FormalPara Key Summary Points

Why carry out this study?

Preservative-containing glaucoma drops are associated with decreased patient compliance which may affect therapeutic efficacy over time and cause an undue public health burden.

This study compared 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. Better tolerability may lead to greater patient compliance.

What was learned from the study?

Preservative-free latanoprost and preservative-containing latanoprost were equally effective at reducing intraocular pressure. However, preservative-free latanoprost was better tolerated. The findings suggest that preservative-free latanoprost has features that may improve patient compliance, potentially improving long-term intraocular pressure-lowering efficacy.

Digital Features

This article is published with digital features, including a summary slide to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.14237282.

Introduction

Patients with glaucoma may require topical therapy much longer than previous generations because of the increasing life span of the population. Additionally, the prevalences of glaucoma and ocular surface disease (OSD) increase with age. Combined, these population dynamics indicate that mitigating OSD over the lifetime of a patient with glaucoma will be important for achieving successful outcomes. Preservatives in topical glaucoma medications have been associated with OSD [1]. Patients on long-term topical therapy that contains preservatives are at greater risk of OSD, dry eye, and ocular toxicity that may affect deeper ocular tissues in the anterior chamber angle and the retina [1,2,3]. Often, patients with glaucoma require lifetime topical therapy and OSD has been reported in up to 59% of patients [4, 5]. Preservatives in topical antiglaucoma drops disrupt the ocular surface by a variety of mechanisms resulting in decreased tear film stability and increased evaporation [6, 7]. The side effects of preserved eye drop administration include ocular hyperemia, burning, stinging, and itching that are exacerbated by an unstable tear film [7].

The effectiveness of topical glaucoma therapy depends on patient adherence to their treatment, yet nonadherence with the topical therapy regimen has been reported in up to 30% of patients with glaucoma [8]. Additionally, nonadherence doubles in patients with side effects associated with the treatment or among patients using preservative-containing drops [8]. This is clinically pertinent because of the surreptitious nature of glaucoma where patients may not experience any untoward signs or symptoms of halting or decreasing the frequency of eye drop administration. In fact, patients may associate decreasing or halting drops with greater comfort from the reduced conjunctival hyperemia, burning, and stinging [9].

Topical prostaglandin analogues (PGAs) are a common first-line therapy for lowering IOP in glaucoma and ocular hypertension [10]. The efficacy and safety of PGAs has been well documented [11, 12]. Currently the most commonly prescribed PGA for glaucoma is preserved latanoprost and its generic preserved formulation [9, 11, 13,14,15]. Latanoprost (Xalatan®; Pfizer Inc., New York, NY, USA) was the first PGA approved as first-line therapy for glaucoma and has an excellent systemic safety profile and there are a number of generic formulations available worldwide [9, 11, 13,14,15]. Preserved and preservative-free formulations represent 58% and 42%, respectively, of the latanoprost market [9, 11, 13,14,15]. However, preservative-free formulations of latanoprost, such as Monoprost® (Laboratoires Théa, Clermont-Ferrand, France), have been available since 2013. Given the proven benefits of preservative-free topical therapy, including decreased ocular signs and symptoms of OSD and increased adherence, we performed a post hoc pooled analysis of randomized controlled clinical trials and real-world evidence observational studies that compared patient tolerance and efficacy of a preserved latanoprost (Xalatan®) to a preservative-free latanoprost (Monoprost®) [4, 5, 7, 9, 11, 13, 14]. Combining data from randomized controlled trials and real-world observational studies produces more relevant estimators, reducing bias and addressing the drawbacks of each kind of study and may indicate improvements in patient care [15, 16].

Methods

This post hoc pooled analysis integrated and reanalyzed the source data from three randomized clinical trials (two phase III studies and a phase IV study) and two international real-world evidence observational studies that compared preservative-containing latanoprost (PCL) and preservative-free latanoprost (Monoprost®; PFL) (Table 1) [9, 11, 13, 14].

Table 1 Patient demographics of studies that compared preservative-free latanoprost to preserved latanoprost
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The source data from each of the five studies were acquired and reanalyzed in a new database. Each study was approved by the ethics review board in each country and adhered to the tenets of the Declaration of Helsinki and all relevant local regulations. As this is a review of data from previous studies, online registration as a clinical trial was not required.

Primary Objective

The primary objective was tolerance by the evaluation of conjunctival hyperemia with each topical treatment. Most of the studies included here graded conjunctival hyperemia with the McMonnies/Chapman-Davies (MC-D) scale and one study used the Efron scale [17]. To standardize the grading of conjunctival hyperemia, the Efron scale was converted to the MC-D scale as previously described and scored as absent (MC-D grade 0 = grade 0 Efron), mild (MC-D grade 1 or 2 = grade 1 Efron), moderate (MC-D grade 3 = grade 2 Efron), and severe (MC-D grade 4 or 5 = grade 3 or 4 Efron) [18].

