Clinical Ophthalmology
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`Latanoprost in the treatment of glaucoma
`
`Albert Alm
`Department of Neuroscience,
`Ophthalmology, University Hospital,
`Uppsala, Sweden
`
`Correspondence: Albert Alm
`Department of Neuroscience
`(Ophthalmology), Uppsala University
`Biomedical Centre, Husargarten 3,
`Se-751 24, Uppsala, Sweden
`Tel +46 186 115 135
`email albert.alm@akademiska.se
`
`Abstract: Prostaglandins are approved by the European Glaucoma Society guidelines as first-
`line treatment for glaucoma. This review focuses on latanoprost, an ester prodrug of prostaglandin
`(PG) F2α, which was the first of the currently available topical PGF2α analogs to be launched for
`glaucoma or ocular hypertension and which still accounts for the majority of prescriptions. It
`is better absorbed than the parent compound through the cornea, and peak concentration of the
`active drug is in the aqueous humor 1–2 hours after topical dosing (15–30 ng/mL). Metabolism
`occurs mainly in the liver. Latanoprost (0.005%) has been very well studied in clinical trials and
`meta-analyses that show it to be generally as effective as the other PG analogs (bimatoprost,
`travoprost, and tafluprost) and more effective than timolol, dorzolamide, and brimonidine.
`Latanoprost has good short- and long-term safety and tolerability profiles. In common with
`other prostaglandins, it lacks systemic effects, but can cause ocular adverse events such as
`conjunctival hyperemia, pigmentation of the iris, periocular skin or eyelashes, hypertrichosis,
`and ocular surface effects or irritation. Latanoprost is significantly better tolerated than either
`bimatoprost or travoprost. Patients treated with latanoprost have better compliance and persist
`with therapy longer than those that are given other drugs. An improved formulation of latanoprost
`without the preservative benzalkonium chloride has recently been developed. It is as effective
`as conventional latanoprost, has a lower incidence of hyperemia, and can be stored at room
`temperature. In conclusion, latanoprost has the best efficacy–tolerability ratio of the PG analogs
`available for glaucoma treatment, and has good compliance and persistence. These factors should
`be improved further by the recent development of preservative-free latanoprost.
`Keywords: prostaglandin, intraocular pressure, ocular hypertension, hyperemia, glaucoma,
`latanoprost
`
`Introduction
`One of the major risk factors for the development and progression of glaucoma is
`elevated intraocular pressure (IOP).1,2 Topical prostaglandins (PGs), with their pow-
`erful ocular hypotensive effect (which is mainly the result of increasing uveoscleral
`outflow), are therefore an important treatment option for glaucoma.3
`PGs/prostamides are approved as the first-line treatment for glaucoma in the
` European Glaucoma Society guidelines.4 The main reasons for this choice include their
`IOP-lowering efficacy, their lack of relevant systemic side effects, their requirement
`for only once-daily dosing, and their good overall tolerability profile.
`This review focuses on the use of latanoprost, an ester prodrug of prostaglandin
`F2α (PGF2α), in the management of glaucoma. Latanoprost was the first of the cur-
`rently available topical PGF2α analogs to be launched for glaucoma treatment, and it
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`still accounts for the majority of PG-analog prescriptions
`due to its good efficacy–tolerability profile. It was also the
`first PG analog to have generics developed, and an improved
`formulation has recently been produced without benzalko-
`nium chloride (BAK).
`Publications to be considered for inclusion in this
`review were selected in PubMed using the search terms
`“latanoprost”, “glaucoma/drug therapy*[MeSH]”, “meta-
`analysis[publication type]”, “comparative study[publication
`type]”, and “patient compliance[MeSH]”. More recent stud-
`ies that were yet to be indexed were identified from ad hoc
`searches and the author’s own database.
`
`Prostaglandins
`PGs were initially isolated from prostate tissue in 1935.5
`They are now known to be produced by almost all nucle-
`ated cells. They are a family of lipid compounds that are
`derived enzymatically from essential fatty acids,6 with each
`one containing 20 carbon atoms, including a 5-carbon ring.
