Journal Pre-proof

Safety and Efficacy of 0.1% Nepafenac versus 1% Prednisolone Acetate Eye Drops
after Laser Iridotomy – A Prospective, Randomized Trial

Keerthi Gayam, MD, Pradeep Y. Ramulu, MD MHS PhD, Rengaraj Venkatesh, MD,
Srinivasan Kavitha, MD

PII: S2589-4196(20)30051-X
DOI: https://doi.org/10.1016/j.ogla.2020.02.006
Reference: OGLA 153

To appear in: OPHTHALMOLOGY GLAUCOMA

Received Date: 5 September 2019

Revised Date: 17 February 2020
Accepted Date: 21 February 2020

Please cite this article as: Gayam K, Ramulu PY, Venkatesh R, Kavitha S, Safety and Efficacy of
0.1% Nepafenac versus 1% Prednisolone Acetate Eye Drops after Laser Iridotomy – A Prospective,
Randomized Trial, OPHTHALMOLOGY GLAUCOMA (2020), doi: https://doi.org/10.1016/
j.ogla.2020.02.006.

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© 2020 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology

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1 Safety and Efficacy of 0.1% Nepafenac versus 1% Prednisolone Acetate Eye Drops after

2 Laser Iridotomy – A Prospective, Randomized Trial

3 Keerthi Gayam MD1 , Pradeep Y Ramulu MD MHS PhD2,3 , Rengaraj Venkatesh MD1,

4 Srinivasan Kavitha MD1

1
5 Aravind Eye Hospital, Pondicherry, India

2
6 Dana Center for Preventive Ophthalmology, Johns Hopkins University, Baltimore, USA

3
7 Wilmer Eye Institute, John Hopkins University, Baltimore, USA

8 Corresponding author: Srinivasan Kavitha

9 Meeting Presentation: Presented at, Association for Research in Vision and Ophthalmology

10 Annual meeting, May 2017, Baltimore, USA

11 Financial Support: None

12 Conflict of Interest: No conflicting relationship exists for any author.

13 Running head: Nepafenac vs. Prednisolone after LPI

14 Address for reprints: Dr. Srinivasan Kavitha, Aravind Eye Hospital, Thavalakuppam,

15 Pondicherry, India- 605007; email: skavitha.shree@gmail.com

16

17

18

19
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20 ABSTRACT:

21 Purpose: To compare 0.1% nepafenac, a topical non-steroidal anti-inflammatory drop, with 1%

22 prednisolone acetate in controlling inflammation after Nd:YAG laser peripheral iridotomy (LPI)

23 in primary angle closure suspects (PACS).

24 Design: Prospective randomized controlled trial.

25 Participants: One hundred and fifty-two PACS patients undergoing bilateral LPI.

26 Methods: Patients were randomized to 0.1% nepafenac or 1% prednisolone acetate eye drop in

27 both eyes. Medications were given 4 times daily for 7 days, then twice daily for additional 7

28 days. Investigators were masked to the type of medication. Right eyes in patients with bilateral

29 PACS and the eye with PACS in asymmetrical disease (primary angle closure in fellow eye)

30 were analyzed.

31 Outcome measures: Non-inferior control of inflammation, defined as absence of cell in the

32 anterior chamber at 2weeks and absence of rebound iritis with medication discontinuation, was

33 the primary outcome, while difference in the rise in intraocular pressure (IOP) was a secondary

34 outcome.

35 Results: Both groups were comparable in baseline characteristics, including IOP, and total laser

36 energy. Nepafenac was non-inferior to prednisolone with regards to inflammation control, with

37 one(1.3%) nepafenac-treated patient failing to meet the primary endpoint because of 1+ anterior

38 chamber cell at 2 weeks and 4(5.4%) prednisolone-treated eyes failing to meet the primary

39 endpoint because of rebound iritis (p <0.001). A greater rise in IOP from baseline to 2 weeks was

40 observed in the prednisolone group compared to the nepafenac group (+2.6 vs. +0.6 mmHg;

41 p=0.004), though at 4 weeks IOPs were not significantly different than baseline in either group