Secondary Objectives

The secondary criteria for the evaluation of tolerance included a change in signs and symptoms of OSD with a reduction indicating an improvement in tolerability and increased OSD indicating lower tolerability. Tolerability was based on a composite OSD score integrating ocular signs and symptoms between instillation of drops, patient and investigator satisfaction, and ocular and systemic adverse events. For standardization of ocular signs and symptoms, a five-parameter OSD composite score (0–100) was calculated from weighted parameters: the five variables assessed for this composite score were weighted as follows: eyelid redness (15), eyelid swelling (15), corneal staining (25), conjunctival staining (25), and tear film breakup time (TBUT) (20) (Table 2).

Table 2 Summary of parameters in each study comparing preservative-containing latanoprost to preservative-free latanoprost
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The weighting assigned to each of the ocular signs for the calculation of this score was defined by the expert authors. Other secondary objectives compared the IOP-lowering efficacy between medications and ocular signs and symptoms. Ocular signs and symptoms included eye dryness/tearing/foreign body sensation, irritation/stinging/burning, itching/sticky eye sensation, itching, red eye/lid redness, blurred vision, pain or discomfort, lid swelling, fluorescein staining (corneal and conjunctival), and TBUT.

Patient and investigator satisfaction with treatment were graded as “very unsatisfied”, “unsatisfied”, “satisfied”, and “very satisfied”.

Statistical Analysis

Data Sources

This pooled study was based on individual patient data (IPD) from the five studies (two phase III, one phase IV, and two real-world evidence studies). These studies were selected owing to common inclusion criteria: all patients included were diagnosed with glaucoma and treated with PL or PFL and there was complete information on conjunctival hyperemia and IOP. All relevant data from the individual datasets were combined into one dataset.

Data Collection and Endpoints

Data were collected on patient demographics including gender and age (Table 1), IOP for efficacy; conjunctival hyperemia and ocular signs for tolerability, patient satisfaction, and adverse events. For each individual study, all the data were collected and verified (Table 2).

Patients who did not meet inclusion and non-inclusion criteria were excluded from the analysis. Inclusion of IPD in the final database was verified by the investigator and the statistician. Improvement of conjunctival hyperemia was defined as a decrease in the grade of conjunctival hyperemia between baseline (day 0) and day 84 after initiating treatment.

Analysis and Statistics

Descriptive statistics were provided depending on the nature of the considered criterion: number of observed (and missing, if any) values, mean, standard deviation, median, first and third quartiles, as well as minimum and maximum, for quantitative data; number of observed (and missing, if any) values, number and percentage of patients for qualitative data. All data were presented as overall values according to the studies.

A pooled analysis of IPD was performed to analyze primary and secondary endpoints. Randomized clinical trials and observational studies were combined to produce this pooled analysis. Shrier et al. have demonstrated that combining data from randomized clinical trials and non-randomized clinical trials produces more relevant estimators, reducing bias and mitigating the limitations of each type of study [15].

Evaluation of the one-step and two-step approach yielded very similar results, indicating that the analysis was robust with either approach; hence, we elected to go with the two-step analysis. A two-step IPD pooled analysis approach was chosen as this approach allows the use of forest plots to estimate odds ratio (OR) and 95% confidence intervals (CIs) and to illustrate heterogeneity and individual and pooled results. The I2 statistic was used to determine heterogeneity, which measures inconsistency (percentage of total variation across studies due to heterogeneity) of effects. As a result of the different study designs (e.g., crossover, parallel group, randomized, naive patients, and switching between different medications), heterogeneity between studies was examined by checking the results of the I2 statistic both for primary and secondary endpoint analyses. If heterogeneity was evident, it was incorporated using random effects modelling.

Two-Step IPD Pooled Analysis

The first step of the two-step IPD pooled analysis approach consists of analyzing the studies separately and individually. For each study, a logistic regression model was performed to provide estimates, variances, and covariances of the mean difference between treatments (including OR and 95% CIs). Logistic regression was used with the presence or absence of improvement (for both endpoints) as the binary dependent variable and treatment as a categorical independent variable.

The second step of the two-step approach combines the study estimates. The variances and covariances obtained in the first step are used as the variance and covariance of the residual errors. All studies were weighted on the inverse of the variance (within- and between-studies variances) to obtain the results of the pooled analysis. For the IPD pooled analysis on the primary and secondary endpoints, statistical analysis was performed using SAS® 9.4 software (SAS Institute Inc., Cary, NC, USA).

