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• Benzalkonium chloride (BAK)-preserved anti-glaucoma drops elicits Ocular surface inflammation in naïve glaucomatous patients starting 6 months onwards
  Imran Mohammed, Harminder Singh Dua and Anthony J. King
  Published on: 10 May 2021
• Is it really the same?
  Anastasios G Konstas, Gábor Holló, Andreas Katsanos, Konstadinos G Boboridis, Anna-Bettina Haidich and Gordon N Dutton
  Published on: 12 April 2021

• Published on: 10 May 2021

  Benzalkonium chloride (BAK)-preserved anti-glaucoma drops elicits Ocular surface inflammation in naïve glaucomatous patients starting 6 months onwards

  • Imran Mohammed, Senior Research Fellow University of Nottingham, UK
  • Other Contributors:
    • Harminder Singh Dua, Professor and Honorary Consultant Ophthalmologist
    • Anthony J. King, Honorary Professor and Consultant Ophthalmologist

  Dear Editor:

  We welcome the recent meta-analysis by Hedengran and co-workers in the British Journal of Ophthalmology (BJO).1 This study compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye drops with alternatively preserved (AP) and preservative-free (PF) eye drops. The meta-analysis was conducted on 16 studies that range from 15 days to 6 months of study duration. Change in IOP in BAK vs AP and PF groups was meta-analysed as the primary outcome. Conjunctival hyperaemia, ocular hyperaemia, total ocular adverse effects (AE), and TBUT were also meta-analysed. The authors found no evidence of significant change in IOP and conjunctival hyperaemia between BAK vs AP and PF treatment groups. The authors concluded that the main reason for detecting no clinical differences between the groups was related to the lack of long-term clinical studies on the safety of BAK vs AP and PF eye drops. We are in consensus with Kontas AG et al., comments on the deficiencies of this meta-analysis.

  We do not agree to the conclusion, “BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome”. We would like to direct the authors and readers to our recently published study in the journal, Clinical and Experimental Ophthalmology (CEO), which involved the randomised evaluation of the inflammatory effects of PF vs BAK and PF vs polyquad (PQ)-preserved eye drops in naïve glaucomatous patients over the period of 24 months.2 We p...

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  Dear Editor:

  We welcome the recent meta-analysis by Hedengran and co-workers in the British Journal of Ophthalmology (BJO).1 This study compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye drops with alternatively preserved (AP) and preservative-free (PF) eye drops. The meta-analysis was conducted on 16 studies that range from 15 days to 6 months of study duration. Change in IOP in BAK vs AP and PF groups was meta-analysed as the primary outcome. Conjunctival hyperaemia, ocular hyperaemia, total ocular adverse effects (AE), and TBUT were also meta-analysed. The authors found no evidence of significant change in IOP and conjunctival hyperaemia between BAK vs AP and PF treatment groups. The authors concluded that the main reason for detecting no clinical differences between the groups was related to the lack of long-term clinical studies on the safety of BAK vs AP and PF eye drops. We are in consensus with Kontas AG et al., comments on the deficiencies of this meta-analysis.

  We do not agree to the conclusion, “BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome”. We would like to direct the authors and readers to our recently published study in the journal, Clinical and Experimental Ophthalmology (CEO), which involved the randomised evaluation of the inflammatory effects of PF vs BAK and PF vs polyquad (PQ)-preserved eye drops in naïve glaucomatous patients over the period of 24 months.2 We profiled the inflammatory cytokines and analysed the ocular AE (via OSDI questionnaire) at baseline and then at 1, 3, 6, 12 and 24 months, respectively. Our results showed that the pro-inflammatory cytokines such as IL-6, IL-8, and IL-1beta were significantly increased in a time-dependent fashion in BAK group compared to PF and PQ groups. Notably, the increased levels of these cytokines significantly correlated to the OSDI in BAK group. Our results conformed with previously published in-vivo and in-vitro studies.3 4

