Study Group and Protocol

This was a prospective randomized controlled study. All patients were given a full explanation of the study, and written informed consent was obtained from all participants. The study protocol adhered to the tenets of the Declaration of Helsinki. This study was approved by the Institutional Review Board and Ethics Committee, Soonchunhyang University Seoul Hospital (SCHUH 2013-12-012), and registered at http://www.clinicaltrials.gov (identification no. NCT02608489 ). Patients were randomly allocated into the diquafosol group (D group) or the hyaluronate group (H group) using a simple unrestricted randomization method by the controller. The D group used 3% diquafosol tetrasodium ophthalmic solution (Diquas; Santen Pharmaceutical Co, Ltd, Osaka, Japan) 6 times a day and the H group used 0.1% sodium hyaluronate ophthalmic solution (Hyalein; Santen Pharmaceutical Co, Ltd) 6 times a day. Both groups instilled each eye drop from postoperative day 1 to postoperative week 12.

Participants

Consecutive patients aged 20–90 years with bilateral or unilateral cataract undergoing uncomplicated phacoemulsification and intraocular lens (IOL) implantation at Soonchunhyang University Hospital between January 1, 2014 and January 31, 2015 were enrolled. Patients with mild to moderate dry eye (level 1 or 2) based on the dry eye severity scale adopted by the Dry Eye Workshop (DEWS) report and who used only artificial tears occasionally were included. The exclusion criteria were presence of any complications after cataract surgery such as cystoid macular edema, patients using any topical eye drops on a regular basis, treatment history of dry eye beyond artificial tears, any ocular surgery within the prior 6 months, contact lens wear, serious ocular surface disease (eg, Sjögren syndrome, ocular pemphigoid, conjunctival scarring, chemical injury), lacrimal or eyelid disease (eg, anterior blepharitis or moderate to severe posterior obstructive blepharitis ), use of concomitant medications that could cause dry eye (eg, antihistamines, antidepressants, decongestants, anticholinergic drugs), and allergy to any of the study medications.

Objective and Subjective Clinical Assessments of Dry Eye

All patients underwent ophthalmic examinations preoperatively and postoperatively in the following order: uncorrected distance visual acuity (UDVA) test, an Ocular Surface Disease Index (OSDI) questionnaire, changes in HOAs after blinking, Schirmer I test without anesthesia, tear breakup time (TBUT), corneal fluorescein staining, and lissamine green (LG) conjunctival staining. Anterior chamber cells were evaluated by slit-lamp biomicroscopy to assess intraocular inflammation. Routine postoperative examinations were scheduled for 1 week, 4 weeks, and 12 weeks after surgery. The OSDI questionnaire consists of 12 questions that evaluate subjective symptoms related to dry eye and vision. We used total OSDI score to evaluate subjective symptoms of dry eye disease. TBUT was assessed by instilling a drop of 2% sterile fluorescein into the conjunctival sac and recording the interval between the last complete blink and the first appearance of a dry spot or disruption of the tear film. For the Schirmer I test without anesthesia, Schirmer paper strips were placed into the temporal one-third of the lower conjunctival sac for 5 minutes and the wetness on the strips was measured. Ocular surface damage was assessed by the National Eye Institute (NEI) workshop grading system, and corneal fluorescein staining and conjunctival LG staining were evaluated. The maximum staining score was 15 for the cornea and 18 for the conjunctiva. Corneal HOAs and serial measurement of ocular total HOAs were evaluated using a KR-1W wavefront analyzer (Topcon Medical System, Inc, Tokyo, Japan). Serial measurement of total ocular HOAs was measured every second for 10 seconds after complete blinking in continuous measurement mode. The difference between the fifth and first HOA was used to evaluate the tear film instability. The difference between the tenth and first HOA was inaccurate because many patients could not hold blinking for 10 seconds. Corneal trefoil, coma, tetrafoil, and second astigmatism were included in the corneal HOAs. Anterior chamber inflammation was examined with a slit lamp clinically and divided into 6 grades using the Standardization of Uveitis Nomenclature (SUN) working group grading scheme.

Efficacy and Safety Evaluation

To evaluate the efficacy of the 2 different eye drops, we compared each measurement between the 2 groups throughout the study period and at each follow-up, and also compared the patterns of changes in each group to identify which group recovered earlier. Previous studies have demonstrated that inappropriate activation of the P2Y2 receptor is associated with neutrophil-induced hyperinflammation and tissue damage during sepsis, chronic lung disease, and hepatitis in animal models. In addition, patients treated with diquafosol may suffer adverse drug reactions (23.7%), such as eye irritation, discharge, conjunctival injection, pain, pruritus, and other discomfort. Therefore, we evaluated the safety of the 2 eye drops, including anterior chamber inflammation and discontinuation of the eye drops owing to drug-related discomfort. Patients were taught to distinguish between the pain or discomfort due to the surgery itself and that due to the eye drops. The latter was defined as having started after eye drop instillation and lasting several minutes, occurring every time during instillation at any time up to 12 weeks into the follow-up period. Patients that had any adverse events or wanted to stop using the eye drops were excluded from the study, but these patients were included in the safety evaluation.

Surgical Procedure

A 2.8 mm clear corneal incision was made at the location of the steep corneal astigmatism axis. A standard phacoemulsification technique was used with topical anesthesia with 2% lidocaine. A foldable IOL was implanted into the capsular bag. There was no suture at the corneal incision site. Patients received moxifloxacin (Vigamox; Alcon, Fort Worth, Texas, USA) and rimexolone (Vexol; Alcon) 4 times a day after surgery for 4 weeks.

