A Randomized Controlled Trial Comparing Dexamethasone with Loteprednol Etabonate on Postoperative Photorefractive Keratectomy

Abstract

Purpose:

To compare loteprednol etabonate 0.5%/tobramycin 0.3% (Zylet^®) with dexamethasone 0.1%/tobramycin 0.3% (Tobradex^®) in terms of the epithelial healing time, postoperative visual acuity, corneal haziness score, and intraocular pressure (IOP) in postoperative treatment after photorefractive keratectomy (PRK).

Methods:

This prospective, randomized, double-masked (participants and assessors blinded) controlled study included 32 patients who underwent PRK. The patients were allocated equally into 2 groups by block randomization to receive either loteprednol etabonate (Lot) or dexamethasone (Dex) for 1 month after the surgery. The epithelial healing time, uncorrected visual acuity (UCVA), corneal haziness score, and IOP were evaluated at 1 week, 1 month, and 3 months.

Results:

The corneal epithelium was healed within 3 days in both groups; however, the epithelium was closed on the second day in 3 cases in the Lot group compared with 1 case in the Dex group. No significant differences were found for UCVA at 1 and 3 months (Fisher exact test, P>0.01). Similarly, there was no statistically significant difference in corneal haziness scores between the 2 groups at 1 and 3 months (Mann–Whitney U test, P>0.05). The number of patients experiencing significantly increased IOP (≥5 mmHg) from baseline at any visit for the Lot group (1/16 patients) was fewer than for the Dex group (3/16 patients).

Conclusions:

Loteprednol etabonate was effective in postoperative PRK management and was significantly less likely to produce elevations in IOP than was dexamethasone.

Introduction

Photorefractive keratectomy (PRK) is an option for refractive error correction. Due to postoperative ocular discomfort/pain, delayed visual rehabilitation, and a possibility of corneal haziness, it has become less popular compared with laser in situ keratomileusis (LASIK).^1,2 An appropriate anti-inflammatory drug selection may ameliorate these complications. Corticosteroid eye drops are the first treatment recommended; however, the selected compounds and derivatives are still controversial for PRK surgery.³

This study compares the epithelial healing time, grading of corneal haziness, postoperative visual acuity, and intraocular pressure (IOP) of loteprednol etabonate 0.5%/tobramycin 0.3% (Zylet^®; Bausch & Lomb Incorporated) with dexamethasone 0.1%/tobramycin 0.3% (Tobradex^®; Alcon Laboratories) for post-PRK treatment.

Methods

The efficacy and safety of loteprednol etabonate 0.5% were compared with those of dexamethasone 0.1% ophthalmic solution in a randomized, double-masked clinical trial study. To reduce the bias, the participants were blinded by masking drug labels and the assessor was blinded to patient assignment.

The study was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Khon Kaen University Ethics Committee for Human Research. Written informed consent was obtained from all participants before study initiation. Power analysis was performed to justify the number of patients enrolled in the study (ClinicalTrial.gov Identifier: NCT01724892).

Patients

The patients who underwent PRK at the Khon Kaen University LASIK center between January 2012 and February 2013 were included. The exclusion criteria were underlying systemic disease or ocular disorders that may have affected corneal epithelial healing such as diabetes, connective tissue disease, recurrent corneal erosion, and severe dry eye. Corneal scarring or a history of herpes simplex keratitis was also excluded.

All participants were allocated into 2 treatment groups: loteprednol etabonate (Lot) or dexamethasone (Dex) by block randomization (block size of 4). Three cases in Dex group and a case in Lot were myopia, and the remaining patients in both groups were myopic astigmatism. Patients in both groups underwent laser vision correction procedure using the PRK technique with an 8.5 mm abrasion zone. The corneal epithelial debridement was performed by alcohol-assisted technique, and mitomycin-C was applied after ablation in all patients. Contact lenses were placed, and the loteprednol etabonate 0.5% or dexamethasone 0.1% were prescribed for 4 times a day for 1 month. An eye examination was performed daily for all patients until the epithelium was completely closed. Epithelial healing time, IOP, visual acuity, postoperative refraction, and grading of corneal haze were evaluated under double-masked conditions at 1 week, 1 month, and 3 months. Objective corneal haze assessments were evaluated using a slit-lamp biomicroscope.

