- Email: [email protected]
Comparison of prednisolone acetate 1.0% and difluprednate ophthalmic emulsion 0.05% after cataract surgery: Incidence of postoperative steroid-induced ocular hypertension
223
ARTICLE
Comparison of prednisolone acetate 1.0% and difluprednate ophthalmic emulsion 0.05% after cataract surgery: Incidence of postoperative steroid-induced ocular hypertension Marius A. Tijunelis, MD, MBA, Erica Person, MD, MS, Leslie M. Niziol, MS, David C. Musch, PhD, MPH, Paul Ernest, MD, Madeline McBain, Shahzad I. Mian, MD
Purpose: To compare intraocular pressure (IOP) outcomes between 2 common, commercially available corticosteroid drops: difluprednate ophthalmic emulsion 0.05% and prednisolone acetate 1.0%.
Setting: TLC Eyecare and Laser Centers, Jackson, Michigan, USA.
Design: Retrospective chart review.
difluprednate 2 times daily for 30 days. There was no significant difference between the 2 groups in age, sex, or race. In addition, the mean IOP did not differ significantly between the prednisolone acetate group and the difluprednate group at the preoperative measurement or 1 month after surgery, nor was there a difference in the 1-month change in IOP between groups. No association was found between the incidence of a 6 mm Hg or higher increase in IOP 1 month after surgery and steroid treatment. One month postoperatively, 4 eyes in the prednisolone acetate group and 5 eyes in the difluprednate group had an IOP higher than 21 mm Hg.
Methods: The outcomes of consecutive patients who had uneventful cataract surgery from April 2013 to September 2013 and used prednisolone acetate postoperatively were compared with the outcomes of consecutive patients who had uneventful cataract surgery from June 2014 to October 2014 and used difluprednate postoperatively.
Conclusions: There was no significant difference in the mean IOP or percentages showing IOP elevation between eyes treated with difluprednate and eyes treated with prednisolone acetate after cataract surgery. This was likely the result of low-frequency dosing and short duration of steroid use.
Results: The study included 224 eyes treated with prednisolone
J Cataract Refract Surg 2017; 43:223–227 Q 2017 ASCRS and ESCRS
acetate 4 times daily for 30 days and 225 eyes treated with
O
ver the past several decades, topical steroids such as prednisolone acetate 1.0% have been commonly used to treat postoperative inflammation after ophthalmic surgery. In June 2008, the U.S. Food and Drug Administration (FDA) approved a potent new steroidddifluprednate ophthalmic emulsion 0.05% (Durezol)dfor the treatment of postoperative inflammation and pain. Difluprednate (difluoroprednisolone butyrate acetate) is a prednisolone derivative that was modified to increase its potency. The molecule was fluorinated at the C-6 and C-9 positions, and a butyrate ester was added
to the C-17 position. The combination of these changes resulted in an increase in affinity for the glucocorticoid receptor. In addition, an acetate ester was added at position C-21 to enhance tissue penetration, which allows more of the active drug to reach the uvea. These modifications resulted in a drug with an active metabolite that is 56 times stronger than prednisolone.1 Smith et al.2 found that difluprednate administered twice daily, when started 24 hours before cataract surgery, resulted in significantly decreased postoperative inflammation. Donnenfeld et al.3 found that after cataract
Submitted: August 17, 2016 | Final revision submitted: November 28, 2016 | Accepted: December 2, 2016 From the Department of Ophthalmology and Visual Sciences (Tijunelis, Niziol, Musch, Mian) and the Department of Epidemiology (Niziol, Musch), W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, TLC Eyecare and Laser Centers (Person, Ernest), Jackson, and the Michigan State University (McBain), East Lansing, Michigan, USA. Corresponding author: Shahzad I. Mian, MD, Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, Michigan 48105, USA. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.02.002
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surgery, difluprednate in a high-dose pulsed-therapy regiment resulted in reduced inflammation and a more rapid return of vision than prednisolone acetate. Because difluprednate has such high potency and steroids have known associations with intraocular pressure (IOP) elevation, there is concern that its use could result in glaucomatous optic neuropathy if elevated IOP is left untreated. Because of vigilant postoperative preventive measures, the reported incidence of this complication is low; however, approximately 8% of patients have a corticosteroidinduced IOP elevation after cataract surgery.3 In 2014, Jeng et al.4 performed a retrospective chart review and concluded that eyes treated with difluprednate after vitreoretinal surgery were at an increased risk for developing a clinically significant increase in IOP than eyes treated with prednisolone acetate. We sought to determine whether there was a significantly greater incidence of corticosteroid-induced IOP response in eyes treated with difluprednate or eyes treated with prednisolone acetate for postoperative inflammation after cataract surgery. PATIENTS AND METHODS Study Cohort and Patient Enrollment After the University of Michigan Institutional Review Board deemed this study to be not regulated, a retrospective medical record review of consecutive patients who had routine primary cataract extraction by 1 of 2 surgeons (E.P., P.E.) was performed. Two cohorts were identified. The first cohort included patients who had cataract surgery from April 2013 through September 2013 and were treated postoperatively with prednisolone acetate 4 times a day for 30 days, nepafenac (Nevanac) 0.1% 3 times a day for 30 