Results

Demographics Data

The five studies enrolled a total of 3610 patients. Table 1 presents the patient demographics for the five studies enrolled and the combined data. The number of patients and the study variables differed between studies resulting in differences in the number of patients reported for the various variables reported in this study (Tables 1 and 2). The mean age of the patients and the gender distribution were similar between studies. There were 2769 (65.3%) patients in the PFL group and 719 (16.9%) patients in the PCL group, and 754 (17.8%) patients were receiving other topical glaucoma therapy. At day 84, there were 1338 (57.4%) patients in the PFL group and 568 (24.3%) in the PCL group, and 427 (18.3%) patients were receiving other topical glaucoma therapy.

Conjunctival Hyperemia

Figure 1 presents the grading of conjunctival hyperemia at baseline and day 84 for each group. Conjunctival hyperemia remained unchanged (stable) in 64.9% (982) of patients in the PFL group and in 73.2% (729) of patients in the PCL group (Fig. 1). Conjunctival hyperemia significantly improved in 25.6% (388) of patients switched to the PFL group and in 11.7% (117) of patients to the PCL group (Fig. 1; p < 0.001).

Fig. 1
figure 1

Change in conjunctival hyperemia after switching to preservative-containing latanoprost (PCL; Xalatan®: Pfizer Inc., New York, NY, USA) or preservative-free latanoprost (PFL; Monoprost®: Laboratoires Théa, Clermont-Ferrand, France)

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The two-step approach for ensuring validity of the current analyses of hyperemia generated estimates of 0.643 for fixed effects and 0.692 for the random effect model. The one-step approach generated an estimate of 0.673. The similar estimates for both approaches indicate strong validity of the results.

Figure 2 presents the forest plot with the fixed effect model and the random effect models for conjunctival hyperemia. Pooled analysis indicated PFL was two times superior to PCL group in reducing ocular hyperemia (odds ratio, 1.96; p < 0.001) (Fig. 2). The sample size for each study is included in Fig. 2.

Fig. 2
figure 2

Forest plot showing the effect of using preservative-containing (Xalatan®: Pfizer Inc., New York, NY, USA) or preservative-free latanoprost (Monoprost®: Laboratoires Théa, Clermont-Ferrand, France) on conjunctival hyperemia

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Five-Parameter Ocular Surface Disease Composite Score

There was a twice as significant decrease in ocular signs and symptoms in the PFL group [− 32.2%; − 6.8 ± 10.8 (range − 67 to 17)] compared to the PCL group [− 14.1%; − 2.6 ± 7.7 (range − 33 to 22)] (Fig. 3; p < 0.001).

Fig. 3
figure 3

Change in mean weighted five-parameter composite score of ocular signs and symptoms after switching to preservative containing latanoprost (PCL; Xalatan®: Pfizer Inc., New York, NY, USA) or preservative-free latanoprost (PFL; Monoprost®: Laboratoires Théa, Clermont-Ferrand, France). D0 denotes day 0 and D84 denotes day 84; *Denotes statistically significant change, p < 0.001

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Patient Satisfaction

At 3 months after initiating therapy, 95.7% (2671) of patients in the PFL group and 92.8% (305) of patients in the PCL group were very satisfied or satisfied with tolerating their topical eye drops.

Ophthalmologist Satisfaction

At 3 months, ophthalmologists were very satisfied or satisfied with patient tolerance of topical therapy for 362 of 368 (98.4%) patients in the PFL group and for 348 of 351 (99.1%) patients in the PCL group.

Intraocular Pressure

At baseline, the mean IOP was 19.1 ± 4.00 mmHg (range 9–35 mmHg) in the PFL group and 19.9 ± 4.1 (range 9–31 mmHg) in the PCL group. At day 84, the mean IOP was 16.1 ± 2.8 mmHg (range 6–30 mmHg) in the PFL group and 15.5 ± 2.5 (range 8–26 mmHg) in the PCL group. The change in IOP from baseline to day 84 was similar between groups (p = 0.312). The IC estimate was − 0.103 for the fixed effect model and − 0.202 for the random effects model (Fig. 4).

Fig. 4
figure 4

Forest plot showing the effect of using preservative-containing latanoprost (Xalatan®) or preservative-free latanoprost (Monoprost®) on intraocular pressure

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Discussion

This study involved a complete reanalysis of the source data of both observational studies and controlled clinical trials comparing preservative-free to preserved latanoprost for open-angle glaucoma. The inclusion of data from observational studies and clinical trials may aid in the clinical interpretation and in establishing causal inferences [15]. Additionally, the combination of randomized controlled trials and real-world evidence observational studies may increase the precision and allow more clinically valid outcomes for the topic being investigated [15, 16]. In the current analysis, estimates from the 1-step and 2-step approach (fixed and random effects models) resulted in very similar estimates. This outcome indicates that the statistical methods were very robust and appropriate for this comparison of PFL and PCL.

