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      Preserved Versus Preservative-Free Latanoprost for the Treatment of Glaucoma and Ocular Hypertension: A Post Hoc Pooled Analysis

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          To compare the tolerability and efficacy of a preservative-containing latanoprost (PCL) to a preservative-free formulation of latanoprost (PFL) in patients with open-angle glaucoma or ocular hypertension.


          A pooled analysis was performed of data from five published studies. The primary outcome was tolerability as evaluated by the severity of hyperemia. The secondary objectives were patient tolerance based on a composite ocular surface disease (OSD) score arising from ocular signs and symptoms, patient and investigator satisfaction, and a comparison of IOP-lowering efficacy.


          There were three randomized controlled trials and two observational studies included in the analysis. Conjunctival hyperemia improved significantly in 25.6% (388) of patients switched to the PFL group versus 11.7% (117) of patients switched to the PCL group ( p < 0.001). PFL was two times superior to PCL in reducing ocular hyperemia (odds ratio = 1.96; p < 0.001). The mean OSD composite score decreased by 32.2% in patients switched to the PFL group and 14.1% in the PCL group ( p < 0.001). At 3 months, the mean IOP was similar between groups ( p = 0.312).


          This post hoc pooled analysis confirmed the findings of the individual studies that PFL is as efficacious at reducing IOP as PCL but better tolerated. After switching to PFL, there was twice the improvement in the OSD composite score. PFL was twice as effective at reducing ocular hyperemia and other ocular signs. These findings suggest that PFL has features that may improve patient compliance, thereby potentially improving the IOP-lowering efficacy on a long-term basis.

          Plain Language Summary

          Preservatives in eye drops for glaucoma can cause side effects such as stinging and eye redness. These side effects can cause some patients to reduce the frequency of the drops as prescribed or stop using the drops. One of the most common drops for glaucoma is latanoprost. This study evaluated whether a preservative-free latanoprost (PFL) is as effective as preservative-containing latanoprost (PCL) for reducing eye pressure and whether PFL is better tolerated in patients with glaucoma. The results of the study indicated that PFL was as effective as PCL for reducing eye pressure. The results also indicated PFL was much better at reducing the side effects related to PCL. For example PFL reduces eye redness up to twofold compared to PCL. By reducing the side effects associated with PCL patients may continue to take their glaucoma drops as directed and thereby reduce the risk of vision loss from glaucoma.

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          Most cited references 30

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          Preservatives in eyedrops: the good, the bad and the ugly.

          There is a large body of evidence from experimental and clinical studies showing that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, corneal surface impairment, and the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been described in patients receiving antiglaucoma treatments for long periods of time. However, the mechanisms involved, i.e., allergic, toxic, or inflammatory, as well as the respective roles of the active compound and the preservative in inducing the toxic and/or proinflammatory effects of ophthalmic solutions, is still being debated. The most frequently used preservative, benzalkonium chloride (BAK), has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies. As a quaternary ammonium, this compound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, and damage to deeper ocular tissues. The mechanisms causing these effects have not been fully elucidated, although the involvement of immunoinflammatory reactions with the release of proinflammatory cytokines, apoptosis, oxidative stress, as well as direct interactions with the lipid components of the tear film and cell membranes have been well established. Preservative-induced adverse effects are therefore far from being restricted to only allergic reactions, and side effects are often very difficult to identify because they mostly occur in a delayed or poorly specific manner. Care should therefore be taken to avoid the long-term use of preservatives, otherwise a less toxic alternative to BAK should be developed, as this weakly allergenic but highly toxic compound exerts dose- and time-dependent effects. On the basis of all these experimental and clinical reports, it would be advisable to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those suffering from preexisting or concomitant ocular surface diseases, and those experiencing side effects related to the ocular surface. Indeed, mild symptoms should not be underestimated, neglected, or denied, because they may very well be the apparent manifestations of more severe, potentially threatening subclinical reactions that may later cause major concerns. Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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            Prevalence of ocular surface disease in glaucoma patients.

