- Email: [email protected]
Loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of inflammation after cataract surgery
ARTICLE
Loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of inflammation after cataract surgery Stephen S. Lane, MD, Edward J. Holland, MD
PURPOSE: To evaluate the efficacy of loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the control of postoperative inflammation in patients having routine cataract surgery. SETTING: Private practice, Stillwater, Minnesota, and Cincinnati Eye Institute, Cincinnati, Ohio, USA. DESIGN: Comparative case series. METHODS: Patients were at least 18 years of age and scheduled for routine cataract surgery. Patients were excluded from the study if they had preexisting medical conditions (ie, elevated intraocular pressure [IOP], retinopathy, maculopathy, uveitis) or required medications the investigator believed would put the patient at risk or confound the study. Patients were randomized to receive loteprednol etabonate or prednisolone acetate 4 times daily in addition to bromfenac 0.09% and besifloxacin 0.6% after surgery. Visual acuity, IOP, and anterior chamber cell and flare intensity were assessed over 3 weeks after cataract surgery. The primary endpoint was the level of anterior chamber cell and flare intensity in patients treated with loteprednol etabonate or prednisolone acetate. RESULTS: The study enrolled 88 patients (46 loteprednol etabonate, 42 prednisolone acetate). Equivalency was achieved between the 2 treatment groups with no significant differences throughout the 3-week follow-up. There was less fluctuation in IOP assessments in patients treated with loteprednol etabonate than in patients treated with prednisolone acetate, in particular 1 day and 3 days postoperatively. CONCLUSIONS: The results indicate that equivalent control of inflammation can be obtained through treatment with loteprednol etabonate or prednisolone acetate after cataract surgery. In addition, treatment with loteprednol etabonate may result in less IOP fluctuation. Financial Disclosure: Dr. Lane is a consultant to Bausch & Lomb, Rochester, New York, Alcon Laboratories, Inc., Fort Worth, Texas, and ISTA Pharmaceuticals, Irvine, California, USA. Dr. Holland is a consultant to Bausch & Lomb, Rochester, New York, and Alcon Laboratories, Inc., Fort Worth, Texas, USA. Neither author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2013; 39:168–173 Q 2012 ASCRS and ESCRS
Continuous advances in pharmaceutical products, medical devices, and surgical techniques result in high patient expectations with regard to the results of surgical procedures as well as the management of pain and discomfort. It is important to treat and prevent pain and inflammation resulting from cataract surgery to optimize the overall experience for patients. Topical corticosteroids are used to treat a wide variety of ocular conditions that have an inflammatory component and are generally indicated for the treatment of steroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior segment. Postsurgical inflammation related to cataract surgery 168
Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
is most often treated with topical corticosteroids; however, concerns remain regarding the potential for steroid-induced side effects such as elevated intraocular pressure (IOP), glaucoma, and secondary infections.1 As a result of these concerns, ophthalmic corticosteroid use is often limited in duration and IOP levels are monitored throughout the treatment period. Loteprednol etabonate is an ester-based corticosteroid as opposed to a ketone-based corticosteroid such as dexamethasone or prednisolone.2,3 Loteprednol etabonate was designed specifically for ophthalmic use.4 Deesterification of loteprednol etabonate results in the formation of an inactive carboxylic acid 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2012.10.039
LOTEPREDNOL ETABONATE OPHTHALMIC SUSPENSION
metabolite. The ester functional group at the C-20 of loteprednol etabonate, instead of a ketone group, is believed to result in a lower toxicity profile and a reduced propensity for elevation in IOP compared with ketone corticosteroids.5,6 A variety of ophthalmic formulations of loteprednol etabonate have been available for clinical use for more than a decade. Clinical studies of the loteprednol etabonate 0.5% ophthalmic suspension have shown efficacy in the treatment of inflammation related to seasonal allergic conjunctivitis,7 giant papillary conjunctivitis,8,9 anterior uveitis,10 dry eye,11 and cataract surgery.12–14 Results in several clinical studies5,15,16 indicate that treatment with prednisolone and dexamethasone results in a higher mean change in IOP than treatment with loteprednol etabonate. Although loteprednol etabonate has been shown to be effective for the treatment of inflammation related to cataract surgery, clinicians report anecdotally that inflammation is not as well controlled with loteprednol etabonate treatment as with conventional topical corticosteroids, such as prednisolone acetate. This study was performed to evaluate loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of postoperative inflammation in patients having routine cataract surgery. PATIENTS AND METHODS This multicenter investigator-masked randomized study was designed to evaluate the effects of loteprednol etabonate 0.5% (Lotemax) compared with those of prednisolone acetate 1.0% (Pred Forte) on postsurgical inflammation in patients after routine cataract surgery. All visits involved in the study occurred in a clinical setting, and certified investigators and technicians performed all study procedures. The study protocol, informed consent form, and all recruiting materials
Submitted: July 28, 2012. Final revision submitted: September 28, 2012. Accepted: October 16, 2012. From Associated Eye Care (Lane), Stillwater, Minnesota, and Cincinnati Eye Institute (Holland), University of Cincinnati, Cincinnati, Ohio, USA. Supported by an unrestricted Grant from Bausch & Lomb, Inc., Rochester, New York, USA. Terri Flom, COT, and Amy Jost, COT, CCRC, aided in the clinical evaluation of the patients and in data collection. Presented as a poster at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Chicago, Illinois, USA, April 2012. Corresponding author: Stephen S. Lane, MD, Associated Eye Care, 2950 Curve Crest Boulevard, Stillwater, Minnesota 55082, USA. E-mail: [email protected].