Statistical Analysis

For statistical analysis, UDVA was converted from Snellen into logMAR values. Baseline data were compared between the groups using the Mann-Whitney U test, Fisher exact test, and the linear mixed model after adjusting for intereye correlations, age, and sex. In addition, another mixed model was used to compare measurement data between the 2 groups by considering the correlation between both eyes of each patient at each follow-up. To obtain an overall comparison between treatment responses throughout the study period considering the 2 levels of correlation in subjects and follow-up, a bivariate generalized linear mixed (GLM) model with asymmetric random effects was used. In the last step, a bivariate GLM model was also used to identify the patterns of changes in measured data throughout the study period. The intergroup differences in adverse events were analyzed using Fisher exact test. SPSS software (version 21; SPSS, Inc, Chicago, Illinois, USA) was used for all statistical analyses, and P < .05 was taken to indicate statistical significance ( Supplemental Figure ).

Efficacy Evaluation

Regarding the OSDI score, the bivariate GLM model indicated that there were no statistically significant overall differences between the 2 groups throughout the study period ( P = .221). In addition, the patterns of changes in OSDI score also did not differ significantly between the 2 groups ( P = .453). However, the D group (9.76 ± 7.95) had a significantly lower OSDI score than the H group (16.92 ± 13.11) at postoperative week 12 ( P = .015). OSDI score tended to be significantly increased at postoperative week 1, and then started to recover toward baseline levels from 4 weeks after surgery in both groups. OSDI scores at postoperative week 12 were significantly lower than the preoperative scores in both groups (both P < .001) ( Figure 1 ).

Mean changes in Ocular Surface Disease Index (OSDI) scores in patients with dry eye after cataract surgery. Significant improvement from baseline was observed in the diquafosol group and the hyaluronate group at 12 weeks postoperatively. The 3% diquafosol ophthalmic solution showed superior effects to 0.1% sodium hyaluronate ophthalmic solution at 12 weeks postoperatively. However, there were no significant differences between the 2 groups throughout the study period. ∗Significant difference between 2 groups ( P < .05); †overall comparison between 2 groups throughout the study period; ‡comparison of patterns of changes in the data between the 2 groups.

Overall TBUT was significantly longer in the D group than in the H group throughout the study period ( P < .001). The values in the D group were 3.50 ± 1.35, 5.64 ± 1.89, and 6.69 ± 2.23 seconds at postoperative weeks 1, 4, and 12, respectively, and those in the H group were 3.00 ± 1.16, 3.96 ± 1.46, and 4.38 ± 1.92 seconds, respectively, significantly longer at postoperative weeks 4 and 12 in the D group than in the H group (both P < .001). The patterns of changes in TBUT were decreased at 1 week after surgery and then recovered toward baseline levels from 4 weeks after surgery in both groups, but recovered earlier in the D group than in the H group ( P < .001). TBUT at postoperative week 12 was significantly longer than baseline in the D group ( P < .001), while it returned to the baseline level in the H group ( P = .343) ( Figure 2 , Left).

Mean changes in tear breakup time (TBUT) and Schirmer test in patients with dry eye after cataract surgery. (Left) TBUT showed significant improvement from baseline in the diquafosol group but not in the hyaluronate group at 12 weeks postoperatively. The 3% diquafosol ophthalmic solution showed a significantly superior effect to 0.1% sodium hyaluronate ophthalmic solution throughout the study period, and at 4 and 12 weeks postoperatively. (Right) Schirmer test scores recovered to the baseline level at 12 weeks postoperatively in the diquafosol group but not in the hyaluronate group. In addition, 3% diquafosol ophthalmic solution showed superior effects to 0.1% sodium hyaluronate ophthalmic solution at 12 weeks postoperatively. However, there were no significant differences between the 2 groups throughout the study period. ∗Significant difference between 2 groups ( P < .05); †overall comparison between 2 groups throughout the study period; ‡comparison of patterns of changes in the data between the 2 groups.

Schirmer tests indicated no significant overall differences throughout the study period or in the patterns of changes between the 2 groups. However, the D group (4.10 ± 2.87) was significantly superior to the H group (2.52 ± 2.08) at 12 weeks postoperatively ( P = .025). The patterns of changes were similar to OSDI and TBUT, showing aggravation at postoperative week 1 and recovery from postoperative week 4 in both groups. There were no statistically significant differences between preoperative and postoperative week 12 data in the D group ( P = .505). Conversely, Schirmer test had not yet returned to the baseline level in the H group ( P = .016) ( Figure 2 , Right).

The overall corneal fluorescein staining score was significantly lower in the D group than in the H group throughout the study period ( P = .045). However, there were no significant differences at each follow-up or in the patterns of changes over time between groups. The scores at postoperative week 12 were significantly improved compared to the preoperative scores in both groups ( P < .001 for the D group, P = .025 for the H group) ( Figure 3 , Left).

Mean changes in corneal fluorescein and conjunctival lissamine staining scores in patients with dry eye after cataract surgery. (Left) Corneal fluorescein staining score showed significant improvement from baseline in the diquafosol and hyaluronate groups at 12 weeks postoperatively. The 3% diquafosol ophthalmic solution showed significantly superior effects to 0.1% sodium hyaluronate ophthalmic solution throughout the study period. (Right) Conjunctival lissamine green staining score showed significant improvement from baseline in both groups at 12 weeks postoperatively. The 3% diquafosol ophthalmic solution showed significantly superior effects to 0.1% sodium hyaluronate ophthalmic solution throughout the study period, and at 4 and 12 weeks postoperatively. ∗Significant difference between the 2 groups ( P < .05); †overall comparison between 2 groups throughout the study period; ‡comparison of patterns of changes in the data between the 2 groups.

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