`They act locally as autocrine or paracrine mediators with a
`wide range of effects throughout the body.
`
`effects of prostaglandins
`in ophthalmology and development
`for glaucoma treatment
`Several PGs are naturally synthesized in the iris and ciliary
`body and are released following trauma to the eye.7 One of the
`PGs that is released is PGF2α, which is now known to cause a
`powerful reduction in IOP. Animal studies have shown that this
`hypotensive activity is mainly due to an enhanced uveoscleral
`outflow, with minor effects on trabecular outflow and aqueous
`flow.3 One potential mechanism behind this enhanced outflow
`is the regulation of matrix metalloproteinases and remodeling
`of the extracellular matrix, which changes the permeability
`of tissues associated with the outflow pathways resulting in
`alterations in outflow resistance and/or outflow rates.3
`Discovery of the effect of PGs on IOP led to the devel-
`opment of PG analogs as a potential glaucoma treatment.
`Initial research focused on PGF2α. The initial steps included
`esterification of the carboxylic acid of PGF2α to improve
`corneal penetration and reduce side effects.8 One of the most
`promising of these prodrugs of PGF2α was the isopropyl ester
`form. However, despite having excellent pharmacokinetic
`properties, it still caused unacceptable foreign-body sen-
`sation and conjunctival hyperemia.9,10 Modification of the
`omega chain of this molecule led to improved selectivity for
`PGF receptors and a greatly improved tolerability profile.11
`This molecule was subsequently known as latanoprost and
`
` underwent clinical development as a treatment for glaucoma.
`Later studies in knock-out mice showed that intact PGF and
`PGE3 receptors were necessary for IOP reduction.12,13
`
`Latanoprost
`Latanoprost (0.005%) was launched in 1996 and was the
`first of the currently available topical PGF2α analogs on the
`market for glaucoma treatment. Later introductions included
`travoprost (0.004%), bimatoprost (0.03%), and, most recently,
`tafluprost (0.0015%). Latanoprost still accounts for approxi-
`mately 65% of PG-analog prescriptions.
`
`Pharmacokinetics
`Latanoprost is an esterified prodrug of PGF2α and, as such,
`is more lipophilic than the parent compound.11 This means
`that it is better absorbed through the cornea, where it is
`undergoes hydrolysis to latanoprost acid. In adult humans,
`peak concentration of the active drug was detected in the
`aqueous humor 1–2 hours after topical dosing and amounted
`to 15–30 ng/mL.14 In the systemic circulation, the peak con-
`centration occurred after 5 minutes and reached a level of
`53 pg/mL. The elimination half-life was 2–3 hours from the
`eye and 17 minutes from the circulation. The median peak
`plasma concentration and area under the concentration-time
`curve after adult dosing were found to be higher in infants
`less than 3 years old than in older subjects, primarily due to
`lower body weight and smaller blood volume; but latanoprost
`acid was rapidly eliminated in all age groups.15
`Metabolism mainly occurs in the liver where latanoprost
`acid undergoes beta-oxidation to 1,2-dinor and 1,2,3,4-tetra-
`nor latanoprost acid, the main metabolites of latanoprost.14
`The majority of the dose is excreted via the urine (88%) with
`the remainder being recovered in the feces.