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were approved by the Biomed Institutional Review Board (IRB) (Biomedical Research Institute of America, San Diego, California, USA). This study was performed in accordance with current Good Clinical Practice guidelines and the Declaration of Helsinki. Before its initiation, the study was registered at the National Institutes of Health Clinical Trials site under the registry number NCT01384266.A The patients who participated in this study were recruited from patients scheduled for routine cataract surgery at the 2 clinical sites. All patients were required to be at least 18 years of age (postmenopausal for female patients). Patients were considered ineligible for the study if at the time of screening they were being treated for elevated IOP, retinopathy, maculopathy, uveitis, or cornea or vitreous opacities that would interfere with visual acuity. In addition, patients were excluded from the study if they had previous ocular trauma or intraocular surgery or had a visual potential in the fellow eye of worse than 20/60. Patients were ineligible for the study if they were expected to require the use of concurrent ocular or systemic nonsteroidal antiinflammatory drugs (NSAIDs), mast cell stabilizers, antihistamines, or decongestants within 2 days before or 21 days after surgery. (Intraoperative NSAIDs for mydriasis were permitted.) Also, patients were excluded if they were expected to require concurrent ocular or systemic corticosteroids or immunosuppressants (including cyclosporine [Restasis]) within 14 days before or 21 days after surgery. A signed IRB-approved informed consent form was required for each patient before any study-related procedures were performed. Six study visits were required for each patient to complete the study as follows: screening (within 14 days before surgery), surgery, 1 day postoperatively, 3 days (G1 day) postoperatively, 7 days (G2 days) postoperatively, and the exit visit 21 days (21 to 25 days) postoperatively. The following assessments were performed on the study eye only at each study visit, except on the day of surgery: logMAR corrected distance visual acuity (CDVA) (pinhole acuity was allowed on the 1-day postoperative visit), evaluation of anterior chamber cells and flare intensity, and IOP (Goldmann applanation tonometry). A fundus examination was performed preoperatively at the screening visit and at the exit visit. Adverse events were also queried and recorded at each study visit. Randomization of patients to loteprednol etabonate 0.5% or prednisolone acetate 1.0% was performed at the screening visit. Randomization was performed at the time the surgery was scheduled, and assignments were made based on a table of random numbers. Investigators remained masked to the study drug treatment group randomization. Investigators were masked throughout the study by having each patient assigned to prednisolone acetate or loteprednol etabonate by the surgical scheduler, who was not involved in preoperative or postoperative patient care at the time of scheduling. In addition, documentation in the chart was noted as “steroid 4 times a day” without designation to the steroid name. In addition to the randomized study drug, all patients were also provided with besifloxacin 0.6% (Besivance) and bromfenac 0.09% (Xibrom) after surgery. Patients were instructed how to administer the medications and were provided with information detailing the treatment regimen for each as follows: loteprednol etabonate or prednisolone acetate 4 times a day for 3 weeks after surgery, besifloxacin 4 times a day for 2 weeks after surgery, and bromfenac 2 times a day for 2 weeks after surgery. Descriptive statistics (mean G standard deviation or mean G standard error) were prepared for the patient
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Table 1. Patient demographics by treatment group and overall.
Parameter Age (y) Mean G SD Range Sex, n (%) Male Female Missing Race, n (%) White Hispanic Missing
Prednisolone (n Z 42)
Loteprednol (n Z 46)
All Patients (N Z 88)
67.7 G 10.4 32-87
71.2 G 8.4 44-89
69.5 G 9.5 32-89
23 (54.8) 18 (42.9) 1 (2.3)
23 (50.0) 22 (47.8) 1 (2.2)
46 (52.3) 40 (45.5) 2 (2.2)
41 (97.6) 1 (2.4) 0
43 (93.4) 1 (2.2) 2 (4.4)
84 (95.4) 2 (2.3) 2 (2.3)
demographic information and the following clinical endpoints assessed in the study: IOP, change in IOP from baseline, and CDVA. Cell assessments were categorized by the number of cells observed within a 1.0 mm 6.0 mm slit-beam parallelogram and scored on a scale of 0 to 3 (0 Z no cells; 1 Z 1 to 5 cells; 2 Z 6 to 15 cells; 3 Z 16 to 30 cells). Flare assessments were categorized by severity and scored on a scale of 0 to 3 (0 Z none; 1 Z mild; 2 Z moderate; 3 Z severe). Statistical testing was performed using a 2-tailed t test (demographic data and IOP), Wilcoxon rank-sum test (CDVA), and contingency table analysis (cell and flare assessments). A P value of 0.05 or less was the threshold for determining statistical significance. The primary endpoint in this study was equivalency in anterior chamber cell and flare intensity between treatment groups.