Statistical analysis

Baseline characteristics were compared using the Fisher exact test and Mann–Whitney U test. The epithelial healing time was recorded in numbers of days and compared by using the Fisher exact test. Uncorrected visual acuity (UCVA) of the treatment eye was evaluated as an independent observation and compared between the treatment groups using 2-tailed Fisher exact test. A P value<0.01 was considered statistically significant. Ablation depth, corneal haziness grading, and postoperatively refractive outcomes were analyzed by using the Mann–Whitney U test, P values of less than 0.05 were defined as statistically significant. The amount of IOP elevation and the numbers of patients with increased IOPs were compared between the 2 treatment groups. The Fisher exact test was used to assess difference in number of IOP increased between 2 groups, and the result with P<0.05 was considered statistically significant.

Results

The study included 32 participants, and there were 16 patients in each group. The baseline characteristics of subjects in the Lot or Dex groups were summarized in Table 1. There were no statistically significant differences between groups for age, gender, and preoperative refraction (P>0.05).

Table 1.

Baseline Characteristics

	Dex (n=16)	Lot (n=16)	P-value
Age, mean±SD	23.0±4.7	25.5±6.9	0.23
Gender			1.00
Male, n (%)	8 (50)	9 (56.2)
Female, n (%)	8 (50)	7 (43.8)
Manifest refraction (preop)
Spherical, mean±SD	−2.63±1.45	−2.97±1.23	0.54
Cylinder, mean±SD	−0.84±0.46	−0.76±0.46	0.79

Dex, dexamethasone; Lot, loteprednol etabonate; SD, standard deviation.

The mean ablation depth was 46.68±17.74 in Dex group and 49.89±16.08 in Lot group. There was no significant difference in the depth of ablation between the 2 groups (P=0.63).

The epithelium was healed within 3 days in all patients in both groups. On the second day, the epithelium was closed in 3 cases in the Lot group and in 1 case in the Dex group. There was no statistically significant difference on the second day (P=0.60) (Table 2).

Table 2.

Epithelial Healing Time

Time to epithelial closure	First day	Second day	Third day
No. of patient in Dex group (%)	0 (0)	1 (6.3)	16 (100)
No. of patient in Lot group (%)	0 (0)	3 (18.8)	16 (100)

At 1 and 3 months, there was no statistically significant difference (P>0.01) in the percentage of eyes attaining a UCVA of 20/20 or better, or 20/30 or better or 20/40 or better between the 2 treatment groups (Table 3). For refractive outcomes, no significant differences were observed for both sphere and cylinder between the 2 groups (P>0.05) (Table 4).

Table 3.

Postoperative Uncorrected Visual Acuity and Refraction

VA	1 month	3 month
20/20 or better
Dex, n (%)	6 (37.5)	12 (75.0)
Lot, n (%)	9 (56.3)	13 (81.3)
P-value	0.47	1.00
20/30 or better
Dex, n (%)	12 (75.0)	14 (87.5)
Lot, n (%)	14 (87.5)	16 (100)
P-value	0.65	0.48
20/40 or better
Dex, n (%)	16 (100)	16 (100)
Lot, n (%)	16 (100)	16 (100)
P-value	1.00	1.00

VA, visual acuity.

Table 4.

Postoperatively Refractive Outcomes at 3 Months After Photorefractive Keratectomy

	Dex (n=16)	Lot (n=16)	P-value
Manifest refraction (postop)
Spherical, mean±SD	−0.13±0.36	−0.15±0.28	0.53
Cylinder, mean±SD	−0.16±0.2	−0.14±0.20	0.83

Corneal haze was evaluated using a slit-lamp biomicroscope and graded according to the haze grading system reported by Fantes et al.⁴; grade 0, totally clear; grade 0.5, a trace or a faint corneal haze seen only by indirect broad tangential illumination; grade 1, haze of minimal density seen with difficulty with direct and diffuse illumination; grade 2, a mild haze easily visible with direct focal slit illumination; grade 3, a moderately dense opacity that partially obscures the iris details; and grade 4, a severely dense opacity that completely obscures the details of intraocular structures. There were no statistically significant differences between the 2 groups at 1 month (P=0.62, 2-tailed) and 3 months (P=0.63). Corneal haziness was totally clear (grade 0) in all patients from both groups within 3 months except for 1 case in the Lot group who had grade 0.5 without significant visual deterioration (VA=20/20).