`The reduction in IOP seen with latanoprost begins after
`3–4 hours, reaches a maximum after 8–12 hours, and is
`maintained for at least 24 hours.16
`
`Efficacy
`Latanoprost has been very well studied, with numerous
`publications of clinical trials, meta-analyses, and reviews.17
`Initial studies showed once-daily topical latanoprost (0.005%)
`to be safe and effective in the short- and long-term treat-
`ment of glaucoma or ocular hypertension. A review of three
`masked multicenter Phase III studies in 829 patients with
`elevated IOP in Scandinavia, the USA, and the UK showed
`that 6 months treatment with latanoprost reduced IOP by
`35%, if given in the evening, and by 31%, if given in the
`morning.18 Conjunctival hyperemia and darkening of the
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`Latanoprost in glaucoma
`
`iris color were the only notable side effects. Subsequently,
`darker and longer eye lashes were also reported.19 Later open
`studies conducted over 2 years reported that the reduction in
`IOP was maintained during long-term treatment and no other
`clinically significant side effects developed.20,21 Similarly
`good results were reported in 5-year studies, although the
`main focus was on safety and tolerability.22–24
`
`Latanoprost versus other prostaglandins
`Bimatoprost
`Latanoprost has been extensively compared with bimato-
`prost in randomized controlled trials. One of the largest of
`these involved 411 patients with open-angle glaucoma or
`ocular hypertension treated for 12 weeks with latanoprost,
`bimatoprost, or travoprost.25 At the end of the study, there
`was a significant (P,0.001) reduction in 8 am IOP in all
`groups. The estimated mean reduction was 8.6±0.3 mmHg
`with latanoprost and 8.7±0.3 mmHg with bimatoprost. The
`adjusted differences in mean IOP reductions at 8 am also
`showed equivalence between latanoprost and bimatoprost
`(0.13 mmHg; 95% confidence interval [CI] 0.84–0.58).
`No significant differences were observed between the two
`treatments in IOP reduction at noon, 4 pm, and 8 pm, or in
`changes in mean diurnal IOP levels. A subsequent study
`in 48 patients with open-angle glaucoma also failed to find
`statistically significant differences between latanoprost and
`bimatoprost in IOP reductions at 8 am, 10 am, 1 pm, 4 pm,
`8 pm, 11 pm, and 3 am after 8 weeks of treatment.26
`One double-blind, crossover study focused on circadian
`IOP in 44 patients with open-angle glaucoma or ocular
`hypertension.27 After 1 month, latanoprost and bimatoprost
`were equally effective in reducing IOP, with no significant
`differences between them, and the authors concluded that
`they were both powerful agents in controlling around-the-
`clock IOP. A more recent crossover study assessed IOP
`reduction in 54 patients with angle-closure glaucoma treated
`with latanoprost or bimatoprost for 6 weeks.28 At the end of
`treatment, mean IOP was reduced by 8.4±3.8 mmHg with
`latanoprost and 8.9±3.9 mmHg with bimatoprost, with no
`significant differences between the groups.
`Some discrepancies have been reported in other stud-
`ies, however, with bimatoprost being significantly more
`effective than latanoprost at certain time points. An older
`study in 232 patients with glaucoma or ocular hyperten-
`sion found that bimatoprost reduced IOP significantly
`more than latanoprost at noon (P=0.021), but not at 8 am
`(primary efficacy parameter), 4 pm, or 8 pm after 3 months
`of treatment.29 In another double-blind study, no statistically
`
`significant differences in IOP reduction were seen between
`latanoprost (20%–31%) and bimatoprost (26%–34%) at
`any time point measured on day 14 or 29 in 64 patients with
`open-angle glaucoma or ocular hypertension.30 However,
`on day 29, bimatoprost had a significantly (P=0.0378)
`larger area under the curve for IOP reduction. Similarly, in
`a 7-week double-blind crossover study in 44 patients with
`open-angle glaucoma, bimatoprost was significantly more
`effective than latanoprost regarding diurnal curve IOP only
`at 6 pm (P=0.008 after Bonferroni correction), but not at
`2 am, 6 am, 10 am, 2 pm, or 10 pm.31 The mean 24 hour
`IOP was also significantly (P=0.01) lower with bimatoprost
`(16.7±2.4 mmHg) than latanoprost (17.3±2.8 mmHg).