RESULTS Ninety-three patients were enrolled in the study, 45 in the prednisolone acetate group and 48 in the loteprednol etabonate group. Eighty-eight patients met the inclusion criteria and completed the study. One patient randomized to the prednisolone acetate group was prematurely discontinued from the study due to an adverse event that was classified as unrelated to the treatment. Table 1 shows the demographic
Figure 1. Mean IOP G standard error by treatment group and study visit (IOP Z intraocular pressure).
information collected from the patients. No statistically significant differences were observed in any demographic parameter between treatment groups (age: PZ.15, 2-tailed t test). Figure 1 shows the mean IOP at screening and 1, 3, 7, and 21 days postoperatively. At each assessment, the mean IOP was higher in patients treated with prednisolone acetate than in patients treated with loteprednol etabonate; however, there were no statistically significant differences between the treatment groups (2-tailed t test). Similarly, the mean change in IOP readings was higher in the prednisolone acetate group than in the loteprednol etabonate group; however, no statistically significant differences were observed (2-tailed t test) (Figure 2). Figure 3 shows the mean CDVA over time. The mean preoperative CDVA was similar between the 2 treatment groups. Postoperative improvements in the mean CDVA occurred in both groups at 1 day; the CDVA continued to improve out to 7 days postoperatively. A statistically significant difference in CDVA was observed between the treatment groups 3 days postoperatively (PZ.05, Wilcoxon rank-sum test). Control of inflammation was equivalent between treatment groups by assessment of cell and flare grading 1, 3, 7, and 21 days postoperatively. Figure 4 shows the mean scores for the anterior chamber cell assessment for each visit after surgery. Figure 5 shows the mean scores for flare intensity in each treatment group. There were no statistically significant differences in cell or flare between the 2 treatment groups (contingency table analysis). The study treatments were well tolerated. There were no complications at the time of surgery in any patient enrolled in the study. Five patients (3 prednisolone acetate group, 2 loteprednol etabonate group) reported adverse events during the course of the study. The adverse events reported by 4 patients were deemed unrelated to study treatment; 2 patients
Figure 2. Mean change in IOP G standard error after surgery compared with the preoperative baseline by treatment group and visit (IOP Z intraocular pressure).
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Figure 3. Mean CDVA G standard error by treatment group and study visit (CDVA Z corrected distance visual acuity).
had an elevation in IOP higher than 10 mm Hg the day after the surgical procedure that resolved with pressure-lowering medication, 1 patient had anterior chamber inflammation in the contralateral eye that resolved with treatment, and 1 patient reported transient worsening of back pain. One patient in the prednisolone acetate treatment group had an elevation in IOP higher than 10 mm Hg 7 days postoperatively; the increase was deemed related to the study treatment. The elevated IOP was controlled with subsequent treatment and follow-up. DISCUSSION In this study, we found that administration of loteprednol etabonate or prednisolone acetate as part of the postsurgical regimen resulted in equivalent control of postsurgical-related inflammation. In addition, the mean change in IOP readings was higher in patients treated with prednisolone acetate; however, no statistically significant differences were observed between the 2 treatment groups. Both study drugs (loteprednol etabonate and prednisolone acetate) were well tolerated. Ocular adverse events reported in the study were predominantly
Figure 4. Mean cell score G standard error by group and study visit.
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related to elevation of IOP. Only 1 patient had an ocular adverse event that was deemed related to the study drug treatment. That patient was in the prednisolone acetate group and had elevated IOP at visit 5 (7 days after cataract surgery); the IOP increased to 40 mm Hg compared with a baseline reading of 17 mm Hg. The use of topical corticosteroid to control pain and inflammation after surgical procedures is a commonly accepted practice. Although prednisolone acetate is generally considered a high-potency steroid among the ketone-based steroid class, evaluation of the relative potency between topical steroids in a clinical setting is challenging. Large, well-controlled studies, such as clinical trials used for registration and approval of ophthalmic formulations, are typically performed in a manner that allows evaluation of the efficacy of the antiinflammatory properties of the agent in comparison with a placebo14,17 rather than an active comparator. Head-to-head studies on this scale, designed to evaluate a differential efficacy component, would be prohibitively expensive and are not required for regulatory approval. This study was designed to allow evaluation of the relative safety profile of loteprednol etabonate and prednisolone acetate in addition to the therapeutic efficacy pertaining to the control of postsurgical inflammation related to routine cataract surgery. The branded formulation of prednisolone acetate (Pred Forte) was used in an attempt to avoid potential concerns regarding the accepted efficacy and dose uniformity of the prednisolone acetate formulation.18 Equivalent control of postsurgical inflammation was achieved through the use of both agents. Antiinflammatory agents such as loteprednol etabonate were developed to retain the conventional steroid therapeutic efficacy while minimizing complications due to side effects4; however, they have been considered to have less potency than steroids such as prednisolone acetate based on anecdotal evidencedhence the designation of these agents as soft steroids. The results in this study
Figure 5. Mean flare score G standard error by treatment group and study visit.