            To examine the prevalence of ocular surface disease (OSD) in glaucoma patients. This was a cross-sectional study. One hundred and one patients, 18 years of age or older, with open-angle glaucoma or ocular hypertension were consecutively recruited for the study. Patients with a history of use of cyclosporine, steroids, topical ocular nonsteroidal anti-inflammatory drugs, or punctal plugs within the last 3 months were excluded. Each patient completed an Ocular Surface Disease Index questionnaire and underwent evaluation by Schirmer test, corneal and conjunctival lissamine green staining, and tear break-up time. Using Ocular Surface Disease Index for measuring symptoms of dry eye, 60 (59%) patients reported symptoms in at least 1 eye. Severe symptoms were reported by 27 (27%) patients. Schirmer testing showed 62 (61%) patients with decrease in tear production in at least 1 eye. Severe tear deficiency was presented in 35 (35%) patients. Corneal and conjunctival lissamine green staining showed positive results in 22 (22%) patients. None had severe staining. Tear break-up time showed abnormal tear quality in 79 (78%) patients and severe decrease in tear quality was found in at least 1 eye in 66 (65%) patients. Multivariate logistic regression models were used to investigate the association between the number of benzalkonium chloride (BAK)-containing eyedrops and results on the clinical tests of OSD. After adjustment for age and sex, each additional BAK-containing eyedrop was associated with an approximately 2 times higher odds of showing abnormal results on the lissamine green staining test (odds ratio=2.03; 95% confidence interval: 1.06 to 3.89; P=0.034). A large proportion of patients with open-angle glaucoma or ocular hypertension had signs and/or symptoms of OSD in at least 1 eye. The coexistence of OSD and the use of BAK-containing medications may impact vision-related quality of life in this patient population.
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              Should meta-analyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles.

              Some authors argue that systematic reviews and meta-analyses of intervention studies should include only randomized controlled trials because the randomized controlled trial is a more valid study design for causal inference compared with the observational study design. However, a review of the principal elements underlying this claim (randomization removes the chance of confounding, and the double-blind process minimizes biases caused by the placebo effect) suggests that both classes of study designs have strengths and weaknesses, and including information from observational studies may improve the inference based on only randomized controlled trials. Furthermore, a review of empirical studies suggests that meta-analyses based on observational studies generally produce estimates of effect similar to those from meta-analyses based on randomized controlled trials. The authors found that the advantages of including both observational studies and randomized studies in a meta-analysis could outweigh the disadvantages in many situations and that observational studies should not be excluded a priori.

                Author and article information

                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                23 April 2021
                23 April 2021
                : 38
                : 6
                : 3019-3031
                [1 ]GRID grid.14848.31, ISNI 0000 0001 2292 3357, University of Montreal, ; Montreal, Canada
                [2 ]Bellevue Ophthalmology Clinics and Montreal Glaucoma Institute, Montreal, Canada
                [3 ]GRID grid.39381.30, ISNI 0000 0004 1936 8884, Ivey Eye Institute, , Western University, ; London, ON Canada
                [4 ]GRID grid.503422.2, ISNI 0000 0001 2242 6780, Ophthalmology Department, , University of Lille, ; Lille, France
                [5 ]GRID grid.411347.4, ISNI 0000 0000 9248 5770, Hospital Ramón y Cajal, Universidad Alcalá, Ophthalmology, ; Madrid, Spain
                [6 ]Queen Sofia Hospital, Stockholm, Sweden
                [7 ]GRID grid.478149.7, ISNI 0000 0000 9173 726X, Praktikertjänst, ; Stockholm, Sweden
                [8 ]GRID grid.412180.e, ISNI 0000 0001 2198 4166, Department of Ophthalmology, , HEH, Hospices Civils de Lyon, ; Lyon, France
                [9 ]GRID grid.415610.7, ISNI 0000 0001 0657 9752, Quinze-Vingts National Ophthalmology Hospital, ; Paris, France
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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                © Springer Healthcare Ltd., part of Springer Nature 2021


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