` Significant between-group differences in mean IOP reduc-
`tion in favor of bimatoprost were seen at 8 am (P#0.033),
`but not at noon or 4 pm, in a 3-month double-blind trial in
`60 patients with normal tension glaucoma.32 In contrast to
`these findings, a 6-month study involving 269 patients with
`glaucoma or ocular hypertension showed bimatoprost to be
`significantly (P,0.004) more effective than latanoprost in
`reducing IOP at all time points measured (8 am, noon, and
`4 pm).33
`Recent studies have evaluated the effects of latanoprost
`on central corneal thickness, which allows for a more accurate
`estimate of IOP.34,35 Central corneal thickness was signifi-
`cantly (P,0.001) reduced by latanoprost (−14.95±5.04 µm)
`and bimatoprost (−17.00±6.23 µm) after a mean follow-up
`of 17 months in 69 patients with glaucoma or ocular
` hypertension.36 The duration of treatment had no effect, with
`a lack of significant difference being seen in patients treated
`for #6 months as well as those treated for .6 months.
`In summary, the considerable amount of data avail-
`able indicates that latanoprost is equally as effective as
`bimatoprost. Some studies have shown small advantages for
`bimatoprost at certain time points, although there appears to
`be no consistency in these findings. There is some evidence
`to suggest that bimatoprost is hydrolyzed to its free acid,
`a potent PG F receptor agonist, in sufficient levels in the
`aqueous humor to account for at least some of its ability to
`reduce IOP.37
`
`Travoprost
`As with bimatoprost, a considerable number of randomized
`controlled trials have compared travoprost and latanoprost.
`In a 12-week trial in 411 patients with open-angle glau-
`coma or ocular hypertension, the estimated mean reduction
`in 8 am IOP at the end of treatment was 8.6±0.3 mmHg
`with latanoprost and 8.0±0.3 mmHg with travoprost.25 The
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`adjusted differences in mean 8 am IOP reductions also
`showed no significant difference between latanoprost and
`travoprost (0.56 mmHg; 95% CI 0.15–1.26) as did all second-
`ary efficacy parameters. Similarly, a 1-month double-blind
`crossover study in 44 patients with open-angle glaucoma
`or ocular hypertension showed no statistically significant
`difference between latanoprost and travoprost in circadian
`IOP reduction.27 A study in 48 patients with open-angle
`glaucoma reported no significant differences in efficacy
`on overall diurnal IOP between latanoprost and travoprost
`(and bimatoprost that was also included in the study), but
`significantly greater IOP reductions at 8 am and 10 am, but
`not at 1 pm, 4 pm, 8 pm, 11 pm, and 3 am, after 8 weeks of
`treatment with travoprost versus latanoprost or bimatoprost.26
`A more recent double-blind study in 302 patients with open-
`angle glaucoma or ocular hypertension found no statistically
`significant differences in IOP values after 6 weeks’ treatment
`with travoprost (16.1 mmHg) or latanoprost (16.4 mmHg).38
`The pooled changes in IOP from baseline after 1, 2, 4, and
`6 weeks of treatment did, however, show a significant differ-
`ence in favor of travoprost (−8.3 mmHg versus −7.5 mmHg;
`P=0.009). IOP was measured at 5 pm, 20 hours after drug
`administration. In 69 patients with glaucoma or ocular
`hypertension, central corneal thickness was significantly
`(P,0.001) reduced by both latanoprost (−14.95±5.04 µm)
`and travoprost (−15.73±3.25 µm) after a mean follow-up of
`17 months.36
`The overall results from randomized controlled studies
`therefore show that latanoprost is as effective as travoprost.
`Further evidence is available from meta-analyses that will
`be discussed later in the review.