  Although our study has demonstrated that PF and PQ-preserved eye drops do not elicit ocular AE, the increased levels of IL-1beta in PQ group starting 12-month onwards indicated that PQ preserved eye drops may produce delayed ocular surface discomfort. As the main aim of our study was to compare the BAK vs PF and PQ-preserved eye drops, there is a likelihood that bimatoprost could elicit ocular hyperaemia even when used as a PF formulation. A previous study has reported that bimatoprost causes vasodilation mediated via nitric oxide synthase but not through the induction of pro-inflammatory cytokines.5

  We agree to author’s views, “Longer clinical studies with standardised safety measurements and grading methods are highly advisable to fully identify any potential differences between preservation methods.” We recommend that a longitudinal study comparing the PF-bimatoprost with BAK-preserved bimatoprost should be conducted to validate the ocular responses. Additionally, to comprehensively ascertain the effect of other analogues, it is essential to study the ocular effects of PF-latanoprost vs BAK-latanoprost and PF-travoprost vs BAK-travoprost.

  Imran Mohammed
  Harminder S. Dua
  Anthony J. King

  Academic Ophthalmology, School of Medicine, The University of Nottingham, UK

  References:

  1. Hedengran A, Steensberg AT, Virgili G, et al. Efficacy and safety evaluation of benzalkonium chloride preserved eye-drops compared with alternatively preserved and preservative-free eye-drops in the treatment of glaucoma: a systematic review and meta-analysis. Br J Ophthalmol 2020;104(11):1512-18. doi: 10.1136/bjophthalmol-2019-315623 [published Online First: 2020/02/14]
  2. Mohammed I, Kulkarni B, Faraj LA, et al. Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: A 2-year randomized evaluation study. Clin Exp Ophthalmol 2020;48(7):973-82. doi: 10.1111/ceo.13814 [published Online First: 2020/06/22]
  3. Baudouin C, Denoyer A, Desbenoit N, et al. In vitro and in vivo experimental studies on trabecular meshwork degeneration induced by benzalkonium chloride (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2012;110:40-63. [published Online First: 2013/07/03]
  4. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 1999;106(3):556-63. doi: 10.1016/S0161-6420(99)90116-1 [published Online First: 1999/03/18]
  5. Impagnatiello F, Bastia E, Almirante N, et al. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br J Pharmacol 2019;176(8):1079-89. doi: 10.1111/bph.14328 [published Online First: 2018/04/19]

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  Conflict of Interest:
  None declared.

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• Published on: 12 April 2021

  Is it really the same?

  • Anastasios G Konstas, Ophthalmologist 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece
  • Other Contributors:
    • Gábor Holló, Ophthalmologist
    • Andreas Katsanos, Ophthalmologist
    • Konstadinos G Boboridis, Ophthalmologist
    • Anna-Bettina Haidich, Biostatistician
    • Gordon N Dutton, Ophthalmologist

  Dear Editor,

  In their review and meta-analysis, Hedengran and coworkers1 report no relative therapeutic benefit of preservative-free (PF) therapies over benzalkonium chloride (BAK)-preserved ones. Should the costlier PF medications therefore be abandoned, or should we question this conclusion?
  Ten of the 16 comparative trials analysed were of short duration, (between 15 and 90 days), the longest taking 6 months. Once-a-day medication was used in each trial, yet the dose response curve for BAK toxicity shows that each additional drop of BAK-containing medication doubles the likelihood of lissamine green corneal staining2 and increases the risk of early failure of glaucoma surgery.3 BAK toxicity is slow in onset increasing over time, due to its continual accumulation within ocular tissues.3 Thus, inconsistencies between experimental studies, which document the harmful effects of BAK and clinical trials, which do not, likely relate to the timing, dosing and duration of glaucoma therapy.4 Two to 12 week trials comparing BAK with alternatively preserved eyedrops, or PF formulations have shown no convincing differences in ocular tolerability, yet the benefits from switching from once-a-day preserved to PF therapy, accrue several months later.4 Longer term transition to alternatively preserved, or PF formulations improves tolerability, and there is good evidence that substituting PF tafluprost for BAK-containing latanoprost significantly improves tolerability.3 So sh...