The outcome of this post hoc pooled analysis of the published studies indicates that PFL is better tolerated and as efficacious at reducing IOP as PCL. Topical PFL was twice as effective at reducing conjunctival hyperemia at 3 months compared to topical PCL (p < 0.001). This statistically significant decrease confirmed that removing the preservative benzalkonium chloride (BAK) improved conjunctival hyperemia. The forest plot indicated that the majority of studies favor the preservative-free formulation of latanoprost (Monoprost®) for reducing ocular hyperemia. These outcomes concur with Cucherat et al.’s meta-analyses of PFL versus a number of other preservative-containing PGAs including PCL (Xalatan®) [16]. They reported that PFL carried a statistically significantly lower risk of hyperemia compared to all the other PGAs [16]. Cucherat and colleagues concluded that PFL was better tolerated than all the other PGAs [16]. Additionally, animal studies of BAK indicate that it was found in deeper structures that are affected by glaucoma such as the trabecular meshwork and the optic nerve [2, 3].

In the current study, the weighted five-parameter OSD composite score indicated a 32.2% decrease in ocular signs and symptoms (eyelid redness and corneal and conjunctival staining and TBUT) in the PFL group compared to a 14.1% decrease in the PCL group. This outcome indicates that PFL was twice as efficient at reducing the OSD composite score compared to the PCL group after switching treatments. This is the first publication that reports a five-parameter OSD composite score to quantify the global clinical changes in the ocular surface. We believe that using a five-parameter OSD score is much more clinically relevant compared to using only one or two tolerability parameters. This score may serve as a useful metric for quantifying OSD in future studies.

Preservatives disrupt the ocular surface by numerous mechanisms including cellular apoptosis and neurotoxicity causing OSD and reducing patient tolerability [6, 7, 19, 20]. Furthermore, preservatives may cause some local corneal anesthesia masking the symptoms of OSD that may increase severity over time [17, 21, 22]. Reduced patient tolerability can lead to decreased patient compliance or discontinuation of glaucoma therapy, further reducing the intended therapeutic effect [23]. Taken together, the reduced hyperemia and the mitigation of ocular signs with PFL should result in greater patient tolerability of the treatment and, potentially, a better health-related quality of life [24, 25].

The increased patient tolerance has been reported to result in greater patient satisfaction with topical therapy [13, 22]. In the current study, patient satisfaction to both formulations was very high (greater than 92%). Ophthalmologists were also very satisfied or satisfied with the efficacy of both formulations in over 93% of their patients. This observation indicates that ophthalmologists considered PFL had similar IOP-lowering effects to PCL. A recent international study of preserved glaucoma medications reported that despite high patient satisfaction, various ocular signs were reported in 10.3–42.5% of 793 patients that resulted in low tolerance to preserved medications [26]. Hence preservative-free formulations may allow greater patient tolerance which is likely to lead to better long-term compliance with therapy resulting in greater long-term efficacy of glaucoma therapy.

In the current study, the IOP decrease at 3 months after initiating or starting treatment was similar between groups, indicating a similar efficacy of the preserved and preservative-free formulations. The change in IOP is similar to previous publications of PCL [27]. Some have postulated that the disruption of the corneal epithelium by preservatives may allow greater therapeutic efficacy of topical ophthalmic medications [28]. Our results, however, concur with Misiuk-Hojlo and colleagues who reported very similar IOP-lowering effects with PFL and PCL [29]. This observation concurs with a previous meta-analysis of PFL to preserved PGAs that found similar or better IOP-lowering efficacy with PFL [16].

One of the potential limitations in the study is that the patients were asked about satisfaction with their treatment by their own ophthalmologists and patients may minimize their symptoms to avoid disappointing their doctors. However, further research and direct RCT are warranted to support the improvement linked to the use of PF treatments. The current study is innovative in the ophthalmic literature, by providing a pooled analysis of randomized comparative trials and observational studies. However, similar pooled analyses of randomized and observation studies have been recently published in other fields of medicine without significant concerns that incorporation of observational studies might skew the pooled analysis [30,31,32]. Similar to the aforementioned studies, our study protocol and statistical analyses (detailed in “Methods”) incorporated measures to address heterogeneity between studies and response-surface estimation to accommodate the effect of bias from any cause including study design [15, 30,31,32,33,34]. Shrier et al. have previously addressed the advantages of combining randomized and non-randomized studies, including mitigating limitations of each design and increased sample size [15]. However, we are limited to reporting the outcomes of this study as there is no previous pooled analysis comparison in the current ophthalmic literature.

Conclusions

Switching to latanoprost preservative-free formulation was twice as effective as the preserved formulation at reducing ocular hyperemia. Additionally, PFL is twice as efficient at reducing ocular signs such as eyelid redness and corneal and conjunctival staining and TBUT. The IOP-lowering efficacy of PFL is similar to PL. Further studies are warranted to confirm that the improved signs and symptoms from PFL can lead to better patient tolerability improving treatment compliance and potentially maintaining the long-term efficacy of the medication.