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indicate that equivalent antiinflammatory effects may be achieved with either agent. Elevation of IOP, presumably due to a reduction in aqueous humor outflow, is one of the primary safety concerns with the extended use of ophthalmic corticosteroids. Although the precise mechanism by which the elevation of IOP occurs is still not entirely clear, findings in previous studies5,6 indicate a higher frequency of clinically meaningful increases in IOP associated with ketone-based steroids such as prednisolone acetate, as opposed to loteprednol etabonate, an ester-based steroid. The results in the present study confirm these findings. A limitation of this study is the relative small sample size compared with that in larger clinical studies that are used to seek regulatory approval for investigation of new drugs. Also, postsurgical pain was not assessed in the present study. The primary aim was to evaluate the relative antiinflammatory properties of loteprednol etabonate and prednisolone acetate. In placebocontrolled studies, the primary endpoint of similarly designed studies is often complete resolution of anterior chamber inflammation (cell and flare) and the absence of postsurgical pain. This study was designed to enable evaluation of the antiinflammatory properties of both steroids in a relative manner rather than the proportion of patients who achieved complete resolution. In conclusion, the loteprednol etabonate and prednisolone acetate formulations used in the present study provided equivalent control of anterior chamber inflammation after routine cataract surgery. Further investigation in the form of a larger multicenter study may be warranted. WHAT WAS KNOWN Loteprednol etabonate and prednisolone acetate have been shown to be effective for the treatment of inflammation related to cataract surgery. However, clinicians report anecdotally that the inflammation is not as well controlled with loteprednol etabonate as with prednisolone acetate. WHAT THIS PAPER ADDS The findings of this study indicate that contrary to anecdotal reports, equivalent control of anterior chamber inflammation was achieved through the use of loteprednol etabonate and the branded formulation of prednisolone acetate in patients having routine cataract surgery. Patients treated with loteprednol etabonate had less of a mean change in IOP, particularly in the first 3 days after the cataract surgical procedure, although no statistically significant differences were observed between treatment groups.
REFERENCES 1. Pavesio CE, Decory HH. Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol 2008; 92:455–459 2. Bodor N, Loftsson T, Wu W- M. Metabolism, distribution, and transdermal permeation of a soft corticosteroid, loteprednol etabonate. Pharm Res 1992; 9:1275–1278 3. Druzgala P, Wu W-M, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res 1991; 10:933–937 4. Bodor N, Buchwald P. Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems. AAPS J 2005; 7:E820–E833. Available at: http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC2750951/pdf/12248_ 2008_Article_74820.pdf. Accessed October 30, 2012 5. Bartlett JD, Horwitz B, Laibovitz R, Howes JF. Intraocular pressure response to loteprednol etabonate in known steroid responders. J Ocul Pharmacol 1993; 9:157–165 6. Novack GD, Howes J, Crockett RS, Sherwood MB. Change in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma 1998; 7:266–269 7. Dell SJ, Schulman DG, Lowry GM, Howes J. A controlled evaluation of the efficacy and safety of loteprednol etabonate in the prophylactic treatment of seasonal allergic conjunctivitis; Loteprednol Allergic Conjunctivitis Study Group. Am J Ophthalmol 1997; 123:791–797 8. Asbell P, Howes J. A double-masked, placebo-controlled evaluation of the efficacy and safety of loteprednol etabonate in the treatment of giant papillary conjunctivitis. CLAO J 1997; 23:31–36 9. Friedlander MH, Howes J. A double-masked, placebo controlled evaluation of the efficacy and safety of loteprednol etabonate in the treatment of giant papillary conjunctivitis; the Loteprednol Etabonate Giant Papillary Conjunctivitis Study Group I. Am J Ophthalmol 1997; 123:455–464 10. The Loteprednol Etabonate US Uveitis Study Group. Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Am J Ophthalmol 1999; 127:537–544 11. Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva CS, Bartels SP, Micuda T, Proskin HM, Vogel R. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for the treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol 2004; 138:444–457 12. Stewart R, Horwitz B, Howes J, Novack GD, Hart K. Doublemasked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation; Loteprednol Etabonate Post-Operative Inflammation Study Group 1. J Cataract Refract Surg 1998; 24:1480–1489 13. The Loteprednol Etabonate Postoperative Inflammation Study Group 2. A double-masked, placebo-controlled evaluation of 0.5% loteprednol etabonate in the treatment of postoperative inflammation. Ophthalmology 1998; 105:1780–1786 14. Comstock TL, Paterno MR, Singh A, Erb T, Davis E. Safety and efficacy of loteprednol etabonate ophthalmic ointment 0.5% for the treatment of inflammation and pain following cataract surgery. Clin Ophthalmol 2011; 5:177–186. Available at: http://www.ncbi. nlm.nih.gov/pmc/articles/PMC3045067/pdf/opth-5-177.pdf. Accessed October 30, 2012 15. Holland EJ, Bartlett JD, Paterno MR, Usner DW, Comstock TL. Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea 2008; 27:50–55
