Letter to the editor: ‘topical preservative-free ophthalmic treatments an unmet clinical need’

In their interesting review published online Figus and coworkers [1] address the important topic of the value of topical preservative-free (PF) ocular medications placing emphasis on their role in the management of dry eye disease (DED) and glaucoma. We wish to highlight certain key issues, which in our opinion would complement this review.

It is surprising that the author’s comprehensive literature search failed to identify two pertinent reviews [2,3] and a research publication [4] from our group published well before the closure of the authors’ data collection (April 2020). This omission unfortunately occurred despite their claim that ‘all available articles in the English language, up to April 2020, were reviewed.’ It can be argued that our work [2–4] would have reinforced the argument for the superiority of PF medications. Of note, in section 3.2.2 of this review the term ‘glaucoma related-ocular surface disease’ is employed, a term almost identical to the term ‘glaucoma therapy-related ocular surface disease’ we have introduced in the literature in 2018[2].

Primarily, in such a review we feel it is essential to understand the biological properties and mechanism of cumulative toxicity of the commonest preservative in topical eye medications: benzalkonium chloride, (BAK). In section 1 the authors state that ‘due to the rapid BAK concentration clearance in the tear film, the severity of BAK toxicity may be mostly due(?) to the duration of the exposure to the treatment.’ They support this statement with reference #28 by Lemij and coworkers, which is a study exploring patient satisfaction with glaucoma therapy. In fact, one of the most problematic aspects of BAK toxicity is the progressive slow accumulation of this preservative within ocular tissues [2,3,5]. In the same section, they write ‘presumed advantages of newer preservatives such as SofZia®, Purite®, or Polyquad over BAK, are still uncertain.’ Again they support their argument with a reference (#30), which is inconsistent since it states the exact opposite: ‘Cellular viability was moderately reduced by perborate and polyquad-preserved tear substitutes and dramatically reduced by BAK.’ We fully agree however with their statement on the same subject in section 3.2.2. that ‘study lengths are short, whereas the use of BAK in eyedrops is often lifelong.’ This point however, in our view undermines the overall argument for the use of BAK-preserved medications they describe in section 1.

In section 3.1 the authors provide convincing evidence showing that preservatives negatively affect the outcome of DED therapy, inducing tear film instability, goblet cell death, and inducing oxidative and inflammatory ocular surface damage. Yet, in the concluding paragraph of this section they state: ‘the literature does not prove that PF artificial tears are more effective than preserved artificial tears for the treatment of DED.’ They are therefore reluctant to support the advantages of only using PF eyedrops in DED management due to a perceived lack of comparative trials. In reality, however, there is abundant evidence, summarized by the consensus recommendations of the Tear Film and Ocular Surface Society Dry Eye Workshop II [6] which categorically states that sufficient evidence exists to confirm that DED patients, particularly those with severe DED should avoid the use of ocular lubricants preserved with BAK when they need to use them frequently, or need other chronic topical therapies, such as glaucoma medications, because BAK toxicity represents a considerable burden over time. [6] This evidence has shifted the scientific community and industry toward launching and using PF artificial tear drops. Hence, today there is no justification to consider long-term therapy with preserved lubricants. Our primary target is to enhance comfort and safety by eliminating preservatives, and has nothing to do with efficacy.

Contrary to the author’s statement in section 3.2.1 that ‘BAK is rapidly diluting because of tear film clearance,’ the opposite is true, because BAK progressively accumulates in ocular tissues and its toxicity progressively increases over time [2,5,7]. Exposure to BAK exacerbates allergy and inflammation, negatively impacting anti-allergic therapy, and should be avoided [8] as PF medications for inflammatory and allergic conditions are less toxic and more effective.