`
`Tafluprost
`Only two studies have so far been published comparing
`latanoprost with tafluprost. The first of these was a random-
`ized double-blind Phase II trial comparing latanoprost with
`tafluprost treatment for 42 days in 38 patients with open-angle
`glaucoma, exfoliation glaucoma, or ocular hypertension.39
`There was no significant difference between the treatments,
`with maximum IOP reduction occurring after 7 days and
`being maintained on day 42 and day 43. A subsequent
`randomized double-blind Phase III study was considerably
`larger, enrolling 533 patients with open-angle glaucoma or
`ocular hypertension.40 Treatment was given with latanoprost
`or tafluprost for 24 months. Both treatments substantially
`reduced IOP, with a 7.7 mmHg decrease with latanoprost
`and 7.1 mmHg decrease with tafluprost after 24 months. The
`effect of latanoprost was somewhat larger, but non-inferiority
`
`of tafluprost over all diurnal IOP measurements was shown
`with analysis of variance and almost reached with analysis
`of covariance (upper limits of the 95% CIs 1.38 and 1.52,
`respectively). The non-inferiority limit was 1.5 mmHg. In this
`study, there were 18 discontinuations for lack of efficacy on
`tafluprost compared with only three on latanoprost.
`Overall, the relatively restricted amount of data currently
`available suggests no clinically significant difference in
`efficacy between latanoprost and tafluprost, although more
`studies are required.
`
`Results of meta-analyses
`A number of recent meta-analyses of randomized controlled
`trials have compared latanoprost with bimatoprost and tra-
`voprost in patients with glaucoma or ocular hypertension
`(Table 1);41–49 to date, only one meta-analysis has included
`a comparison with tafluprost (Table 1).50
`One of the largest of these analyses was performed by
`Eyawo et al, in 2009,41 who assessed randomized single- or
`double-blind head-to-head comparisons of latanoprost,
`bimatoprost, and travoprost of at least 3 months’ duration.
`Data were included from a total of 15 studies (up to
`12 months’ duration), five of which had more than two treat-
`ment arms. Thus, nine trials compared latanoprost and travo-
`prost (n=1,098), eight compared travoprost and bimatoprost
`(n=714), and eight compared latanoprost and bimatoprost
`(n=943). The IOP-lowering effect at study conclusion was
`expressed by the weighted mean difference across groups.
`This was −0.24 mmHg (95% CI −0.87–0.38) for travoprost
`versus latanoprost and 0.73 mmHg (95% CI 0.10–1.37) for
`latanoprost versus bimatoprost. Response rates were also
`compared between studies that had similar definitions of
`response; three trials comparing latanoprost to bimatoprost
`found a pooled relative risk of 0.98 (95% CI 0.76–1.26,
`P=0.87) and two comparing travoprost to latanoprost found
`a pooled relative risk of 1.15 (95% CI 0.99–1.33, P=0.07).
`A study specifically designed to identify the nonresponder
`rate during latanoprost treatment found that only 14 of 340
`newly diagnosed patients failed to respond to latanoprost.51
`Another large analysis was conducted in 2010 and
`involved 2,943 patients treated with latanoprost, bimatoprost,
`travoprost, or timolol in 18 studies.42 A mixed treatment
`comparison was used to assess the relative efficacy of the
`treatments in terms of absolute on-treatment IOP at 3 months.
`Latanoprost and bimatoprost produced signif icantly
`(P,0.05) lower on-treatment IOP compared with timolol.
`There was no significant difference between latanoprost and
`bimatoprost.