days, and ofloxacin 0.3% 4 times a day for 7 days. The second cohort included patients who had cataract surgery from June through October 2014 and were treated postoperatively with difluprednate 2 times a day for 30 days, nepafenac (Ilevro) 0.3% once a day for 30 days, and ofloxacin 0.3% 4 times a day for 7 days. Neither prednisolone acetate nor difluprednate was weaned over the 30-day administration period. The data collected from the medical record review included age at the preoperative visit, sex, race, history of glaucoma, immunosuppression status, history of diabetes mellitus, preoperative IOP (the IOP measured at the preoperative cataract evaluation), IOP 1 day and 1 month postoperatively, and the type of tonometry used. To obtain IOP measurements, a Tono-Pen (Reichert Technologies), which is a handheld applanation tonometer, or a Goldmann applanation tonometer, which is a mounted tonometer, was used. Consecutive patients aged 18 years or older, who had uneventful cataract surgery, were identified. The exclusion criteria included patients with a planned combined or complicated procedure (eg, hypermature cataract), patients who were comanaged by a referring optometrist who was outside of the TLC Eyecare and Laser Center provider network with incomplete data, and patients who had previous glaucoma surgeries including trabeculectomy or tube shunt placement. Data from Jeng et al.4 were used to estimate the sample size necessary to power this study adequately. Based on the premise that 20% of eyes treated with prednisolone acetate and 35% of eyes treated with difluprednate would develop an IOP spike, 151 eyes in each cohort would be required (using a 2-tailed test) to provide adequate error protection (Type 1 and II error probabilities of 0.05 and 0.20, respectively). Main Outcome Measures The measures used to determine the primary outcomes were the incidence of an increase in IOP higher than 6 mm Hg from the Volume 43 Issue 2 February 2017
preoperative IOP (measured at the preoperative cataract evaluation) or an IOP higher than 21 mm Hg 1 month postoperatively. Data Acquisition and Analysis Characteristics of the sample were assessed with descriptive statistics, including means G SD for continuous measures and frequencies and percentages for categorical measures, and stratified by steroid treatment group. Differences between the 2 treatment groups were assessed with 2-sample t tests and chi-square or Fisher exact tests for person-based measures. The IOP outcomes were compared between steroid treatment groups with linear mixed regression (for continuous IOP) and repeated measures logistic regression models (for threshold levels of IOP or IOP change). These models accounted for the correlation between the eyes of the same patient. The IOP thresholds were an increase in IOP higher than 6 mm Hg from baseline and an IOP higher than 21 mm Hg 1 month postoperatively. Statistical Analysis Software (version 9.4, SAS Institute, Inc.) was used for all statistical analyses.
RESULTS The study assessed 243 patient records, including 123 patients (225 eyes) in the difluprednate cohort and 120 patients (224 eyes) in the prednisolone acetate cohort. Table 1 shows the demographics by postoperative treatment group. There were no statistically significant differences between the 2 groups based on age (prednisolone acetate group 68.1 G 11.4 years, range 33 to 86; difluprednate groups 67.1 G 11.3 years, range 35 to 92) (P Z .4935). There was also no statistically significant difference between the 2 groups in sex, race, diabetes status, glaucoma status, or systemic steroid/immunosuppressant use. The preoperative IOP was similar between eyes treated postoperatively with difluprednate (15.4 G 2.9 mm Hg) and eyes treated postoperatively with prednisolone acetate (14.8 G 3.4 mm Hg) (P Z .0626). One month postoperatively, there was no statistically significant difference in the mean IOP between the prednisolone acetate group (14.3 G 3.4 mm Hg) and the difluprednate group (14.5 G 3.6 mm Hg) (P Z .6582). The change in IOP from baseline to 1 month postoperatively also was not significantly different between the 2 groups (P Z .2803). Table 2 and Figure 1 show the IOP measurements between the groups. From baseline to 1 month postoperatively, 12 eyes (5.4%) in the prednisolone acetate group and 6 eyes (2.7%) in the difluprednate group had an IOP increase that was higher than 6 mm Hg (P Z .1975), whereas 4 eyes (1.8%) in the prednisolone acetate group and 5 eyes (2.2%) in the difluprednate group had an IOP increase higher than 21 mm Hg (P Z .8209). Of the 6 eyes that were treated with difluprednate and had an IOP increase higher that 6 mm Hg from baseline, 1 eye had an IOP of 35 mm Hg 1 month postoperatively. One day postoperatively, this patient was treated with a short course of brimonidine but was no longer on topical glaucoma treatment 1 month postoperatively. The patient was ultimately diagnosed as a steroid responder. Another patient with a preexisting diagnosis of severe-stage primary open-angle glaucoma, who was using 4 topical glaucoma
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Table 1. Patient demographics. Number (%) Difluprednate 0.05%
Prednisolone Acetate 1%
P Value
Male
51 (41.5)
57 (47.5)
.3437
Female
72 (58.5)
63 (52.5)
White
113 (91.9)
104 (88.1)
Black
6 (4.9)
10 (8.5)
Other
4 (3.3)
4 (3.4)
84 (68.3)
80 (66.7)
Type 1
2 (1.6)
4 (3.3)
Type 2
37 (30.1)
36 (30.0)
Parameter Sex
Race .5608
Diabetes None
.7828
Glaucoma None
107
Glaucoma suspect/POAG PACG
(87)
93 (77.5)
12 (9.8)
19 (15.8)
4 (3.3)
8 (6.7)
.1474
Systemic steroid/immunosuppressant None
118 (95.9)
113 (94.2)
Prednisone
5 (4.1)
6 (5.0)
Mycophenolate mofetilt
0
1 (0.8)
.6513
PACG Z primary angle-closure glaucoma; POAG Z primary open-angle glaucoma.