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  Dear Editor,

  In their review and meta-analysis, Hedengran and coworkers1 report no relative therapeutic benefit of preservative-free (PF) therapies over benzalkonium chloride (BAK)-preserved ones. Should the costlier PF medications therefore be abandoned, or should we question this conclusion?
  Ten of the 16 comparative trials analysed were of short duration, (between 15 and 90 days), the longest taking 6 months. Once-a-day medication was used in each trial, yet the dose response curve for BAK toxicity shows that each additional drop of BAK-containing medication doubles the likelihood of lissamine green corneal staining2 and increases the risk of early failure of glaucoma surgery.3 BAK toxicity is slow in onset increasing over time, due to its continual accumulation within ocular tissues.3 Thus, inconsistencies between experimental studies, which document the harmful effects of BAK and clinical trials, which do not, likely relate to the timing, dosing and duration of glaucoma therapy.4 Two to 12 week trials comparing BAK with alternatively preserved eyedrops, or PF formulations have shown no convincing differences in ocular tolerability, yet the benefits from switching from once-a-day preserved to PF therapy, accrue several months later.4 Longer term transition to alternatively preserved, or PF formulations improves tolerability, and there is good evidence that substituting PF tafluprost for BAK-containing latanoprost significantly improves tolerability.3 So short duration studies are unlikely to reveal substantive differences.4
  Several methodological issues within this systematic review merit consideration. First, there is no protocol registration, which questions its transparency. Such protocols safeguard against biased post hoc decisions in review methods, such as selective outcome reporting. Second, there is no flow diagram presenting the process of report selection. Third, cross-over trials were considered as parallel in this meta-analysis, leading to a unit-of-analysis error, which should be avoided. Appropriate unbiased methodology does exist to impute within-patient differences to incorporate cross-over trials into a meta-analysis.5 Fourth, there was no risk-of-bias assessment across studies, such as a funnel plot and an asymmetry test, to elicit evidence of publication bias. A risk-of-bias in individual studies’ evaluation was performed utilizing an old Cochrane tool. Recently, a revised Cochrane risk-of-bias tool (the RoB 2.0) for randomized trials has been introduced, and is now the preferred option.6 Last but not least every meta-analysis should include the GRADE approach for grading the strength and quality of evidence.
  Unfortunately, this review and most published literature focus on mild glaucoma therapy-related ocular surface disease (GTR-OSD). The dosing and number of IOP-lowering medications needed for glaucoma control increase with disease duration so studies to determine the optimal formulations needed to avert longer term moderate/severe GTR-OSD are sorely needed.3 We agree with the authors’ statement that the “study lengths are short, especially in the context of BAK-preserved eyedrop use often being lifelong”, but are unable to accept the conclusion that BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome.

  Anastasios G. Konstas1, Gábor Holló2, Andreas Katsanos3, Konstadinos G. Boboridis1, Anna-Bettina Haidich4, Gordon N. Dutton5.

  1: 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece;
  2: Tutkimusz Ltd and Eye Center, Prima Medica Health Centers, Budapest, Hungary;
  3: Ophthalmology Department, University of Ioannina, Ioannina, Greece;
  4: Department of Hygiene, Social-Preventive Medicine & Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece;
  5: Department of Ophthalmology, Caledonian University, Glasgow, UK.

  Correspondence to: Anastasios G. Konstas, 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece; email: agkonstas@gmail.com

  References
  1. Hedengran A, Steensberg AT, Virgili G, Azuara-Blanco A, Kolko M. Efficacy and safety evaluation of benzalkonium chloride preserved eye-drops compared with alternatively preserved and preservative-free eye-drops in the treatment of glaucoma: a systematic review and meta-analysis. Br J Ophthalmol 2020;104:1512-18.
  2. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350–5.
  3. Konstas AGP, Labbe A, Katsanos A et al. The treatment of glaucoma using topical preservative-free agents: an evaluation of safety and tolerability. Expert Opin Drug Saf 2021;20:453-66.
  4. Rasmussen CA, Kaufman PL, Kiland JA. Benzalkonium chloride and glaucoma. J Ocul Pharmacol Ther 2014;30:163–9.
  5. Elbourne DR, Altman DG, Higgins JP et al. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002;31:140-9.
  6. Sterne JAC, Savović J, Page MJ et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.

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  Conflict of Interest:
  None declared.

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