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`Latanoprost in glaucoma
`
`Table 1 Summary of meta-analyses of randomized controlled trials for the effect of latanoprost and other PG analogs on iOP in
`patients with glaucoma or ocular hypertension
`
`Study
`
`PG analogs
`
`LAT (BAK-preserved
`and preservative-free),
`BiMƒ (BAK-preserved),
`TRA (preserved with BAK,
`polyquaternium-1 or sofzia),
`TAF (BAK-preserved)
`LAT, BiM, TRA
`
`Cucherat
`et al50
`
`Orme
`et al42
`
`Cheng
`et al43
`
`Cheng
`et al44
`
`eyawo
`et al41
`
`Aptel
`et al45
`
`Cheng
`and wei46
`
`Stewart
`et al48
`
`Denis
`et al49
`
`van der
`valk et al47
`
`LAT, BiM, TRA
`
`TiM
`
`LAT, BiM
`
`LAT, BiM, TRA
`
`LAT, BiM, TRA
`
`LAT, BiM
`
`LAT, BiM, TRA
`
`TiM, DOR,
`BRiM
`
`None
`
`None
`
`None
`
`TiM, DOR,
`BRiM
`
`LAT, BiM, TRA
`
`None
`
`LAT, BiM, TRA
`
`TiM, DOR,
`BRiM, BeT,
`BRiN
`
`9
`
`15
`
`15
`
`8
`
`13
`
`11
`
`9
`
`28
`
`1,090
`
`450
`
`2,755
`
`1,610
`
`1,302
`
`386
`
`1,318
`
`6,953 (trough)
`6,841 (peak)
`
`Other drugs
`assessed
`None
`
`Studies
`(n)
`21
`
`Patients
`(n)
`Not
`reported
`
`Duration
`
`Primary efficacy variables
`
`$2 months
`
`Preservative-free LAT significantly
`more effective than TAF regarding iOP
`at 3 months. No significant difference
`between other PG analogs.
`
`TiM
`
`18
`
`2,943
`
`3 months
`
`No significant difference between LAT
`and BiM in on-treatment iOP. LAT and
`BIM significantly more effective than
`TIM. No significant difference between
`TRA and TiM.
`No significant difference in IOP-
`lowering effect from baseline between
`LAT, BiM, TRA, and TiM.
`No significant difference between LAT
`and BiM in iOP reduction from baseline
`at peak, trough, and diurnal assessments.
`3–12 months No significant differences in IOP-
`lowering effects at study conclusion
`between LAT, BiM, and TRA.
`Significantly greater change in IOP with
`BiM than LAT at 8 am, noon, 4 pm, and
`8 pm after 3 months. No significant
`difference between LAT and TRA.
`Percentage reduction in morning iOP
`significantly greater with BIM than LAT
`at 1, 3, and 6 months.
`No significant differences reported in
`the publication between LAT, BiM, and
`TRA in 24-hour IOP efficacy.
`No significant difference between LAT
`and BiM or TRA in iOP levels at the
`end of follow-up.
`No significant difference between LAT,
`BiM, and TRA in iOP change from
`baseline at 1 month.
`
`2 weeks to
`3 months
`
`3 weeks to
`2 months
`
`1–6 months
`
`1–6 months
`
`1–2 months
`
`2 weeks to
`12 months
`
`1–6 months
`
`Note: ƒ0.01% and 0.03%.
`Abbreviations: BAK, benzalkonium chloride; BeT, betaxolol; BiM, bimatoprost (0.03%); BRiN, brinzolamide; BRiM, brimonidine; DOR, dorzolamide; iOP, intraocular
`pressure; LAT, latanoprost (0.005%); PG, prostaglandin; TAF, tafluprost (0.0015%); TIM, timolol; TRA, travoprost (0.004%).
`
`A somewhat smaller analysis in 1,090 patients showed no
`significant difference in the IOP-lowering effects from baseline
`of latanoprost, bimatoprost, travoprost, or timolol in studies
`ranging from 2 weeks to 3 months.43 The difference in absolute
`IOP reduction between PG analogs and timolol ranged from
`0.4–1.6 mmHg for the diurnal curve, 0.9–2.3 mmHg for the
`peak, and 1.3–2.4 mmHg for the trough. For latanoprost, the
`relative IOP reduction was 31% (95% CI 27%–34%) for the
`diurnal curve, 34% (95% CI 31%–37%) for the peak, and 31%
`(95% CI 28%–35%) for the trough. The corresponding values
`were 26% (95% CI 21%–30%), 28% (95% CI 24%–32%),
`and 27% (95% CI 23%–30%) for bimatoprost and 28% (95%
`
`CI 20%–36%), 32% (95% CI 31%–34%), and 31% (95% CI
`29%–33%) for travoprost, respectively.