medications before cataract surgery in both eyes, developed an increase in IOP 1 month postoperatively. This patient was on no additional glaucoma treatment during postoperative recovery. The remaining 3 eyes did not have a known history of ocular hypertension, glaucoma suspect, or glaucoma. Another 15 eyes treated with topical glaucoma medications preoperatively and 5 eyes treated for less than 1 week postoperatively with a topical glaucoma medication did not develop a steroid response 1 month postoperatively. Of the 12 eyes that were treated postoperatively with prednisolone acetate and had an IOP increase higher than 6 mm Hg from baseline, 1 eye had an IOP of 24 mm Hg
1 month postoperatively. This patient used brimonidine for less than 1 week postoperatively. Another patient, who had a postoperative IOP higher than 6 mm Hg in both eyes, required treatment and had a quicker than usual steroid taper. The remaining eyes with IOP increases higher than 6 mm Hg did not require treatment. In addition, there were 4 eyes treated with topical glaucoma medications preoperatively and 7 eyes treated with a topical glaucoma medication for less than 1 week postoperatively that did not develop a steroid response 1 month postoperatively. According to the available medical data, no patients developed glaucomatous optic neuropathy.
Table 2. Preoperative and postoperative IOP measurements. IOP Measurement (mm Hg) Difluprednate (n Z 225 Eyes) Examination
Mean ± SD
Range
Preop
15.4 G 2.9
1-mo postop 1-mo postop change
Prednisolone Acetate (n Z 224 Eyes) Median
P Value
7.0, 29.0
14.0
.0626
14.3 G 3.4
6.0, 25.0
14.0
.6582
0.4 G 4.2
11.0, 12.0
1.0
.2803
Median
Mean ± SD
Range
8.0, 23.0
16.0
14.8 G 3.4
14.5 G 3.6
6.0, 35.0
14.0
1.0 G 4.0
13.0, 20.0
1.0
IOP Z intraocular pressure.
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Figure 1. Comparison of IOP measurements after use of difluprednate or prednisolone acetate (IOP Z intraocular pressure).
DISCUSSION The National Eye Institute estimates that the number of people in the United States with cataract will double from 24.4 million in 2010 to approximately 50 million in 2050.A Data from the Centers for Medicaid and Medicare Services indicate that the national cataract surgery rate has risen from 13.4 per 1000 Medicare beneficiaries in 1980 to 61.8 per 1000 beneficiaries in 2004.5 The estimated number of cataract surgeries in the U.S. billed to Medicare in 2013 was 3.8 million. These increasing rates show the importance of evaluating ways to standardize postoperative care that is evidence-based and cost-effective. Part of the difficulty in reviewing the literature on corticosteroid-induced ocular hypertension is the numerous ways this complication is defined. In 1965, Becker6 used an absolute IOP of 20 mm Hg as the lower limit of a clinically significant IOP response and an IOP of 31 mm Hg as the cutoff value for stopping the use of betamethasone. In 1968, Armaly7 stratified a relative IOP steroid response (increased IOP) into 3 groups: low (5 mm Hg or lower), intermediate (6 to 15 mm Hg), and high (16 mm Hg or higher). He used 6 mm Hg as the lower limit of a clinically significant response. In 1984, Stewart et al.8 proposed that an increase of 10 mm Hg or higher should be considered clinically significant. Although we used the corticosteroid-induced ocular hypertension criteria set by Armaly,8 our conclusions would have been similar if we used the definition from Stewart et al.8 (1 eye [0.4%] in the difluprednate treatment group and 1 eye [0.5%] in the prednisolone acetate treated group showed an IOP increase higher than 10 mm Hg from baseline to 1 month postoperatively). There was a 2-fold difference between the prednisolone acetate group and the difluprednate group (5.4% versus 2.7%, respectively) when examining the percentage of eyes that had an increase in IOP higher than 6 mm Hg from baseline to 1 month postoperatively. Although this difference was not statistically significant, a larger study would be necessary to fully evaluate this relative difference. Volume 43 Issue 2 February 2017
To obtain IOP measurements, our study used a handheld Tono-Pen applanation tonometer or a mounted Goldmann applanation tonometer. In 2001, Iester et al.9 found that in 77% of patients who had IOP evaluated with both tonometers, there was more than 3 mm Hg difference in measurement. Although this introduces another variable into our results, 92% of the IOP measurements in our study were with the Goldmann applanation tonometer. The dosing for both topical steroids in this study was at a fixed schedule for the entire 30 days of treatment; therefore, there was no tapering regiment. In the prednisolone acetate cohort, the medication was administered 4 times a day and in the difluprednate cohort, the medication was administered 2 times a day. In the initial clinical data submitted to the FDA for approval of difluprednate, Korenfeld et al.10 found there was a steroid response in 3% of patients regardless of whether the medication was administered 2 times a day or 4 times a day, whereas there was a steroid response in 1% of patients when a placebo was administered. Recently, Jeng et al.4 found a statistically significant corticosteroid IOP response in patients who took difluprednate versus prednisolone acetate after vitreoretinal surgery. We believe that the difference between our results and those of Jeng et al. was that we only prescribed difluprednate twice a day for 30 days, whereas Jeng et al. prescribed difluprednate 4 times a day for 30 days. The difference in dosage between the 2 studies might explain why there was no statistical difference 1 month postoperatively in IOP increases higher than 6 mm Hg between the 2 groups in our study. A study powered for detecting the difference found we would require a much larger sample size. Patients who have an excessive amount of postoperative inflammation or patients who might not be able to adhere to 4 times a day dosing postoperatively might benefit more from difluprednate use. In 1990, Eisen et al.11 reported that less complicated dosing regimens result in better adherence. For this reason, nepafenac 0.3% once daily was used in the difluprednate group rather than nepafenac 0.1% 3 times daily in the prednisolone acetate group. In addition, difluprednate was shown to have increased bioavailability and dose uniformity resulting from the formulation of difluprednate as an emulsion rather than a suspension.12 In both circumstances, patients would benefit with difluprednate, a medication that requires less frequent dosing and has a better dose uniformity. There is still considerable debate as to what is the most effective postoperative management after cataract surgery. Kessel et al.13 compared the use of nonsteroidal antiinflammatory drugs (NSAIDs) with the use of topical steroids in patients who had uneventful cataract surgery. They concluded that topical NSAIDs were more effective in reducing inflammation and postoperative cystoid macular edema, and there were no differences in adverse events or visual outcomes. The most notable limitation in this study is that it is a retrospective chart review limited to a single center. Because a consecutive series of patients was included in both steroid