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16. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin 2008; 24:287–296 17. Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS, and the Difluprednate Ophthalmic Emulsion 0.05% (Durezol) Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg 2009; 35:26–34 18. Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. Clin Ophthalmol 2010; 4:1119–1124. Available at: http://www.dovepress.com/getfile.php?fileIDZ7784. Accessed October 30, 2012
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OTHER CITED MATERIAL A. U.S. National Institutes of Health. Clinical Trials. A Comparison of 0.5% Loteprednol Etabonate Versus 1% Prednisolone Acetate Following Cataract Surgery, Study number NCT01384266. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01384266? termZnct01384266&rankZ1. Accessed October 30, 2012
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First author: Stephen S. Lane, MD Private practice, Stillwater, Minnesota, USA
Loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of inflammation after cataract surgery Stephen S. Lane, MD, Edward J. Holland, MD
PURPOSE: To evaluate the efficacy of loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the control of postoperative inflammation in patients having routine cataract surgery. SETTING: Private practice, Stillwater, Minnesota, and Cincinnati Eye Institute, Cincinnati, Ohio, USA. DESIGN: Comparative case series. METHODS: Patients were at least 18 years of age and scheduled for routine cataract surgery. Patients were excluded from the study if they had preexisting medical conditions (ie, elevated intraocular pressure [IOP], retinopathy, maculopathy, uveitis) or required medications the investigator believed would put the patient at risk or confound the study. Patients were randomized to receive loteprednol etabonate or prednisolone acetate 4 times daily in addition to bromfenac 0.09% and besifloxacin 0.6% after surgery. Visual acuity, IOP, and anterior chamber cell and flare intensity were assessed over 3 weeks after cataract surgery. The primary endpoint was the level of anterior chamber cell and flare intensity in patients treated with loteprednol etabonate or prednisolone acetate. RESULTS: The study enrolled 88 patients (46 loteprednol etabonate, 42 prednisolone acetate). Equivalency was achieved between the 2 treatment groups with no significant differences throughout the 3-week follow-up. There was less fluctuation in IOP assessments in patients treated with loteprednol etabonate than in patients treated with prednisolone acetate, in particular 1 day and 3 days postoperatively. CONCLUSIONS: The results indicate that equivalent control of inflammation can be obtained through treatment with loteprednol etabonate or prednisolone acetate after cataract surgery. In addition, treatment with loteprednol etabonate may result in less IOP fluctuation. Financial Disclosure: Dr. Lane is a consultant to Bausch & Lomb, Rochester, New York, Alcon Laboratories, Inc., Fort Worth, Texas, and ISTA Pharmaceuticals, Irvine, California, USA. Dr. Holland is a consultant to Bausch & Lomb, Rochester, New York, and Alcon Laboratories, Inc., Fort Worth, Texas, USA. Neither author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2013; 39:168–173 Q 2012 ASCRS and ESCRS
Continuous advances in pharmaceutical products, medical devices, and surgical techniques result in high patient expectations with regard to the results of surgical procedures as well as the management of pain and discomfort. It is important to treat and prevent pain and inflammation resulting from cataract surgery to optimize the overall experience for patients. Topical corticosteroids are used to treat a wide variety of ocular conditions that have an inflammatory component and are generally indicated for the treatment of steroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior segment. Postsurgical inflammation related to cataract surgery 168
Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
is most often treated with topical corticosteroids; however, concerns remain regarding the potential for steroid-induced side effects such as elevated intraocular pressure (IOP), glaucoma, and secondary infections.1 As a result of these concerns, ophthalmic corticosteroid use is often limited in duration and IOP levels are monitored throughout the treatment period. Loteprednol etabonate is an ester-based corticosteroid as opposed to a ketone-based corticosteroid such as dexamethasone or prednisolone.2,3 Loteprednol etabonate was designed specifically for ophthalmic use.4 Deesterification of loteprednol etabonate results in the formation of an inactive carboxylic acid 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2012.10.039
LOTEPREDNOL ETABONATE OPHTHALMIC SUSPENSION