`Another analysis by Cheng et al in 450 patients with
`normal tension glaucoma reported no statistically significant
`differences between latanoprost and bimatoprost with regard
`to reductions in IOP at peak, trough, and diurnal assessments
`(−20% at all assessments with latanoprost versus 21%, 18%,
`and 17%, respectively, with bimatoprost).44
`The 24-hour IOP lowering efficacy, determined in one
`analysis of 386 patients, showed a statistically significant
`difference between monotherapy treatments with PG ana-
`logs, timolol, brimonidine, and dorzolamide (P=0.026).48
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`As a class, the PG analogs were reported to be the most
`effective, with reductions of 24% with latanoprost, 27% with
`travoprost, and 29% with bimatoprost. The mean reduction
`seen at night-time assessments was significantly lower than
`that at day-time assessments for latanoprost (P=0.031) but
`not for the other PG analogs.
`Two slightly older meta-analyses, each of which
`included more than 1,000 patients, also failed to report
`statistically significant differences in IOP-lowering efficacy
`between latanoprost and bimatoprost or travoprost.47,49 The
`only exception to this was a significantly higher adjusted
`favorable response rate (IOP ,18 mmHg) with bimato-
`prost and travoprost than with latanoprost (incidence rate
`ratio 1.17; 95% CI 1.00–1.35l, P,0.040) in one of the
`analyses.49
`In contrast to these previous meta-analyses, Aptel et al45
`found that latanoprost was significantly less effective than
`bimatoprost, and equally as effective as travoprost, in reduc-
`ing IOP after 3 months in an analysis of 1,610 patients.
`The IOP change from baseline was statistically signifi-
`cantly greater with bimatoprost than latanoprost at all time
`points assessed: 8 am (weighted mean 0.50 mmHg; 95%
`CI 0.01–0.99, P=0.05), noon (weighted mean 1.17 mmHg;
`95% CI 0.68–1.66, P,0.001), 4 pm (weighted mean 0.78
`mmHg; 95% CI 0.26–1.29, P=0.003), and 8 pm (weighted
`mean 0.67 mmHg; 95% CI 0.02–1.32, P=0.04). Data for 8
`pm were available from only three studies compared with
`data for the other time-points which were available from
`five studies. No significant heterogeneity was seen between
`studies.
`Another meta-analysis published in the same year
`and in a similar number of patients reported significant
`advantages of bimatoprost over latanoprost on some, but
`not all, parameters.46 Bimatoprost resulted in statistically
`significantly greater reductions from baseline in morning
`(8 am to 10 am) IOP compared with latanoprost after 1, 3,
`and 6 months (weighted mean differences 2.59%, 2.41%, and
`5.60%, respectively). In contrast, there were no statistically
`significant differences between the treatments in diurnal
`reduction in IOP after 1 and 3 months (no data available at
`6 months) or in the proportion of patients achieving the target
`IOP (#17 mmHg) after 1 or 6 months. At 3 months, more
`patients treated with bimatoprost reached target IOP (pooled
`rate difference 12%; 95% CI 4–21, P=0.004). However, the
`number of studies measuring diurnal IOP reduction and
`achievement of target IOP is small. Interestingly, in a post-hoc
`analysis excluding studies that were not industry- sponsored,
`the difference between bimatoprost and latanoprost in the
`
`reduction in morning IOP remained statistically significant
`only at 6 months.46
`Finally, the most recent meta-analysis has included
`tafluprost in a comparison with latanoprost, including
`preservative-free latanoprost, and the other PG analogs.50
`In contrast to the previous meta-analyses, which involved
`direct pairwise comparisons between treatments, this analy-
`sis used adjusted indirect comparisons in the absence of
`head-to-head trial data. Although the evidence from large
`double-blind randomized trials directly comparing the
`available treatments would clearly be stronger, it has been
`suggested that indirect comparisons are more appropriate
`than pairwise direct comparisons of a limited number of
`treatments as they allow comparison of all the options.50
`A total of 21 trials of $2 months’ duration were included in
`the analysis; five trials comparing more than two treatments
`in a three-arm design were included as a total of ten entries,
`thus yielding 26 pairwise comparisons overall. Where no
`3-month data were available, the data at 2–6 months were
`used, taking the longest period in case of multiple time points.