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groups, the inherent biases (selection bias in particular) are mitigated. Also, our study was not powered to detect differences in IOP elevation of the low magnitude we observed, although both groups showed low incidence rates with no substantial absolute differences. Another limitation is that it was not clear how long an elevated IOP persists after discontinuation of topical steroids in a patient with steroid response. The IOP could return to normal within 2 to 4 weeks after discontinuation of corticosteroid therapy,14 although there is anecdotal data that this response can be significantly quicker. In our study, at the 1-month postoperative visit, 73.8% of the difluprednate eyes and 63.8% of the prednisolone eyes were still actively being treated with a topical steroid. This might be an important variable to try to control, although it might be difficult because the 1-month postoperative visit is usually scheduled based on both physician and patient availability. Until more data on how long a steroid response lasts after discontinuation of topical steroid treatment are available, the difference noted in this study might be usable. In conclusion, patients who were treated with topical steroids in this study had a low incidence of IOP elevation. Even so, it is important to carefully monitor postoperative patients using difluprednate or prednisolone acetate. Patients using either of these steroids to limit inflammation after cataract surgery can have a clinically significant steroid response.
3.
4.
5. 6.
7. 8.
9.
10.
11.
12.
13.
WHAT WAS KNOWN Anecdotal reports suggest significant steroid-induced ocular hypertension might occur with the use of difluprednate or prednisolone acetate. In particular, it has been hypothesized that because of its increased potency, difluprednate use will result in a greater incidence of corticosteroid response.
WHAT THIS PAPER ADDS There was no significant difference in corticosteroid-induced ocular hypertension when comparing difluprednate with prednisolone acetate at the dosing regimens prescribed in this study.
14.
sion 0.05% (DurezolÒ) administered two times daily for managing ocular inflammation and pain following cataract surgery. Clin Ophthalmol 2010; 4:983–991. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2938279/pdf/opth-4-983.pdf. Accessed December 27, 2016 Donnenfeld ED, Holland EJ, Solomon KD, Fiore J, Gobbo A, Prince J, Sandoval HP, Shull ER, Perry HD. A multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol 2011; 152:609–617 Jeng KW, Fine HF, Wheatley HM, Roth D, Connors DB, Prenner JL. Incidence of steroid-induced ocular hypertension after vitreoretinal surgery with difluprednate versus prednisolone acetate. Retina 2014; 34:1990– 1996 Schein OD, Cassard SD, Tielsch JM, Gower EW. Cataract surgery among Medicare beneficiaries. Ophthalmic Epidemiol 2012; 19:257–264 Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 1965; 4:198–205. Available at: http://iovs.arvojournals.org/ article.aspx?articleidZ2203651. Accessed December 27, 2016 Armaly MF. Genetic factors related to glaucoma. Ann NY Acad Sci 1968; 151:861–874 Stewart RH, Smith JP, Rosenthal AL. Ocular pressure response to fluorometholone acetate and dexamethasone sodium phosphate. Curr Eye Res 1984; 3:835–839 Iester M, Mermoud A, Achache F, Roy S. New TonoPen XL: comparison with the Goldmann tonometer. Eye 2001; 15:52–58. Available at: http://www.na ture.com/eye/journal/v15/n1/pdf/eye200113a.pdf. Accessed December 27, 2016 Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS, and the Difluprednate Ophthalmic Emulsion 005% (Durezol) Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg 2009; 35:26–34 Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150:1881–1884 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 December 27, 2016 Kessel L, Tendal B, Jørgensen KJ, Erngaard D, Flesner P, Lundgaard Andresen J, Hjortdal J. Post-cataract prevention of inflammation and macula edema by steroid and nonsteroidal anti-inflammatory eye drops; a systematic review. Ophthalmology 2014; 121:1915–1924. Available at: http:// www.aaojournal.org/article/S0161-6420(14)00389-3/pdf. Accessed December 27, 2016 Tripathi RC, Parapuram SK, Tripathi BJ, Zhong Y, Chalam KV. Corticosteroids and glaucoma risk. Drugs Aging 1999; 15:439–450
OTHER CITED MATERIAL A. National Eye Institute. Cataract defined tables. Available at: https://nei.nih. gov/eyedata/cataract/tables#5. Accessed December 27, 2016
Disclosure: None of the authors has a financial or proprietary interest in any material or methods mentioned.
First author: Marius A. Tijunelis, MD, MBA
REFERENCES 1. Donnenfeld ED. Difluprednate for the prevention of ocular inflammation postsurgery: an update. Clin Ophthalmol 2011; 5:811–816. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130919/pdf/opth-5-811. pdf. Accessed December 27, 2016 2. Smith S, Lorenz D, Peace J, McLeod K, Crockett RS. Vogel R and the Difluprednate ST601-004 Study Group. Difluprednate ophthalmic emul-
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
Volume 43 Issue 2 February 2017
ARTICLE
Comparison of prednisolone acetate 1.0% and difluprednate ophthalmic emulsion 0.05% after cataract surgery: Incidence of postoperative steroid-induced ocular hypertension Marius A. Tijunelis, MD, MBA, Erica Person, MD, MS, Leslie M. Niziol, MS, David C. Musch, PhD, MPH, Paul Ernest, MD, Madeline McBain, Shahzad I. Mian, MD
Purpose: To compare intraocular pressure (IOP) outcomes between 2 common, commercially available corticosteroid drops: difluprednate ophthalmic emulsion 0.05% and prednisolone acetate 1.0%.