metabolite. The ester functional group at the C-20 of loteprednol etabonate, instead of a ketone group, is believed to result in a lower toxicity profile and a reduced propensity for elevation in IOP compared with ketone corticosteroids.5,6 A variety of ophthalmic formulations of loteprednol etabonate have been available for clinical use for more than a decade. Clinical studies of the loteprednol etabonate 0.5% ophthalmic suspension have shown efficacy in the treatment of inflammation related to seasonal allergic conjunctivitis,7 giant papillary conjunctivitis,8,9 anterior uveitis,10 dry eye,11 and cataract surgery.12–14 Results in several clinical studies5,15,16 indicate that treatment with prednisolone and dexamethasone results in a higher mean change in IOP than treatment with loteprednol etabonate. Although loteprednol etabonate has been shown to be effective for the treatment of inflammation related to cataract surgery, clinicians report anecdotally that inflammation is not as well controlled with loteprednol etabonate treatment as with conventional topical corticosteroids, such as prednisolone acetate. This study was performed to evaluate loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of postoperative inflammation in patients having routine cataract surgery. PATIENTS AND METHODS This multicenter investigator-masked randomized study was designed to evaluate the effects of loteprednol etabonate 0.5% (Lotemax) compared with those of prednisolone acetate 1.0% (Pred Forte) on postsurgical inflammation in patients after routine cataract surgery. All visits involved in the study occurred in a clinical setting, and certified investigators and technicians performed all study procedures. The study protocol, informed consent form, and all recruiting materials
Submitted: July 28, 2012. Final revision submitted: September 28, 2012. Accepted: October 16, 2012. From Associated Eye Care (Lane), Stillwater, Minnesota, and Cincinnati Eye Institute (Holland), University of Cincinnati, Cincinnati, Ohio, USA. Supported by an unrestricted Grant from Bausch & Lomb, Inc., Rochester, New York, USA. Terri Flom, COT, and Amy Jost, COT, CCRC, aided in the clinical evaluation of the patients and in data collection. Presented as a poster at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Chicago, Illinois, USA, April 2012. Corresponding author: Stephen S. Lane, MD, Associated Eye Care, 2950 Curve Crest Boulevard, Stillwater, Minnesota 55082, USA. E-mail: [email protected].
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were approved by the Biomed Institutional Review Board (IRB) (Biomedical Research Institute of America, San Diego, California, USA). This study was performed in accordance with current Good Clinical Practice guidelines and the Declaration of Helsinki. Before its initiation, the study was registered at the National Institutes of Health Clinical Trials site under the registry number NCT01384266.A The patients who participated in this study were recruited from patients scheduled for routine cataract surgery at the 2 clinical sites. All patients were required to be at least 18 years of age (postmenopausal for female patients). Patients were considered ineligible for the study if at the time of screening they were being treated for elevated IOP, retinopathy, maculopathy, uveitis, or cornea or vitreous opacities that would interfere with visual acuity. In addition, patients were excluded from the study if they had previous ocular trauma or intraocular surgery or had a visual potential in the fellow eye of worse than 20/60. Patients were ineligible for the study if they were expected to require the use of concurrent ocular or systemic nonsteroidal antiinflammatory drugs (NSAIDs), mast cell stabilizers, antihistamines, or decongestants within 2 days before or 21 days after surgery. (Intraoperative NSAIDs for mydriasis were permitted.) Also, patients were excluded if they were expected to require concurrent ocular or systemic corticosteroids or immunosuppressants (including cyclosporine [Restasis]) within 14 days before or 21 days after surgery. A signed IRB-approved informed consent form was required for each patient before any study-related procedures were performed. Six study visits were required for each patient to complete the study as follows: screening (within 14 days before surgery), surgery, 1 day postoperatively, 3 days (G1 day) postoperatively, 7 days (G2 days) postoperatively, and the exit visit 21 days (21 to 25 days) postoperatively. The following assessments were performed on the study eye only at each study visit, except on the day of surgery: logMAR corrected distance visual acuity (CDVA) (pinhole acuity was allowed on the 1-day postoperative visit), evaluation of anterior chamber cells and flare intensity, and IOP (Goldmann applanation tonometry). A fundus examination was performed preoperatively at the screening visit and at the exit visit. Adverse events were also queried and recorded at each study visit. Randomization of patients to loteprednol etabonate 0.5% or prednisolone acetate 1.0% was performed at the screening visit. Randomization was performed at the time the surgery was scheduled, and assignments were made based on a table of random numbers. Investigators remained masked to the study drug treatment group randomization. Investigators were masked throughout the study by having each patient assigned to prednisolone acetate or loteprednol etabonate by the surgical scheduler, who was not involved in preoperative or postoperative patient care at the time of scheduling. In addition, documentation in the chart was noted as “steroid 4 times a day” without designation to the steroid name. In addition to the randomized study drug, all patients were also provided with besifloxacin 0.6% (Besivance) and bromfenac 0.09% (Xibrom) after surgery. Patients were instructed how to administer the medications and were provided with information detailing the treatment regimen for each as follows: loteprednol etabonate or prednisolone acetate 4 times a day for 3 weeks after surgery, besifloxacin 4 times a day for 2 weeks after surgery, and bromfenac 2 times a day for 2 weeks after surgery. Descriptive statistics (mean G standard deviation or mean G standard error) were prepared for the patient
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Table 1. Patient demographics by treatment group and overall.
