3 Ivano Riva,2
`James C Tsai,4 Theodoros Giannopoulos,1 Irini C Voudouragkaki,1 Eleni Paschalinou,1
`Irene Floriani,5 Anna-Bettina Haidich6
`
`ABSTRACT
`Aim To compare 24 h intraocular pressure (IOP) control
`obtained with preservative free (PF) tafluprost 0.0015%
`versus branded preservative containing latanoprost
`0.005% administered as first choice monotherapy in
`patients with primary open angle glaucoma (POAG) or
`ocular hypertension (OHT).
`Methods This prospective, observer-masked, crossover
`study included consecutive newly diagnosed patients
`with POAG or OHT, and baseline IOP between 24 and
`33 mm Hg. Qualifying patients underwent baseline
`untreated 24 h IOP monitoring in habitual positions,
`with Goldmann tonometry at times 10:00, 14:00, 18:00
`and 22:00, and Perkins supine tonometry at times 02:00
`and 06:00. They were then randomised to either
`latanoprost or tafluprost, administered in the evening, for
`3 months and then switched to the opposite therapy for
`another 3 months. 24 h monitoring was repeated at the
`end of each treatment period.
`Results 38 patients completed the study. Mean
`untreated 24 h IOP (24.9 mm Hg) was significantly
`reduced with both prostaglandins (p<0.001). Tafluprost
`demonstrated similar mean 24 h efficacy compared with
`latanoprost (17.8 vs 17.7 mm Hg; p=0.417).
`Latanoprost demonstrated significantly better 24 h
`trough IOP (15.9 vs 16.3 mm Hg; p=0.041) whereas
`tafluprost provided significantly lower 24 h IOP
`fluctuation (3.2 vs 3.8 mm Hg; p=0.008). No significant
`difference existed between the two prostaglandins for
`any adverse event.
`Conclusions PF tafluprost achieved similar 24 h IOP
`reduction to branded latanoprost. The current study
`highlights the importance of complete assessment of
`efficacy over 24 h.
`Clinical trials registration NCT01162603.
`
`INTRODUCTION
`Prostaglandin analogues have become a popular
`firstline therapeutic option for the decrease in
`intraocular pressure (IOP) in patients with open
`angle glaucoma or ocular hypertension (OHT) due
`to their superior 24 h potency, convenient dosing
`and favourable
`systemic
`safety profile. Until
`recently, all available prostaglandin analogues were
`formulated as preservative containing solutions.
`Preservatives used in ophthalmic solutions, and in
`particular benzalkonium chloride (BAK), have been
`associated with ocular tissue toxicity and decreased
`
`thus potentially limiting
`long term tolerability,
`adherence and undermining the success of chronic
`therapy.1–5 Long term tolerability has
`medical
`emerged as a key issue for the successful manage-
`ment of glaucoma patients. Furthermore, there is
`growing recognition that preservatives are asso-
`ciated with ocular surface disease, which negatively
`impacts on quality of life in glaucoma patients.6
`Tafluprost 0.0015% is a relatively new prosta-
`glandin analogue that first became commercially
`available as a BAK preserved formulation. The first
`studies indicated that the IOP lowering effect of
`preserved tafluprost is comparable, or slightly infer-
`ior, to that of latanoprost7 8 and travoprost.9 More
`recently, a preservative free (PF) formulation of
`tafluprost has been made available in several coun-
`tries worldwide.10–17 The comparative efficacy of
`PF tafluprost versus other prostaglandins needs to
`be further elucidated in controlled prospective
`studies.
`To date, the 24 h efficacy of PF tafluprost has
`not been determined. In order to select the optimal
`initial monotherapy, it is important to compare the
`efficacy of all available prostaglandin analogues
`over 24 h. Therefore, the present investigation eval-
`uated the 24 h IOP efficacy of PF tafluprost
`0.0015% versus BAK preserved branded latano-
`prost 0.005% when both were administered as first
`choice therapy in patients with primary open angle
`glaucoma (POAG) or OHT.
`
`MATERIALS AND METHODS
`The research protocol adhered to the tenets of the
`Declaration of Helsinki and was approved by the
`institutional review boards of
`the participating
`centres. Written informed consent was obtained
`from all participants prior to enrolment. The trial
`was registered at clinicaltrials.gov (NCT01162603).