Setting: TLC Eyecare and Laser Centers, Jackson, Michigan, USA.
Design: Retrospective chart review.
difluprednate 2 times daily for 30 days. There was no significant difference between the 2 groups in age, sex, or race. In addition, the mean IOP did not differ significantly between the prednisolone acetate group and the difluprednate group at the preoperative measurement or 1 month after surgery, nor was there a difference in the 1-month change in IOP between groups. No association was found between the incidence of a 6 mm Hg or higher increase in IOP 1 month after surgery and steroid treatment. One month postoperatively, 4 eyes in the prednisolone acetate group and 5 eyes in the difluprednate group had an IOP higher than 21 mm Hg.
Methods: The outcomes of consecutive patients who had uneventful cataract surgery from April 2013 to September 2013 and used prednisolone acetate postoperatively were compared with the outcomes of consecutive patients who had uneventful cataract surgery from June 2014 to October 2014 and used difluprednate postoperatively.
Conclusions: There was no significant difference in the mean IOP or percentages showing IOP elevation between eyes treated with difluprednate and eyes treated with prednisolone acetate after cataract surgery. This was likely the result of low-frequency dosing and short duration of steroid use.
Results: The study included 224 eyes treated with prednisolone
J Cataract Refract Surg 2017; 43:223–227 Q 2017 ASCRS and ESCRS
acetate 4 times daily for 30 days and 225 eyes treated with
O
ver the past several decades, topical steroids such as prednisolone acetate 1.0% have been commonly used to treat postoperative inflammation after ophthalmic surgery. In June 2008, the U.S. Food and Drug Administration (FDA) approved a potent new steroidddifluprednate ophthalmic emulsion 0.05% (Durezol)dfor the treatment of postoperative inflammation and pain. Difluprednate (difluoroprednisolone butyrate acetate) is a prednisolone derivative that was modified to increase its potency. The molecule was fluorinated at the C-6 and C-9 positions, and a butyrate ester was added
to the C-17 position. The combination of these changes resulted in an increase in affinity for the glucocorticoid receptor. In addition, an acetate ester was added at position C-21 to enhance tissue penetration, which allows more of the active drug to reach the uvea. These modifications resulted in a drug with an active metabolite that is 56 times stronger than prednisolone.1 Smith et al.2 found that difluprednate administered twice daily, when started 24 hours before cataract surgery, resulted in significantly decreased postoperative inflammation. Donnenfeld et al.3 found that after cataract
Submitted: August 17, 2016 | Final revision submitted: November 28, 2016 | Accepted: December 2, 2016 From the Department of Ophthalmology and Visual Sciences (Tijunelis, Niziol, Musch, Mian) and the Department of Epidemiology (Niziol, Musch), W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, TLC Eyecare and Laser Centers (Person, Ernest), Jackson, and the Michigan State University (McBain), East Lansing, Michigan, USA. Corresponding author: Shahzad I. Mian, MD, Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, Michigan 48105, USA. E-mail: [email protected]. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.02.002
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COMPARISON OF 2 STEROID EYEDROPS AFTER CATARACT SURGERY
surgery, difluprednate in a high-dose pulsed-therapy regiment resulted in reduced inflammation and a more rapid return of vision than prednisolone acetate. Because difluprednate has such high potency and steroids have known associations with intraocular pressure (IOP) elevation, there is concern that its use could result in glaucomatous optic neuropathy if elevated IOP is left untreated. Because of vigilant postoperative preventive measures, the reported incidence of this complication is low; however, approximately 8% of patients have a corticosteroidinduced IOP elevation after cataract surgery.3 In 2014, Jeng et al.4 performed a retrospective chart review and concluded that eyes treated with difluprednate after vitreoretinal surgery were at an increased risk for developing a clinically significant increase in IOP than eyes treated with prednisolone acetate. We sought to determine whether there was a significantly greater incidence of corticosteroid-induced IOP response in eyes treated with difluprednate or eyes treated with prednisolone acetate for postoperative inflammation after cataract surgery. PATIENTS AND METHODS Study Cohort and Patient Enrollment After the University of Michigan Institutional Review Board deemed this study to be not regulated, a retrospective medical record review of consecutive patients who had routine primary cataract extraction by 1 of 2 surgeons (E.P., P.E.) was performed. Two cohorts were identified. The first cohort included patients who had cataract surgery from April 2013 through September 2013 and were treated postoperatively with prednisolone acetate 4 times a day for 30 days, nepafenac (Nevanac) 0.1% 3 times a day for 30 days, and ofloxacin 0.3% 4 times a day for 7 days. The second cohort included patients who had cataract surgery from June through October 2014 and were treated postoperatively with difluprednate 2 times a day for 30 days, nepafenac (Ilevro) 0.3% once a day for 30 days, and ofloxacin 0.3% 4 times a day for 7 days. Neither prednisolone acetate nor difluprednate was weaned over the 30-day administration period. The data collected from the medical record review included age at the preoperative visit, sex, race, history of glaucoma, immunosuppression status, history of diabetes mellitus, preoperative IOP (the IOP measured at the preoperative cataract evaluation), IOP 1 day and 1 month postoperatively, and the type of tonometry used. To obtain IOP measurements, a Tono-Pen (Reichert Technologies), which is a handheld applanation tonometer, or a Goldmann applanation tonometer, which is a mounted tonometer, was used. Consecutive patients aged 18 years or older, who had uneventful cataract surgery, were identified. The