To compare the anti-inflammatory efficacy and subjective tolerability of preservative-free and preserved diclofenac 0.1% and preserved ketorolac 0.5% eye drops for prophylaxis and management of inflammation after cataract surgery.
Prospective, randomized, investigator-masked, parallel-group, comparative clinical trial.
One hundred two patients who underwent small-incision phacoemulsification cataract surgery in an institutional setting were assigned randomly to receive preservative-free diclofenac sodium 0.1% (Voltaren ophtha SDU; Novartis Pharma), preserved diclofenac sodium 0.1% (Voltaren ophtha; Novartis Pharma), or preserved ketorolac tromethamine 0.5% (Acular; Pharm Allergan) eyedrops 4 times daily for 4 weeks after surgery. During the 1-month follow-up, anterior chamber flare and mean foveal thickness were evaluated for objective comparison of the anti-inflammatory effect. Ocular tolerability was assessed by observer-based grading of conjunctival hyperemia and ocular discomfort, as well as obtaining subjective ratings of ocular tolerability on a visual analog scale. Distance and near visual acuity and intraocular pressure served as safety measures.
All 3 formulations demonstrated equal anti-inflammatory efficacy as measured by reduction of anterior chamber flare after surgery and prevention of postoperative macular edema. Patients treated with preservative-free diclofenac eyedrops reported significantly better subjective tolerability values ( P = .001), were classified as having less ocular discomfort ( P < .001), and experienced earlier reduction of postoperative conjunctival hyperemia ( P = .029).
Anti-inflammatory efficacy was comparable for all 3 agents. However, preservative-free diclofenac 0.1% eyedrops exhibited a significantly better postoperative subjective and objective tolerability when compared with preserved eyedrops containing ketorolac or diclofenac.
Ketorolac tromethamine and diclofenac sodium are potent nonsteroidal anti-inflammatory drugs (NSAIDs) that are in widespread use worldwide as anti-inflammatory and analgesic agents in inflammatory conditions. Their anti-inflammatory activity results mainly from cyclooxygenase inhibition leading to reduction in prostaglandin synthesis. Ketorolac tromethamine 0.5% ophthalmic solution as well as diclofenac sodium 0.1% ophthalmic solution have been approved as ophthalmic NSAID formulations for the treatment of a variety of ocular inflammatory conditions, including prophylaxis and treatment of postoperative inflammation and pseudophakic macular edema occurring after cataract surgery.
Although topical NSAID eyedrops should alleviate ocular discomfort after surgery, they are at the same time known to be inherently irritating to the ocular surface because of their acidic formulation, the most common adverse reactions after topical instillation of NSAID ophthalmic preparations being transient burning and stinging. Because the irritative potential can be increased further by the addition of preservatives like benzalkonium chloride (BAC), these ocular symptoms also may be related to or worsened by the preservatives used in the formulations. Furthermore, as described by Miyake and associates, after cataract surgery, a pseudophakic maculopathy can be found after application of glaucoma drops containing preservatives. Comparing the active ingredients, preservatives, and vehicles contained in various glaucoma medications, the authors hypothesized that preservatives themselves may be a causative factor for postoperative macular edema.
Recently, the formulation of diclofenac sodium 0.1% was changed because the previous preservative thiomersal was replaced by BAC. Additionally, preservative-free diclofenac sodium 0.1% eyedrops have been approved and offer a new option to the preserved diclofenac and ketorolac eyedrops that currently are the most widely used NSAID eyedrops after cataract surgery in Austria. Comparative data of efficacy and tolerability of this new preparation of diclofenac sodium 0.1% versus the BAC-preserved preparations of diclofenac sodium 0.1% and ketorolac tromethamine 0.5% are missing. Furthermore, the arguments cited above give reason to the question whether preservative-free NSAID eyedrops should be considered as postoperative medication for better ocular tolerability and utmost prevention of pseudophakic cystoid macular edema (CME).
We therefore conducted this study to compare the anti-inflammatory efficacy and tolerability of preservative-free diclofenac sodium 0.1% (Voltaren ophtha SDU; Novartis Pharma, Vienna, Austria) with BAC-preserved diclofenac sodium 0.1% (Voltaren ophtha; Novartis Pharma) and BAC-preserved ketorolac tromethamine 0.5% eye drops (Acular; Pharm Allergan, Ettlingen, Germany) after uncomplicated cataract surgery.