`Consecutive adults with newly diagnosed POAG
`or OHT were recruited at two participating centres.
`Eligible subjects had to exhibit untreated sitting
`morning IOP, evaluated with Goldmann tonometry,
`of 24–33 mm Hg in the study eye on two separate
`baseline IOP measurements performed at
`time
`10:00 (±1 h). Additional eligibility criteria were
`central corneal thickness between 500 and 600 μm
`and age 39–85 years. In each case, the diagnosis of
`POAG or OHT was made by one of two glaucoma
`specialists (AGPK or LQ) based on the European
`
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`Konstas AGP, et al. Br J Ophthalmol 2013;97:1510–1515. doi:10.1136/bjophthalmol-2012-303026
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`Glaucoma Society criteria following a comprehensive clinical
`examination.
`Exclusion criteria for ophthalmic conditions were corneal or
`other anatomical abnormalities preventing reliable applanation
`tonometry, severe dry eye, use of contact lenses, intolerance or
`contraindication to latanoprost, tafluprost or BAK, history of
`poor medication adherence, laser treatment or ocular surgery of
`any type in the study eye, best corrected visual acuity less than
`Snellen 0.1, mean deviation worse than −12 dB on Humphrey
`24–2 SITA standard perimetry, cup to disc ratio >0.8, or the
`possibility of optic nerve damage and visual function deterior-
`ation due to study procedures according to the investigator’s
`judgment. Exclusion criteria for systemic conditions were preg-
`nancy or lactation, unwillingness to avoid pregnancy and use of
`corticosteroids within the 2 months before enrolment.
`
`Procedures
`The trial was designed as a prospective, randomised, observer
`masked, active controlled, crossover study. First, eligible partici-
`pants were admitted at the participating academic centres and
`underwent baseline untreated 24 h IOP monitoring in habitual
`positions, with Goldmann sitting tonometry, at times 10:00,
`14:00, 18:00 and 22:00, and Perkins supine tonometry at times
`02:00 and 06:00 (±1 h). In each centre, the same calibrated
`Goldmann and Perkins tonometers were used for all measure-
`ments. In all cases, the investigator who performed the IOP
`measurements was blinded to the treatment regimen. Following
`the untreated 24 h IOP curve, participants were randomised to
`either 3 months of chronic therapy with preserved latanoprost
`0.005% solution (Xalatan; Pfizer) dosed in the evening (20:00),
`or to 3 months of therapy with PF tafluprost 0.0015% solution
`(Saflutan; MSD) dosed also in the evening (20:00). Both eyes
`were treated. Instructions regarding correct eyedrop instillation
`and adherence were also provided. At the end of this initial 3
`month treatment period, all participants underwent a treated 24
`h IOP assessment, as previously described. Patients were then
`crossed over to the opposite prostaglandin therapy for another
`3 months and instructions regarding correct eyedrop instillation
`and adherence were repeated. At the end of this final therapy
`period, participants underwent a third 24 h IOP curve with
`identical methodology. A comprehensive clinical examination
`was performed at all visits. Additionally, patient reported com-
`plains and symptoms, as well as investigator noted adverse
`events, were recorded at the end of each treatment period.
`
`Statistics
`The primary efficacy endpoint for this study was mean 24 h
`IOP. Individual time points, peak, trough and fluctuations in 24
`h IOP were evaluated as secondary endpoints. The study had
`80% power to identify a 1.25 mm Hg difference between indi-
`vidual time points and between the mean 24-h IOP, assuming an
`SD of 2.8 mm Hg between the two prostaglandin monother-
`apies. One randomly selected eye per participant was analysed.
`A mixed model was used for the crossover repeated measures
`design to adjust for period and carryover effects.18 Additionally,
`the model was adjusted for the centre effect. A 95% CI was
`constructed for the adjusted difference in means. An intention
`to treat approach was adopted, and subjects were analysed
`according to their randomised group.