`The treatments compared were BAK-preserved latanoprost
`(12 trials), preservative-free latanoprost (one trial), BAK-
`preserved bimatoprost 0.03% (15 trials), BAK-preserved
`bimatoprost 0.01% (two trials), BAK-preserved travoprost
`(15 trials), travoprost preserved with polyquaternium-1
`or sofZia (two trials), and BAK-preserved tafluprost (one
`trial). There were no statistically significant differences in
`mean IOP at 3 months between preservative-free latanoprost
`and polyquaternium-1-travoprost (weighted mean differ-
`ence 0.47; 95% CI −0.58–1.51), BAK bimatoprost 0.03%
`(weighted mean difference 0.49; 95% CI −0.13–1.10), BAK
`bimatoprost 0.01% (weighted mean difference 0.19; 95%
`CI −0.60–1.06), BAK travoprost (weighted mean difference
`0.27; 95% CI −0.50–1.03), or BAK latanoprost (weighted
`mean difference 0.40; 95% CI −0.02 to 0.82). However,
`preservative-free latanoprost was statistically significantly
`superior to BAK tafluprost (weighted mean difference −0.90;
`95% CI −1.52 to −0.28). No data were available for sofZia
`travoprost.
`Overall, the majority of meta-analyses have found no
`statistically significant differences between the efficacy of
`latanoprost and that of bimatoprost or travoprost. In a few
`cases, bimatoprost has shown significantly better efficacy
`than latanoprost in some parameters, but the numerical dif-
`ferences tend to be small and the clinical relevance unknown.
`The only meta-analysis that has so far included tafluprost
`reported it to be significantly less effective than preservative-
`free latanoprost.
`
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`Latanoprost in glaucoma
`
`Latanoprost versus other agents
`Timolol
`Latanoprost is more effective than conventional treatment
`with the beta-blocker timolol (0.5%) and has the added advan-
`tage of being required only once-daily, while beta-blockers
`are often applied twice daily. The benefits of latanoprost
`have been demonstrated in numerous clinical trials and
`meta-analyses.
`One meta-analysis involving 829 patients with open-
`angle glaucoma or ocular hypertension enrolled in three
`double-blind randomized studies reported that latanoprost
`reduced mean diurnal IOP by 7.7 mmHg after 6 months,
`compared with 6.5 mmHg with timolol.52 This difference of
`1.2 mmHg was statistically significant (P,0.001). Morning
`IOP was reduced significantly (P,0.001) more at 6 months
`than at 2 weeks in patients treated with latanoprost; no such
`increased efficacy was seen with timolol. In a subanalysis
`of 441 patients with ocular hypertension, mean diurnal IOP
`was reduced to a significantly greater extent with latanoprost
`than timolol (1.1±0.2 mmHg; 95% CI 1.6–0.7, P,0.001).53
`A reduction in diurnal IOP from baseline of $20% was
`achieved in 83% of patients treated with latanoprost and
`62% treated with timolol.
`Analogous findings were seen in another meta-analysis of
`eleven randomized controlled trials, ten of which were double-
`blind, conducted in 1,256 patients with open-angle glaucoma or
`ocular hypertension.54 Both drugs significantly decreased IOP.
`However, the reductions were greater with latanoprost than with
`timolol for assessments performed at 1 week (6.9 mmHg; 95%
`CI 0.4–13.4), 1 month (3.8 mmHg; 95% CI 1.2–6.3), 3 months
`(5.0 mmHg; 95% CI 2.8–7.3), 6 months (5.0 m