exclusion criteria included patients with a planned combined or complicated procedure (eg, hypermature cataract), patients who were comanaged by a referring optometrist who was outside of the TLC Eyecare and Laser Center provider network with incomplete data, and patients who had previous glaucoma surgeries including trabeculectomy or tube shunt placement. Data from Jeng et al.4 were used to estimate the sample size necessary to power this study adequately. Based on the premise that 20% of eyes treated with prednisolone acetate and 35% of eyes treated with difluprednate would develop an IOP spike, 151 eyes in each cohort would be required (using a 2-tailed test) to provide adequate error protection (Type 1 and II error probabilities of 0.05 and 0.20, respectively). Main Outcome Measures The measures used to determine the primary outcomes were the incidence of an increase in IOP higher than 6 mm Hg from the Volume 43 Issue 2 February 2017
preoperative IOP (measured at the preoperative cataract evaluation) or an IOP higher than 21 mm Hg 1 month postoperatively. Data Acquisition and Analysis Characteristics of the sample were assessed with descriptive statistics, including means G SD for continuous measures and frequencies and percentages for categorical measures, and stratified by steroid treatment group. Differences between the 2 treatment groups were assessed with 2-sample t tests and chi-square or Fisher exact tests for person-based measures. The IOP outcomes were compared between steroid treatment groups with linear mixed regression (for continuous IOP) and repeated measures logistic regression models (for threshold levels of IOP or IOP change). These models accounted for the correlation between the eyes of the same patient. The IOP thresholds were an increase in IOP higher than 6 mm Hg from baseline and an IOP higher than 21 mm Hg 1 month postoperatively. Statistical Analysis Software (version 9.4, SAS Institute, Inc.) was used for all statistical analyses.
RESULTS The study assessed 243 patient records, including 123 patients (225 eyes) in the difluprednate cohort and 120 patients (224 eyes) in the prednisolone acetate cohort. Table 1 shows the demographics by postoperative treatment group. There were no statistically significant differences between the 2 groups based on age (prednisolone acetate group 68.1 G 11.4 years, range 33 to 86; difluprednate groups 67.1 G 11.3 years, range 35 to 92) (P Z .4935). There was also no statistically significant difference between the 2 groups in sex, race, diabetes status, glaucoma status, or systemic steroid/immunosuppressant use. The preoperative IOP was similar between eyes treated postoperatively with difluprednate (15.4 G 2.9 mm Hg) and eyes treated postoperatively with prednisolone acetate (14.8 G 3.4 mm Hg) (P Z .0626). One month postoperatively, there was no statistically significant difference in the mean IOP between the prednisolone acetate group (14.3 G 3.4 mm Hg) and the difluprednate group (14.5 G 3.6 mm Hg) (P Z .6582). The change in IOP from baseline to 1 month postoperatively also was not significantly different between the 2 groups (P Z .2803). Table 2 and Figure 1 show the IOP measurements between the groups. From baseline to 1 month postoperatively, 12 eyes (5.4%) in the prednisolone acetate group and 6 eyes (2.7%) in the difluprednate group had an IOP increase that was higher than 6 mm Hg (P Z .1975), whereas 4 eyes (1.8%) in the prednisolone acetate group and 5 eyes (2.2%) in the difluprednate group had an IOP increase higher than 21 mm Hg (P Z .8209). Of the 6 eyes that were treated with difluprednate and had an IOP increase higher that 6 mm Hg from baseline, 1 eye had an IOP of 35 mm Hg 1 month postoperatively. One day postoperatively, this patient was treated with a short course of brimonidine but was no longer on topical glaucoma treatment 1 month postoperatively. The patient was ultimately diagnosed as a steroid responder. Another patient with a preexisting diagnosis of severe-stage primary open-angle glaucoma, who was using 4 topical glaucoma
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COMPARISON OF 2 STEROID EYEDROPS AFTER CATARACT SURGERY
Table 1. Patient demographics. Number (%) Difluprednate 0.05%
Prednisolone Acetate 1%
P Value
Male
51 (41.5)
57 (47.5)
.3437
Female
72 (58.5)
63 (52.5)
White
113 (91.9)
104 (88.1)
Black
6 (4.9)
10 (8.5)
Other
4 (3.3)
4 (3.4)
84 (68.3)
80 (66.7)
Type 1
2 (1.6)
4 (3.3)
Type 2
37 (30.1)
36 (30.0)
Parameter Sex
Race .5608
Diabetes None
.7828
Glaucoma None
107
Glaucoma suspect/POAG PACG
(87)
93 (77.5)
12 (9.8)
19 (15.8)
4 (3.3)
8 (6.7)
.1474
Systemic steroid/immunosuppressant None
118 (95.9)
113 (94.2)
Prednisone
5 (4.1)
6 (5.0)
Mycophenolate mofetilt
0
1 (0.8)
.6513
PACG Z primary angle-closure glaucoma; POAG Z primary open-angle glaucoma.
medications before cataract surgery in both eyes, developed an increase in IOP 1 month postoperatively. This patient was on no additional glaucoma treatment during postoperative recovery. The remaining 3 eyes did not have a known history of ocular hypertension, glaucoma suspect, or glaucoma. Another 15 eyes treated with topical glaucoma medications preoperatively and 5 eyes treated for less than 1 week postoperatively with a topical glaucoma medication did not develop a steroid response 1 month postoperatively. Of the 12 eyes that were treated postoperatively with prednisolone acetate and had an IOP increase higher than 6 mm Hg from baseline, 1 eye had an IOP of 24 mm Hg
1 month postoperatively. This patient used brimonidine for less than 1 week postoperatively. Another patient, who had a postoperative IOP higher than 6 mm Hg in both eyes, required treatment and had a quicker than usual steroid taper. The remaining eyes with IOP increases higher than 6 mm Hg did not require treatment. In addition, there were 4 eyes treated with topical glaucoma medications preoperatively and 7 eyes treated with a topical glaucoma medication for less than 1 week postoperatively that did not develop a steroid response 1 month postoperatively. According to the available medical data, no patients developed glaucomatous optic neuropathy.