`To correct for multiple comparisons at individual time points,
`a Bonferroni adjustment was used. Thus Bonferroni adjusted p
`values are reported for individual time point comparisons. All
`other reported p values are two tailed, with p<0.05 considered
`significant. Mean 24 h IOP fluctuation was defined as the
`
`Clinical science
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`Figure 1 Flowchart of the study participants.
`
`average of the difference between the highest IOP reading
`minus the lowest IOP reading within the 24 h curve for each
`patient. Adverse events were evaluated using a McNemar test.
`All analyses were conducted using IBM-SPSS 20.0.
`
`RESULTS
`Patients
`Thirty-eight of 40 enrolled participants completed the study.
`Their flowchart and demographics are presented in figure 1 and
`table 1. Two study patients (one in each therapy group) were
`lost to follow-up.
`
`Intraocular pressure
`Compared with untreated baseline readings, mean 24 h, peak,
`trough, fluctuation and IOP at individual time points were all
`significantly reduced with both prostaglandin monotherapies
`(p<0.001 for all comparisons) (table 2). When the two prosta-
`glandins were directly compared, PF tafluprost demonstrated
`similar mean 24 h efficacy compared with preserved latanoprost
`(17.8±2.2 vs 17.7±2.1 mm Hg; p=0.417). Furthermore, there
`
`Table 1 Participant demographics
`
`Characteristic
`
`Sex (M/F)
`Age (years)
`CCT (μm)
`Snellen BCVA
`C/D
`MD (dB)
`
`18/20
`66.7 (9.1)
`551 (24.4)
`0.8 (0.2)
`0.6 (0.1)
`5.41 (3.1)
`
`Values are mean (SD) or number.
`BCVA, best corrected visual acuity; CCT, central corneal thickness; C/D, cup/disc ratio;
`MD, mean deviation.
`
`Konstas AGP, et al. Br J Ophthalmol 2013;97:1510–1515. doi:10.1136/bjophthalmol-2012-303026
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`Table 2 Intraocular pressure results at baseline and after treatment with the study medications
`
`IOP measurements (time)
`
`Baseline
`(mean (95% CI))
`
`Latanoprost
`(mean (95% CI))*
`
`PF tafluprost
`(mean (95% CI))*
`
`Adjusted difference (mean (95% CI))*
`
`p Value
`
`06:00
`10:00
`14:00
`18:00
`22:00
`02:00
`Mean 24 h
`Peak 24 h
`Trough 24 h IOP
`24 h fluctuation
`
`25.1 (24.2 to 26.0)
`26.9 (26.1 to 27.7)
`24.1 (23.2 to 25.0)
`23.8 (23.0 to 24.6)
`24.9 (23.8 to 26.0)
`24.4 (23.6 to 25.2)
`24.9 (24.2 to 25.5)
`27.7 (26.8 to 28.6)
`18.3 (17.8 to 18.8)
`3.7 (3.4 to 4.0)
`
`17.5 (16.7 to 18.3)
`17.9 (17.0 to 18.8)
`17.3 (16.5 to 18.2)
`17.3 (16.4 to 18.1)
`17.8 (16.9 to 18.8)
`18.0 (17.2 to 18.9)
`17.7 (16.9 to 18.4)
`19.7 (18.8 to 20.5)
`15.9 (15.2 to 16.6)
`3.8 (3.2 to 4.3)
`
`17.5 (16.8 to 18.4)
`18.4 (17.5 to 19.3)
`17.8 (17.0 to 18.6)
`17.7 (16.8 to 18.5)
`17.6 (16.6 to 18.5)
`17.6 (16.8 to 18.4)
`17.8 (17.0 to 18.5)
`19.5 (18.6 to 20.3)
`16.3 (15.6 to 17.0)
`3.2 (2.6 to 3.7)
`
`0.00 (−0.44 to 0.44)
`−0.50 (−1.03 to 0.03)
`−0.47 (−1.05 to 0.10)
`−0.39 (−0.88 to 0.09)
`0.24 (−0.20 to 0.67)
`0.45 (−0.07 to 0.96)
`−0.11 (−0.39 to 0.17)
`0.24 (−0.18 to 0.66)
`−0.39 (−0.78 to −0.01)
`0.63 (0.18 to 1.08)
`
`1.000†
`0.372†
`0.624†
`0.648†
`1.000†
`0.516†
`0.416
`0.277
`0.041
`0.008
`
`Depicted p values refer to comparison between latanoprost and PF tafluprost. All comparisons between baseline and latanoprost or preservative free tafluprost were statistically
`significant (p<0.001).