This prospective, randomized, investigator-masked, parallel-group, open-label, comparative, 4-week trial was conducted from July 2005 through February 2008 in an institutional setting at the Department of Ophthalmology and Optometry, Medical University of Vienna. One hundred two consecutive patients scheduled for phacoemulsification cataract surgery with implantation of a posterior chamber intraocular lens were enrolled in the study. Baseline patient characteristics are given in the Table .
|Parameter||Preservative-Free Diclofenac||Preserved Diclofenac||Preserved Ketorolac||P Value|
|Mean age ± SD (range), yrs||66.2 ±10.4 (52 to 85)||68.2 ± 10.4 (51 to 86)||70.8 ± 9.9 (49 to 85)||.17 a|
|Gender, n (%)||.53 b|
|Male||15 (44.1%)||19 (55.9%)||15 (44.1%)|
|Female||19 (55.9%)||15 (44.1%)||19 (55.9%)|
|Median VA (range)|
|Distance (logMAR)||0.39 (0.15 to 1.0)||0.3 (0.1 to 1.3)||0.3 (0.1 to 0.7)||.82 c|
|Near (Jaeger)||2 (1 to 4)||2 (1 to 16)||2 (1 to 9)||.25 c|
|Mean IOP ± SD, mm Hg||15.7 ± 1.9||15.2 ± 2.5||16.2 ± 2.9||.28 a|
|Median anterior chamber flare (range), ph/ms||8.4 (4.0 to 16.8)||6.9 (3.1 to 20.4)||8.2 (2.6 to 20.3)||.88 c|
|Mean foveal thickness ± SD (μm)||148.1 ± 16.8||152.6 ± 15.5||152.4 ± 20.4||.69 a|
|Iris color, n (%)||.74 b|
|Blue, green, grey||17 (50%)||19 (55.9%)||20 (58.8%)|
|Hazel, brown||17 (50%)||15 (44.1%)||14 (41.2%)|
a One-way analysis of variance.
Patients were included if they were older than 40 years and scheduled for phacoemulsification surgery of cataract with posterior chamber intraocular lens implantation. Exclusion criteria consisted of: history of intraocular inflammation or uveitis, pseudoexfoliation syndrome, significant posterior segment disease involving the macular region, and previous ocular surgery, recent topical glaucoma treatment, or both. In addition, subjects with known hypersensitivity to diclofenac sodium, ketorolac tromethamine, any ingredient of the study medications, or a combination thereof, in the case of recent use of topical or systemic NSAIDs or in case of intraoperative or postoperative complications, were excluded from the study.
All operations were performed in a standard way and by the same experienced surgeon (M.A.). Briefly, mydriasis was achieved by instillation of cyclopentolate 1% (Alcon-Couvreur, Puurs, Belgium), tropicamide 1% (Mydriaticum; Nycomed, Linz, Austria), and phenylephrine 2.5% eyedrops. Surgery then was performed under topical anesthesia with oxybuprocaine 1%. Phacoemulsification surgery was carried out via a temporal clear corneal incision, and a foldable posterior chamber intraocular lens was implanted into the capsular bag. The same irrigating solution (BSS solution; Alcon Inc., Fort Worth, Texas, USA) and ophthalmic viscoelastic device (Healon; Advanced Medical Optics, Santa Ana, California, USA) were used in all cases. At the end of surgery, gentamycin–dexamethasone ointment (Dexagenta POS; Ursapharm, Saarbruecken, Germany; preservative free) and a clear cartella shield were applied. Postoperative therapy starting at the first postoperative day consisted of 1 of the 3 study medications containing a NSAID; no additional topical steroids or antibiotics were used.
Study Medications and Study Protocol
Eyes of qualified patients were assigned in a 1:1:1 ratio to 1 of 3 treatment groups using a computer-generated randomization list. The study medications were preservative-free diclofenac sodium 0.1% eye drops, preserved diclofenac sodium 0.1% eye drops (preservative, BAC), or preserved ketorolac tromethamine 0.5% eye drops (preservative, BAC). One drop of the study medication was instilled 4 times daily in the operated eye, starting on the first postoperative day after surgery. Except for the coordinator distributing the study medications (G.K.), all investigators remained blinded to the allocation throughout the entire study. Anti-inflammatory efficacy was evaluated using the parameters listed below. If not stated otherwise, measurements were performed preceding the surgery (preoperative) and 1 day, 1 week, and 1 month after surgery.