Table 2. Preoperative and postoperative IOP measurements. IOP Measurement (mm Hg) Difluprednate (n Z 225 Eyes) Examination
Mean ± SD
Range
Preop
15.4 G 2.9
1-mo postop 1-mo postop change
Prednisolone Acetate (n Z 224 Eyes) Median
P Value
7.0, 29.0
14.0
.0626
14.3 G 3.4
6.0, 25.0
14.0
.6582
0.4 G 4.2
11.0, 12.0
1.0
.2803
Median
Mean ± SD
Range
8.0, 23.0
16.0
14.8 G 3.4
14.5 G 3.6
6.0, 35.0
14.0
1.0 G 4.0
13.0, 20.0
1.0
IOP Z intraocular pressure.
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COMPARISON OF 2 STEROID EYEDROPS AFTER CATARACT SURGERY
Figure 1. Comparison of IOP measurements after use of difluprednate or prednisolone acetate (IOP Z intraocular pressure).
DISCUSSION The National Eye Institute estimates that the number of people in the United States with cataract will double from 24.4 million in 2010 to approximately 50 million in 2050.A Data from the Centers for Medicaid and Medicare Services indicate that the national cataract surgery rate has risen from 13.4 per 1000 Medicare beneficiaries in 1980 to 61.8 per 1000 beneficiaries in 2004.5 The estimated number of cataract surgeries in the U.S. billed to Medicare in 2013 was 3.8 million. These increasing rates show the importance of evaluating ways to standardize postoperative care that is evidence-based and cost-effective. Part of the difficulty in reviewing the literature on corticosteroid-induced ocular hypertension is the numerous ways this complication is defined. In 1965, Becker6 used an absolute IOP of 20 mm Hg as the lower limit of a clinically significant IOP response and an IOP of 31 mm Hg as the cutoff value for stopping the use of betamethasone. In 1968, Armaly7 stratified a relative IOP steroid response (increased IOP) into 3 groups: low (5 mm Hg or lower), intermediate (6 to 15 mm Hg), and high (16 mm Hg or higher). He used 6 mm Hg as the lower limit of a clinically significant response. In 1984, Stewart et al.8 proposed that an increase of 10 mm Hg or higher should be considered clinically significant. Although we used the corticosteroid-induced ocular hypertension criteria set by Armaly,8 our conclusions would have been similar if we used the definition from Stewart et al.8 (1 eye [0.4%] in the difluprednate treatment group and 1 eye [0.5%] in the prednisolone acetate treated group showed an IOP increase higher than 10 mm Hg from baseline to 1 month postoperatively). There was a 2-fold difference between the prednisolone acetate group and the difluprednate group (5.4% versus 2.7%, respectively) when examining the percentage of eyes that had an increase in IOP higher than 6 mm Hg from baseline to 1 month postoperatively. Although this difference was not statistically significant, a larger study would be necessary to fully evaluate this relative difference. Volume 43 Issue 2 February 2017
To obtain IOP measurements, our study used a handheld Tono-Pen applanation tonometer or a mounted Goldmann applanation tonometer. In 2001, Iester et al.9 found that in 77% of patients who had IOP evaluated with both tonometers, there was more than 3 mm Hg difference in measurement. Although this introduces another variable into our results, 92% of the IOP measurements in our study were with the Goldmann applanation tonometer. The dosing for both topical steroids in this study was at a fixed schedule for the entire 30 days of treatment; therefore, there was no tapering regiment. In the prednisolone acetate cohort, the medication was administered 4 times a day and in the difluprednate cohort, the medication was administered 2 times a day. In the initial clinical data submitted to the FDA for approval of difluprednate, Korenfeld et al.10 found there was a steroid response in 3% of patients regardless of whether the medication was administered 2 times a day or 4 times a day, whereas there was a steroid response in 1% of patients when a placebo was administered. Recently, Jeng et al.4 found a statistically significant corticosteroid IOP response in patients who took difluprednate versus prednisolone acetate after vitreoretinal surgery. We believe that the difference between our results and those of Jeng et al. was that we only prescribed difluprednate twice a day for 30 days, whereas Jeng et al. prescribed difluprednate 4 times a day for 30 days. The difference in dosage between the 2 studies might explain why there was no statistical difference 1 month postoperatively in IOP increases higher than 6 mm Hg between the 2 groups in our study. A study powered for detecting the difference found we would require a much larger sample size. Patients who have an excessive amount of postoperative inflammation or patients who might not be able to adhere to 4 times a day dosing postoperatively might benefit more from difluprednate use. In 1990, Eisen et al.11 reported that less complicated dosing regimens result in better adherence. For this reason, nepafenac 0.3% once daily was used in the difluprednate group rather than nepafenac 0.1% 3 times daily in the prednisolone acetate group. In addition, difluprednate was shown to have increased bioavailability and dose uniformity resulting from the formulation of difluprednate as an emulsion rather than a suspension.12 In both circumstances, patients would benefit with difluprednate, a medication that requires less frequent dosing and has a better dose uniformity. There is still considerable debate as to what is the most effective postoperative management after cataract surgery. Kessel et al.13 compared the use of nonsteroidal antiinflammatory drugs (NSAIDs) with the use of topical steroids in patients who had uneventful cataract surgery. They concluded that topical NSAIDs were more effective in reducing inflammation and postoperative cystoid macular edema, and there were no differences in adverse events or visual outcomes. The most notable limitation in this study is that it is a retrospective chart review limited to a single center. Because a consecutive series of patients was included in both steroid