`*Adjusted for period, carryover effect and centre.
`†Bonferroni adjusted p values.
`IOP, intraocular pressure; PF, preservative free.
`
`were no statistically significant differences for individual time
`points (table 2, figure 2).
`With regard to other 24 h IOP characteristics, PF tafluprost
`demonstrated significantly lower 24 h IOP fluctuation (3.2±1.7
`vs 3.8±1.8 mm Hg; p=0.008). In contrast,
`latanoprost pro-
`vided significantly lower 24 h trough IOP (15.9±2.1 vs 16.3
`±2.2 mm Hg; p=0.041). There was no significant difference in
`24 h peak IOP between the two prostaglandins (19.7 vs
`19.5 mm Hg, respectively; p=0.277) (table 2).
`
`Adverse events
`No serious adverse events and no adverse event related with-
`drawal occurred during the study. In addition, there was no sig-
`nificant difference between the two agents for any adverse event
`
`Figure 2 Intraocular pressure (mean±95% CI) at each individual time
`point and for the 24 h pressure at baseline (gray solid line), in the
`latanoprost (solid black line) and preservative free (Pf) tafluprost (black
`dotted line) treatment groups.
`
`(table 3). Overall, the number of adverse events with latanoprost
`and PF tafluprost treatment were 22 and 14, respectively. The
`most frequently encountered adverse event was ocular hyper-
`aemia (n=6 during latanoprost treatment period; n=5 during
`PF tafluprost treatment period).
`
`DISCUSSION
`The present study is the first to evaluate the 24 h efficacy of PF
`tafluprost compared with branded preserved latanoprost as a
`first choice monotherapy in newly diagnosed patients with
`POAG or OHT. The results showed identical mean IOP lower-
`ing over 24 h (mean 24 h IOP difference was only 0.1 mm Hg).
`Greater 24 h trough IOP reduction was observed during latano-
`prost therapy while significantly lower 24 h IOP fluctuation was
`documented with PF tafluprost.
`Tafluprost, a fluorinated analogue of prostaglandin F2a, is a
`potent and selective agonist of the human prostanoid FP recep-
`tor with a reported 12 fold greater affinity for the FP receptor
`than latanoprost.19 It was first introduced in Japan in 2008 as a
`BAK containing multidose formulation, and in Germany in
`2008 with approval for both a preserved and a PF tafluprost for-
`mulation.20 21 Currently, however, throughout the rest of the
`world, only the PF formulation is marketed.20 21 Initial reports
`in healthy eyes indicated that preserved tafluprost was at least as
`well tolerated and safe as preserved latanoprost when used over
`short periods.22–25 Furthermore, it was demonstrated that the
`efficacy of preserved tafluprost was comparable with that of pre-
`served latanoprost in healthy volunteers.22–26
`Due to its short marketing history, there are limited long term
`efficacy data for preservative containing tafluprost in patients
`with glaucoma or OHT. Two studies have reported that pre-
`served tafluprost attained a mean diurnal IOP reduction of
`28.6% and 29.1%, respectively, from untreated baseline.8 9 A
`third short term phase II study7 reported that the mean IOP
`change from baseline of preserved tafluprost was similar to that
`of branded latanoprost after 42 days (−9.7 mm Hg for tafluprost
`and −8.8 mm Hg for latanoprost). In a 24 month, parallel,
`double blind, multicenter study performed by Uusitalo et al,8
`tafluprost lowered daytime IOP by 6–8 mm Hg (27–31%) com-
`pared with 7–9 mm Hg (29–35%) with branded latanoprost. In
`this study, after 24 months of therapy, the mean decrease in IOP
`from baseline was reported to be somewhat superior with lata-
`(−7.7 mm Hg, 32.2%)
`noprost
`than preserved tafluprost
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`Table 3 Adverse events of the study medications
`
`Adverse event
`
`Ocular hyperaemia
`
`n (%)
`Stinging
`
`n (%)
`Foreign body sensation
`
`n (%)
`Blurring of vision
`
`n (%)
`Watering
`
`n (%)
`Itchiness
`
`n (%)
`Burning
`
`n (%)
`Ocular ache
`
`n (%)
`
`PF, preservative free.