Progressive GTR-OSD affects the quality of life of millions of patients worldwide and reduces the success of medical and surgical glaucoma therapy [2,5,9,10]. The causative GTR-OSD, often goes under-recognized and undertreated [10], is fast becoming a major health concern, with 45–60% of patients using glaucoma eyedrops reportedly being affected by toxicity [2,9,10]. The authors clearly describe the key role of preservative toxicity in the development of this condition and provide substantive evidence for reduced tolerability and a greater rate of GTR-OSD with preserved medications. Yet they focus on the lack of difference in reported efficacy between PF and preserved medications, not recognizing the benefits of PF antiglaucoma therapy. Nearly all published, short-term clinical studies involving patients with GTR-OSD have confirmed improved tolerance when preserved medications are switched to PF ones [2,5,10]. This is in fact borne out by the evidence the authors employ in Table 1: eleven out of the twelve studies they quote demonstrate a significant tolerability benefit with PF versus preserved medications. The only trial that failed to do so was a small, phase II, pilot study (reference #92 in the review) targeting bioequivalence.

The authors overlook the positive relationship between good tolerability and consequent adherence, to the overall success of long-term antiglaucoma therapy [10,11]. This consideration alone is sufficient to justify a change from preserved to PF medications. Moreover, over time, most glaucoma patients require combined medical therapy to adequately control intraocular pressure. However, as the dosing and number of glaucoma medications prescribed increase, both the prevalence and severity of GTR-OSD escalate [4,10], owing to cumulative BAK toxicity. Currently, detection and management of GTR-OSD remain unsatisfactory [9], particularly for glaucoma patients on multiple drug therapy, for whom evidence of greater efficacy with PF medications already exists [12] and for which future controlled trials are likely to confirm.

One aspect missing from the present review is a critical discussion on the lack of convincing correlation between signs and symptoms [5,7] and inconsistencies in diagnostic testing [9], which add further challenges in the management of DED-OSD and GTR-OSD[10]. The clinical tests typically used in practice (tear film break up time and Schirmer’s test) assess only tear film parameters and lack accuracy and consistency. In contrast, more focused diagnostic testing (Oxford score, osmolarity, matrix-metalloproteinase-9 over-expression and Meibomian gland dysfunction score) can delineate inflammation and associated tissue damage[10].

The authors express doubts concerning the sterility of PF medications and their use by elderly patients. It is important to highlight that currently available PF single unit pipettes and multidose containers are greatly improved from those that were criticized for possible microbial contamination more than 25 years ago [2,10]. Critical analysis of available evidence indicates that newer PF medications do not differ in safety, efficacy and use from currently available multidose preserved medications. In two recent reviews [13,14] we have compared in depth, the efficacy, tolerability and safety of all antiglaucoma PF formulations versus their preserved counterparts. These reviews were not available at the time of the authors’ data collection. In one of these reviews [14] we have analyzed all available data and experience with preserved and PF unit-dose and multidose formulations of the most popular antiglaucoma medication in Europe (dorzolamide/timolol fixed combination). We have confirmed that PF formulations are safe, better tolerated than the preserved counterparts and are not associated with application-related ocular surface injury or increased chances of microbial contamination [2,13,14]. We therefore believe that the authors’ doubts concerning the risk of potential contamination and the perceived difficulty in the use of PF agents do not represent real-life issues for the vast majority of glaucoma patients.0

Importantly, a recent 2-year randomized trial [15] has demonstrated a significant sterile inflammatory response to BAK-preserved topical eyedrops on the ocular surface within 3 months of therapy instigation, which was maintained thereafter, whereas PF eyedrops and polyquad-preserved eyedrops did not do so.

To conclude, we agree with the authors that there remains an unmet need for long-term controlled evidence, novel approaches and technology advances to increase our knowledge of PF therapies. However, it is alarming that the authors do not identify or highlight the tangible benefits of PF medications. In our opinion, this is unwarranted. It even contradicts the evidence for the superior tolerability of PF medications reported by the authors themselves. In our view, there is compelling evidence that PF medications provide superior tolerability compared with preserved eyedrops. Finally, for us ophthalmologists the key issue that should concern us is the insidious damage that preserved drops inflict to the ocular surface of our patients and the inevitable penalty they will pay with more severe GTR-OSD, fibrosis, more often unsuccessful glaucoma surgery and potential blindness as a result.

Declaration of interest

G Holló is a consultant for Aerie and Santen and received speaker fees from Aerie, Santen. A K Katsanos received research funding from Laboratoires Théa and congress expenses/speaker fees from Santen, Vianex, Cooper. AG Konstas received` research funding from Allergan, Bayer and Santen; travel support from Vianex; honoraria from Allergan, Mundipharma, Santen and Vianex.