Parameter Age (y) Mean G SD Range Sex, n (%) Male Female Missing Race, n (%) White Hispanic Missing
Prednisolone (n Z 42)
Loteprednol (n Z 46)
All Patients (N Z 88)
67.7 G 10.4 32-87
71.2 G 8.4 44-89
69.5 G 9.5 32-89
23 (54.8) 18 (42.9) 1 (2.3)
23 (50.0) 22 (47.8) 1 (2.2)
46 (52.3) 40 (45.5) 2 (2.2)
41 (97.6) 1 (2.4) 0
43 (93.4) 1 (2.2) 2 (4.4)
84 (95.4) 2 (2.3) 2 (2.3)
demographic information and the following clinical endpoints assessed in the study: IOP, change in IOP from baseline, and CDVA. Cell assessments were categorized by the number of cells observed within a 1.0 mm 6.0 mm slit-beam parallelogram and scored on a scale of 0 to 3 (0 Z no cells; 1 Z 1 to 5 cells; 2 Z 6 to 15 cells; 3 Z 16 to 30 cells). Flare assessments were categorized by severity and scored on a scale of 0 to 3 (0 Z none; 1 Z mild; 2 Z moderate; 3 Z severe). Statistical testing was performed using a 2-tailed t test (demographic data and IOP), Wilcoxon rank-sum test (CDVA), and contingency table analysis (cell and flare assessments). A P value of 0.05 or less was the threshold for determining statistical significance. The primary endpoint in this study was equivalency in anterior chamber cell and flare intensity between treatment groups.
RESULTS Ninety-three patients were enrolled in the study, 45 in the prednisolone acetate group and 48 in the loteprednol etabonate group. Eighty-eight patients met the inclusion criteria and completed the study. One patient randomized to the prednisolone acetate group was prematurely discontinued from the study due to an adverse event that was classified as unrelated to the treatment. Table 1 shows the demographic
Figure 1. Mean IOP G standard error by treatment group and study visit (IOP Z intraocular pressure).
information collected from the patients. No statistically significant differences were observed in any demographic parameter between treatment groups (age: PZ.15, 2-tailed t test). Figure 1 shows the mean IOP at screening and 1, 3, 7, and 21 days postoperatively. At each assessment, the mean IOP was higher in patients treated with prednisolone acetate than in patients treated with loteprednol etabonate; however, there were no statistically significant differences between the treatment groups (2-tailed t test). Similarly, the mean change in IOP readings was higher in the prednisolone acetate group than in the loteprednol etabonate group; however, no statistically significant differences were observed (2-tailed t test) (Figure 2). Figure 3 shows the mean CDVA over time. The mean preoperative CDVA was similar between the 2 treatment groups. Postoperative improvements in the mean CDVA occurred in both groups at 1 day; the CDVA continued to improve out to 7 days postoperatively. A statistically significant difference in CDVA was observed between the treatment groups 3 days postoperatively (PZ.05, Wilcoxon rank-sum test). Control of inflammation was equivalent between treatment groups by assessment of cell and flare grading 1, 3, 7, and 21 days postoperatively. Figure 4 shows the mean scores for the anterior chamber cell assessment for each visit after surgery. Figure 5 shows the mean scores for flare intensity in each treatment group. There were no statistically significant differences in cell or flare between the 2 treatment groups (contingency table analysis). The study treatments were well tolerated. There were no complications at the time of surgery in any patient enrolled in the study. Five patients (3 prednisolone acetate group, 2 loteprednol etabonate group) reported adverse events during the course of the study. The adverse events reported by 4 patients were deemed unrelated to study treatment; 2 patients
Figure 2. Mean change in IOP G standard error after surgery compared with the preoperative baseline by treatment group and visit (IOP Z intraocular pressure).
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Figure 3. Mean CDVA G standard error by treatment group and study visit (CDVA Z corrected distance visual acuity).
had an elevation in IOP higher than 10 mm Hg the day after the surgical procedure that resolved with pressure-lowering medication, 1 patient had anterior chamber inflammation in the contralateral eye that resolved with treatment, and 1 patient reported transient worsening of back pain. One patient in the prednisolone acetate treatment group had an elevation in IOP higher than 10 mm Hg 7 days postoperatively; the increase was deemed related to the study treatment. The elevated IOP was controlled with subsequent treatment and follow-up. DISCUSSION In this study, we found that administration of loteprednol etabonate or prednisolone acetate as part of the postsurgical regimen resulted in equivalent control of postsurgical-related inflammation. In addition, the mean change in IOP readings was higher in patients treated with prednisolone acetate; however, no statistically significant differences were observed between the 2 treatment groups. Both study drugs (loteprednol etabonate and prednisolone acetate) were well tolerated. Ocular adverse events reported in the study were predominantly
Figure 4. Mean cell score G standard error by group and study visit.