`
`Latanoprost
`
`PF tafluprost
`Yes
`
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`Yes
`No
`Total
`
`2
`3
`5 (13.2)
`1
`3
`4 (10.5)
`0
`2
`2 (5.3)
`1
`0
`1 (2.6)
`1
`0
`1 (2.6)
`0
`0
`0 (0)
`0
`0
`0 (0)
`0
`1
`1 (2.6)
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`No
`
`4
`29
`33 (87.8)
`3
`31
`34 (89.5)
`2
`34
`36 (94.7)
`3
`34
`37 (97.4)
`1
`36
`37 (97.4)
`2
`36
`38 (100)
`2
`36
`38 (100)
`0
`37
`37 (97.4)
`
`n (%)
`Total
`
`6 (15.8)
`32 (84.2)
`38 (100)
`4 (10.5)
`34 (89.5)
`38 (100)
`2 (5.3)
`36 (94.7)
`38 (100)
`4 (10.5)
`34 (89.5)
`38 (100)
`2 (5.3)
`36 (94.7)
`38 (100)
`2 (5.3)
`36 (94.7)
`38 (100)
`2 (5.3)
`36 (94.7)
`38 (100)
`0 (0)
`38 (100)
`38 (100)
`
`p Value
`
`1.000
`
`1.000
`
`1.000
`
`0.250
`
`1.000
`
`0.500
`
`0.500
`
`1.000
`
`(−7.1 mm Hg, 29.1%).8 This study demonstrated that the non-
`inferiority criterion for tafluprost was reached with ANOVA and
`almost
`reached with ANCOVA for
`all
`daytime
`IOP
`measurements.
`There is convincing evidence suggesting that PF tafluprost
`exhibits comparable efficacy to preserved tafluprost. First, a
`pharmacokinetic study27 did not detect a difference in systemic
`bioavailability between the two formulations after 8 days.
`Second, Hamacher et al10 evaluated the IOP lowering equiva-
`lency between the two formulations and observed an overall
`efficacy difference of only 0.01 mm Hg (95% CI −0.46 to 0.49;
`p=0.96) at 4 weeks.
`Several open label non-interventional studies have examined
`the efficacy and tolerability of PF tafluprost in naïve16 or previ-
`ously treated patients with open angle glaucoma or OHT, who
`were either poorly controlled or had tolerability issues with
`other medications.12–15 28 Overall, these investigations have
`reported a mean diurnal IOP reduction of 22.9–32.1% from
`untreated baseline.13 16 28 Although these studies do not
`provide controlled observations, they indicate that PF tafluprost
`has almost comparable efficacy to latanoprost and will likely
`benefit patients facing tolerability problems with other medica-
`tions. Similar IOP results were reported in a prospective investi-
`gator masked study.29 In a more recent regulatory double
`masked comparative trial, Chabi et al11 demonstrated in patients
`with open angle glaucoma or OHT that PF tafluprost was gener-
`ally well tolerated and was not inferior to PF timolol adminis-
`tered twice daily.
`The current trial investigated for the first time the 24 h IOP
`efficacy provided by a PF tafluprost versus branded latanoprost,
`a well established initial therapy of choice. Both agents provided
`
`clinically meaningful 24 h IOP reduction from baseline (28.5%
`for PF tafluprost and 29.3% for latanoprost). These results are
`comparable with the reported 24 h efficacy of the three previ-
`ously available prostaglandin analogues, as
`reported in a
`meta-analysis by Stewart et al (24–29%).30 A 24 h IOP curve
`may better delineate IOP characteristics and facilitate glaucoma
`management. Thus our study provides evidence to optimise
`selection between available prostaglandin analogues as initial
`therapy.