Measurements of Anti-inflammatory Efficacy
Anterior Chamber Flare
Postoperative intraocular inflammation was evaluated by measurements of anterior chamber flare using laser flare photometry, because this method provides an automated technique to quantify anterior segment inflammation objectively, and it has been used in a variety of research and clinical situations. Laser photometry analysis of flare is accurate, reproducible, and examiner independent and represents a more precise method for quantifying anterior chamber protein than clinical observation. Another advantage is the linear quantification of flare, which allows for detection of differences in even small patient sample sizes. Anterior chamber flare was assessed using the Laser Flare and Cell Meter (LFCM 1000; Kowa, Tokyo, Japan). The pupils were dilated by instillation of 1 drop of tropicamide 1% (Mydriaticum; Agepha, Vienna, Austria). Thirty minutes later, 7 consecutive laser flare readings were obtained, with a background scatter of less than 10%. The highest and lowest readings were discarded, and the remaining 5 were averaged to obtain the flare measurement. Laser flare values were expressed in photons per millisecond (ph/ms). Calibration of the Laser Flare and Cell Meter was performed on a regular basis.
Mean foveal thickness (central 600-μm circle) was measured with the Retinal Thickness Analyzer (software version 4.5; Talia Technology, Neve-Ilan, Israel). A detailed explanation of the Retinal Thickness Analyzer’s optical principle and its application has been described previously.
Measurements of Ocular Tolerability
At each postoperative visit, the patient had to mark a position on a visual analog scale measuring 100 mm. A mark close to the 0 position should indicate a very comfortable feeling when applying the drops; a mark close to 100 mm should indicate severe pain and stinging. Each assessment was independent from the previous one, because the patients did not have access to their earlier assessment(s). The values were expressed in millimeters.
Subjective Ocular Discomfort
This parameter was evaluated before the slit-lamp examination and consisted of questioning about superficial pain, foreign body or gritty sensation, itching, burning, and other forms of nonspecific discomfort. The following grades were possible: 0 = absent, 0.5 = very mild, 1 = mild, 2 = moderate, 3 = severe, 4 = intolerable.
Conjunctival injection was evaluated using an observer-based grading performed during the slit-lamp examination: 0 = no injection of bulbar conjunctiva, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe.
Snellen charts were used to measure best-corrected distance visual acuity (VA) and Jaeger reading charts for near VA. Snellen distance VA values were converted into the logarithm of the minimal angle of resolution (logMAR) values. No VA measurements were recorded on day 1 after surgery.
Intraocular pressure (IOP) was measured using applanation tonometry. The values were given in millimeters of mercury.
In addition, a slit-lamp examination and dilated indirect funduscopy were performed at every visit.
Quantitative variables are described using mean ± standard deviation (SD) or median as well as minimum and maximum value where appropriate. For nominal and ordinal variables, absolute frequencies and percentages are given. To test whether the 3 medications had comparable baseline values concerning the target variables, either the chi-square test, or a 1-way analysis of variance or Kruskal-Wallis test were applied, depending on sample distribution. The 1-way repeated-measures analysis of variance (with Greenhouse-Geisser correction and linear contrasts calculation for post hoc comparisons, where applicable) was used to check quantitative variables for changes over time and influence of medication. To quantify the strength of correlation between 2 metric variables, the Spearman correlation was calculated. The chi-square test was used to test for a dependency of conjunctival injection on the medication. The change of conjunctival injection over time was analyzed by the Friedman test and the Schaich-Hamerle method for post hoc comparisons. All tests were 2-tailed, and the level of significance was set at α = 0.05. SPSS software for Windows, version 16 (SPSS, Inc, Chicago, Illinois, USA) was used for calculation purposes. With a sample size of 30 eyes per group, a power of 0.8, α = 0.05, and an estimated standard deviation of 7 ph/ms, a significant difference in anterior chamber flare between the 3 groups would have been found at a level of 5.2 ph/ms.
Of the 102 subjects enrolled and randomized, 34 eyes were assigned to each of the 3 treatment groups. Ninety-three patients, 31 of the preservative-free diclofenac group (91.2%), 29 of the preserved diclofenac group (85.3%), and 33 of the preserved ketorolac group (97.1%) completed the study ( Figure 1 ). Seven patients were lost to follow-up (1 had urgent orthopedic surgery and 6 did not appear for follow-up and declined an additional visit despite contact by telephone), and 2 patients had to be excluded because of surgery not performed according to the standard procedure (intraoperative iris prolapse). All 102 patients enrolled in the study were included in the efficacy analyses (intention-to-treat analysis, missing values were taken into account as such). The patient profiles at baseline were comparable regarding age, gender, visual acuity, IOP, anterior chamber flare, and retinal thickness ( Table ). Reflecting the white Austrian population, 56 patients (55%) had light irides (blue, grey, green) and 46 patients (45%) had dark irides (hazel, brown).