The number of patients experiencing significant IOP increases ≥5 mmHg from baseline at any visit for Lot group (1/16) was fewer than the Dex group (3/16). However, there was no statistically significant difference (P=0.60). The IOP increased at 1 week in all cases, and the highest IOP was 23 mmHg in patients from Dex group. The IOP decreased to normal within 1 month in all participants after cessation of corticosteroid eye drops.

Discussion

Topical corticosteroid eye drops are used after PRK to reduce inflammation and prevent corneal haziness. Prolonged inflammation with corneal haze and steroid-induced glaucoma can affect final visual acuity, so proper corticosteroid selection is important.⁵ Controversy arose over the use of steroid in PRK patients, and various corticosteroid derivatives have been studied.⁶ For instance, there were no statistically significant differences between the fluorometholone 0.1% and loteprednol 0.5% when comparing postoperative visual acuity, corneal haze, and increased IOP.⁷ Dexamethasone was previously used for post-PRK treatment; however, the tendency for postoperative IOP increases has been reported as dose dependent.^8–10 To reduce this side effect, other corticosteroids have replaced Dexamethasone, such as fluorometholone. Nevertheless, ocular hypertension can still occur with fluorometholone treatment whose incidence is 40% of treated eyes at 2–3 weeks postoperatively as described in the literature.¹¹

Loteprednol etabonate is a new generation of corticosteroid produced by retrometabolic design. The ketone at the carbon-20 (C-20) position is replaced with a chloromethyl ester and the 17a-hydroxyl group is replaced with a carbonate moiety, which is rapidly converted to an inactive and nontoxic metabolite in an aqueous solution.¹² Subsequently, it has been reported to have a lower risk of steroid-induced IOP elevation.^13,14 It was designed using the “inactive metabolite” approach to “soft drug” development, which can be rapidly deactivated. For intraocular inflammation treatment, loteprednol etabonate was proposed to be less potent than prednisolone or dexamethasone.^15,16 It was comparable, however, when used in ocular surface inflammation, such as in allergic conjunctivitis.^13,16,17 For post-PRK, the inflammation is limited to only the ocular surface.

Corticosteroids could retard corneal epithelial healing, particularly the more potent formulations. Dexamethasone 0.1% and prednisolone 1.0% have been shown to retard epithelial wound healing compared with isotonic saline in animal models.^18,19 In this study, re-epithelialization was completed within 3 days in all patients from both groups and there was no difference between the dexamethasone and loteprednol groups. On the second day, 3 patients from Lot group, however, had complete corneal healing compared with only 1 patient from Dex group; hence, patients with loteprednol tended to have more rapid epithelial healing. A limitation of this study was the inability to measure the accurate time of the epithelial healing rate in hours, which may demonstrate true differences.

Corticosteroid eye drops can modify corneal wound healing and prevent corneal haziness.²⁰ Corneal haze, opacification of anterior stroma, is a potential complication that causes reduced contrast sensitivity, glare, and reduced visual acuity. Clinically significant haze occurs in 0.5%–5.0% of PRK cases. To prevent these complications, postoperative corticosteroid eye drops play an important role.^21,22 From this study of low myopia patients, loteprednol etabonate is equivalent to dexamethasone in corneal haziness prevention. It cannot, though, be concluded to have the same results in moderate to high myopia. Keratocyte apoptosis and the subsequent proliferation and generation of myofibroblasts are the cellular responses after PRK. These responses were significantly greater in the high myopia PRK corneas than in the low myopia, and these cellular responses likely underlie the clinical differences in outcome and complications such as regression and stromal haze.^23,24 In this study, the refractive error is only in low myopia, which possesses less potential for corneal haziness. A further study of high myopia patients is required to validate this hypothesis.

Regarding IOP, we found that there was no significant difference. The explanations could be the small sample size and the relatively high percentage of IOP increased in Lot group (6.3%) compared with previous studies (0%–2.7%).^25,26 The clinical significance might be considered due to apparent difference in number of IOP increased between Lot group (1/16, 6.3%) and Dex group (3/16. 18.8%).^25,26 The Loteprednol group was found to have less effect on IOP increases, which are compatible with previous studies.^12–16 The small sample size is the limitation of this study.

In conclusion, the anti-inflammatory effect and stromal haziness prevention of loteprednol etabonate was as effective as dexamethasone. Epithelial wound healing in the loteprednol group was slightly more rapid compared with dexamethasone. Furthermore, it was less likely to produce elevations in IOP. Loteprednol etabonate was shown to be safe and effective for post-PRK management.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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