`This efficacy profile would not have been detected without a
`complete 24 h IOP evaluation. Thus the present study highlights
`the value of a complete efficacy assessment over 24 h in deter-
`mining the true IOP lowering characteristics of a novel antiglau-
`coma medication. In a previous 24 h IOP study in 30 healthy
`Japanese subjects, Mochizuki et al compared the efficacy of
`tafluprost and branded latanoprost.25 Apart from the differences
`in study populations and despite several methodological differ-
`ences (timing of drug administration, duration of therapy and
`different time of IOP measurements), it is interesting to note the
`similarities in findings between the two 24 h studies. The
`Mochizuki study25 also observed a mean 24 h difference of
`0.1 mm Hg and the two prostaglandins exhibited similar ten-
`dencies to preferentially lower IOP during the day (latanoprost)
`and night
`(tafluprost).
`In contrast with the present study,
`however, these IOP lowering differences reached statistical sig-
`nificance in the Japanese study.
`In the present study, PF tafluprost achieved significantly less
`24 h IOP fluctuation than branded latanoprost. Twenty-four
`hour IOP fluctuation and 24 h peak IOP have emerged in some
`24 h studies31–33 as potential risk factors for glaucoma progres-
`sion. This has brought attention to the 24 h IOP lowering
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`Konstas AGP, et al. Br J Ophthalmol 2013;97:1510–1515. doi:10.1136/bjophthalmol-2012-303026
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`profiles with topical medications.34 35 Based on the notion that
`increased circadian IOP fluctuation may be harmful for some
`glaucoma patients,
`it may be clinically desirable to opt for
`favourable 24 h IOP characteristics, such as low 24 h IOP fluc-
`tuation and low 24 h peak IOP. However, the potential long
`term clinical benefit of improved 24 h IOP control requires
`further elucidation.
`The current study was a short term monotherapy study and it
`did not have sufficient power to determine long term safety or
`tolerability. Both medications were well
`tolerated without
`serious adverse events or adverse event related study withdra-
`wals. There was no significant difference in the incidence of
`individual adverse events. Nevertheless,
`the adverse events
`observed in our trial may not accurately portray the true long
`term tolerability profile of these agents.
`Glaucoma requires lifelong treatment and thus long term toler-
`ability is an issue of clinical
`importance. Cumulative evidence
`shows that long term topical treatment with antiglaucoma medica-
`tions leads to the manifestation, or exacerbation, of symptoms and
`signs of ocular surface disease.3 36 As a consequence, patient’s
`quality of life can decline and adherence may be adversely
`affected.37–42 There is convincing evidence that long term exposure
`to preservatives, and especially BAK, can cause histopathological
`changes in ocular tissues that can adversely affect the success of sub-
`sequent glaucoma surgery.4 5 PF medications have become increas-
`ingly popular in glaucoma due to their reduced potential for ocular
`toxicity with presumed enhanced tolerability and improved adher-
`ence.1 38 43 44 The observation of similar drug efficacy versus avail-
`able preservative containing treatment options may encourage
`greater use of PF medications. On the other hand, more evidence is
`needed to confirm the long term potential benefits accrued with
`the use of PF medications, such as improved medication adherence
`leading to better long term visual outcomes. By demonstrating
`comparable 24 h efficacy to branded latanoprost, PF tafluprost can
`be considered as a reasonable firstline choice in glaucoma therapy.
`
`Contributors The study was designed by AGPK and LQ. Data collection was
`performed by IR, A-BH, TG, ICV and EP. Data analysis and interpretation was
`performed by IF, A-BH, AGPK and LQ. The manuscript was drafted by AGPK, AK
`and IR. Critical revision of the manuscript was done by AGPK, LQ and JCT. All
`authors read and approved the final version of the article.
`Competing interests AGPK is a consultant for Alcon, Allergan, MSD and Nicox.
`AGPK has received honoraria or travel reimbursement from Alcon, Allergan and
`Pfizer. LQ has received honoraria or travel reimbursement from Alcon, Allergan,
`MSD, Thea Farmila, and Bausch and Lomb. AK has received travel reimbursement
`from Alcon and MSD. IR has received travel reimbursement from Alcon and MSD.
`Ethics approval The study was approved by the institutional review board of the
`Medical School of Aristotle University, Thessaloniki, Greece, and the institutional
`review board of the Clinica Oculistica, University of Brescia, Brescia, Italy.
`Provenance and peer review Not commissioned; externally peer reviewed.
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