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related to elevation of IOP. Only 1 patient had an ocular adverse event that was deemed related to the study drug treatment. That patient was in the prednisolone acetate group and had elevated IOP at visit 5 (7 days after cataract surgery); the IOP increased to 40 mm Hg compared with a baseline reading of 17 mm Hg. The use of topical corticosteroid to control pain and inflammation after surgical procedures is a commonly accepted practice. Although prednisolone acetate is generally considered a high-potency steroid among the ketone-based steroid class, evaluation of the relative potency between topical steroids in a clinical setting is challenging. Large, well-controlled studies, such as clinical trials used for registration and approval of ophthalmic formulations, are typically performed in a manner that allows evaluation of the efficacy of the antiinflammatory properties of the agent in comparison with a placebo14,17 rather than an active comparator. Head-to-head studies on this scale, designed to evaluate a differential efficacy component, would be prohibitively expensive and are not required for regulatory approval. This study was designed to allow evaluation of the relative safety profile of loteprednol etabonate and prednisolone acetate in addition to the therapeutic efficacy pertaining to the control of postsurgical inflammation related to routine cataract surgery. The branded formulation of prednisolone acetate (Pred Forte) was used in an attempt to avoid potential concerns regarding the accepted efficacy and dose uniformity of the prednisolone acetate formulation.18 Equivalent control of postsurgical inflammation was achieved through the use of both agents. Antiinflammatory agents such as loteprednol etabonate were developed to retain the conventional steroid therapeutic efficacy while minimizing complications due to side effects4; however, they have been considered to have less potency than steroids such as prednisolone acetate based on anecdotal evidencedhence the designation of these agents as soft steroids. The results in this study
Figure 5. Mean flare score G standard error by treatment group and study visit.
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indicate that equivalent antiinflammatory effects may be achieved with either agent. Elevation of IOP, presumably due to a reduction in aqueous humor outflow, is one of the primary safety concerns with the extended use of ophthalmic corticosteroids. Although the precise mechanism by which the elevation of IOP occurs is still not entirely clear, findings in previous studies5,6 indicate a higher frequency of clinically meaningful increases in IOP associated with ketone-based steroids such as prednisolone acetate, as opposed to loteprednol etabonate, an ester-based steroid. The results in the present study confirm these findings. A limitation of this study is the relative small sample size compared with that in larger clinical studies that are used to seek regulatory approval for investigation of new drugs. Also, postsurgical pain was not assessed in the present study. The primary aim was to evaluate the relative antiinflammatory properties of loteprednol etabonate and prednisolone acetate. In placebocontrolled studies, the primary endpoint of similarly designed studies is often complete resolution of anterior chamber inflammation (cell and flare) and the absence of postsurgical pain. This study was designed to enable evaluation of the antiinflammatory properties of both steroids in a relative manner rather than the proportion of patients who achieved complete resolution. In conclusion, the loteprednol etabonate and prednisolone acetate formulations used in the present study provided equivalent control of anterior chamber inflammation after routine cataract surgery. Further investigation in the form of a larger multicenter study may be warranted. WHAT WAS KNOWN Loteprednol etabonate and prednisolone acetate have been shown to be effective for the treatment of inflammation related to cataract surgery. However, clinicians report anecdotally that the inflammation is not as well controlled with loteprednol etabonate as with prednisolone acetate. WHAT THIS PAPER ADDS The findings of this study indicate that contrary to anecdotal reports, equivalent control of anterior chamber inflammation was achieved through the use of loteprednol etabonate and the branded formulation of prednisolone acetate in patients having routine cataract surgery. Patients treated with loteprednol etabonate had less of a mean change in IOP, particularly in the first 3 days after the cataract surgical procedure, although no statistically significant differences were observed between treatment groups.
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16. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin 2008; 24:287–296 17. Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS, and the Difluprednate Ophthalmic Emulsion 0.05% (Durezol) Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg 2009; 35:26–34 18. Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. Clin Ophthalmol 2010; 4:1119–1124. Available at: http://www.dovepress.com/getfile.php?fileIDZ7784. Accessed October 30, 2012
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OTHER CITED MATERIAL A. U.S. National Institutes of Health. Clinical Trials. A Comparison of 0.5% Loteprednol Etabonate Versus 1% Prednisolone Acetate Following Cataract Surgery, Study number NCT01384266. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01384266? termZnct01384266&rankZ1. Accessed October 30, 2012
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First author: Stephen S. Lane, MD Private practice, Stillwater, Minnesota, USA