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COMPARISON OF 2 STEROID EYEDROPS AFTER CATARACT SURGERY
groups, the inherent biases (selection bias in particular) are mitigated. Also, our study was not powered to detect differences in IOP elevation of the low magnitude we observed, although both groups showed low incidence rates with no substantial absolute differences. Another limitation is that it was not clear how long an elevated IOP persists after discontinuation of topical steroids in a patient with steroid response. The IOP could return to normal within 2 to 4 weeks after discontinuation of corticosteroid therapy,14 although there is anecdotal data that this response can be significantly quicker. In our study, at the 1-month postoperative visit, 73.8% of the difluprednate eyes and 63.8% of the prednisolone eyes were still actively being treated with a topical steroid. This might be an important variable to try to control, although it might be difficult because the 1-month postoperative visit is usually scheduled based on both physician and patient availability. Until more data on how long a steroid response lasts after discontinuation of topical steroid treatment are available, the difference noted in this study might be usable. In conclusion, patients who were treated with topical steroids in this study had a low incidence of IOP elevation. Even so, it is important to carefully monitor postoperative patients using difluprednate or prednisolone acetate. Patients using either of these steroids to limit inflammation after cataract surgery can have a clinically significant steroid response.
3.
4.
5. 6.
7. 8.
9.
10.
11.
12.
13.
WHAT WAS KNOWN Anecdotal reports suggest significant steroid-induced ocular hypertension might occur with the use of difluprednate or prednisolone acetate. In particular, it has been hypothesized that because of its increased potency, difluprednate use will result in a greater incidence of corticosteroid response.
WHAT THIS PAPER ADDS There was no significant difference in corticosteroid-induced ocular hypertension when comparing difluprednate with prednisolone acetate at the dosing regimens prescribed in this study.
14.
sion 0.05% (DurezolÒ) administered two times daily for managing ocular inflammation and pain following cataract surgery. Clin Ophthalmol 2010; 4:983–991. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2938279/pdf/opth-4-983.pdf. Accessed December 27, 2016 Donnenfeld ED, Holland EJ, Solomon KD, Fiore J, Gobbo A, Prince J, Sandoval HP, Shull ER, Perry HD. A multicenter randomized controlled fellow eye trial of pulse-dosed difluprednate 0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol 2011; 152:609–617 Jeng KW, Fine HF, Wheatley HM, Roth D, Connors DB, Prenner JL. Incidence of steroid-induced ocular hypertension after vitreoretinal surgery with difluprednate versus prednisolone acetate. Retina 2014; 34:1990– 1996 Schein OD, Cassard SD, Tielsch JM, Gower EW. Cataract surgery among Medicare beneficiaries. Ophthalmic Epidemiol 2012; 19:257–264 Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 1965; 4:198–205. Available at: http://iovs.arvojournals.org/ article.aspx?articleidZ2203651. Accessed December 27, 2016 Armaly MF. Genetic factors related to glaucoma. Ann NY Acad Sci 1968; 151:861–874 Stewart RH, Smith JP, Rosenthal AL. Ocular pressure response to fluorometholone acetate and dexamethasone sodium phosphate. Curr Eye Res 1984; 3:835–839 Iester M, Mermoud A, Achache F, Roy S. New TonoPen XL: comparison with the Goldmann tonometer. Eye 2001; 15:52–58. Available at: http://www.na ture.com/eye/journal/v15/n1/pdf/eye200113a.pdf. Accessed December 27, 2016 Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS, and the Difluprednate Ophthalmic Emulsion 005% (Durezol) Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg 2009; 35:26–34 Eisen SA, Miller DK, Woodward RS, Spitznagel E, Przybeck TR. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150:1881–1884 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 December 27, 2016 Kessel L, Tendal B, Jørgensen KJ, Erngaard D, Flesner P, Lundgaard Andresen J, Hjortdal J. Post-cataract prevention of inflammation and macula edema by steroid and nonsteroidal anti-inflammatory eye drops; a systematic review. Ophthalmology 2014; 121:1915–1924. Available at: http:// www.aaojournal.org/article/S0161-6420(14)00389-3/pdf. Accessed December 27, 2016 Tripathi RC, Parapuram SK, Tripathi BJ, Zhong Y, Chalam KV. Corticosteroids and glaucoma risk. Drugs Aging 1999; 15:439–450
OTHER CITED MATERIAL A. National Eye Institute. Cataract defined tables. Available at: https://nei.nih. gov/eyedata/cataract/tables#5. Accessed December 27, 2016
Disclosure: None of the authors has a financial or proprietary interest in any material or methods mentioned.
First author: Marius A. Tijunelis, MD, MBA
REFERENCES 1. Donnenfeld ED. Difluprednate for the prevention of ocular inflammation postsurgery: an update. Clin Ophthalmol 2011; 5:811–816. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130919/pdf/opth-5-811. pdf. Accessed December 27, 2016 2. Smith S, Lorenz D, Peace J, McLeod K, Crockett RS. Vogel R and the Difluprednate ST601-004 Study Group. Difluprednate ophthalmic emul-
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
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