42 (p>0.05 for both). Two weeks after LPI, 3 nepafenac-treated eyes and 10 prednisolone-treated
 3

43 eyes demonstrated a 6-15 mmHg IOP elevation from baseline (p=0.10); while 2 prednisolone-

44 treated eyes and no nepafenac-treated eyes had IOP elevation >15 mmHg (p=0.20). Four weeks

45 after LPI, more prednisolone-treated eyes had IOP elevation of 6-15 mmHg as compared to

46 nepafenac-treated eyes (6 vs. 1, p=0.04); no eyes had IOP elevation >15 mmHg. In an unplanned

47 exploratory analysis, 8 prednisolone-treated patients, but no nepafenac-treated patients required

48 repeat LPI (p=0.003).

49 Conclusions: In our study, nepafenac was non-inferior to prednisolone acetate in controlling

50 post-LPI inflammation with less impact on IOP.

51

52 INTRODUCTION:

53 Steroids are anti-inflammatory drugs used to treat ocular and systemic conditions, and are often

54 used after ophthalmic procedures as well. One risk of steroids is the creating of steroid induced

55 glaucoma, a form of open angle glaucoma occurring as an adverse event. While post-procedural

56 steroid use should not result in glaucoma, in developing countries like India steroid abuse is very

57 common as it can be obtained easily over the counter, is inexpensive, and provides symptomatic

58 relief to common complaints like itching and redness. The sales of topical steroids in India is

59 twice that of China and 20 times that of United States (US).1 These medications can cause both

60 cataract and glaucoma, but unlike cataract, the blindness associated with glaucoma is

61 irreversible. Around one-third of individuals from the general population experience a moderate

62 rise in intra-ocular pressure (IOP) and 5-6% show marked increase in IOP with topical

63 steroids.2,3 Hence there is a need to consider alternatives like non-steroidal anti-inflammatory

64 drugs (NSAIDS) whenever possible, especially after minor ocular procedures.

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65 NSAIDS act by inhibiting cyclooxygenase-2 enzyme, thus inhibiting the synthesis

66 of prostaglandins and thromboxanes, and avoid the serious side effect of corticosteroids (cataract

67 and IOP rise). They have been suggested to be as effective as corticosteroids for controlling

68 inflammation after cataract surgery4, strabismus surgery5, and small gauge pars plana

69 vitrectomy.6 Nepafenac is a topical NSAID approved by Food and Drug Administration for the

70 treatment of inflammation and pain associated with cataract surgery and has the advantage of

71 better corneal penetration than other NSAIDS.7

72 Laser peripheral iridotomy (LPI) is a minor procedure performed as a treatment to relieve

73 pupillary block in eyes with primary angle closure. It is frequently done as a prophylactic

74 procedure in eyes with primary angle closure suspects (PACS) to prevent progression.8-10 Some

75 degree of transient iritis can occur after LPI, and topical steroids are often prescribed

76 prophylactically to prevent this reaction. Roughly 80,000 LPIs are performed annually in US

77 Medicare population11, with many more performed in non-Medicare population and also in other

78 Asian countries where angle closure is much more prevalent. Given the large volume of LPIs

79 worldwide, it is important to consider NSAID eye drops as a steroid alternative following LPI,

80 as they avoid the vision-threatening adverse effects of topical steroid. However, so far there are

81 no studies evaluating the role of NSAIDs to control post LPI inflammation.

82 The purpose of our study was to compare, in a randomized control fashion, the safety & efficacy

83 of 0.1% nepafenac eye drop, a non-steroidal anti-inflammatory agent, with 1% prednisolone

84 acetate eye drop in controlling inflammation after laser peripheral iridotomy in PACS patients.

85 We hypothesized that topical nepafenac would be non-inferior to topical prednisolone acetate

86 with regards to controlling inflammation associated with LPI. In secondary analyses, we

87 compared IOP changes after LPI across medication group.

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88 METHODS:

89 The study protocol was approved by the institutional ethics committee of the Aravind Eye

90 Hospital and written informed consent was obtained from all study participants. The study

91 complied with the tenets of the Declaration of Helsinki. The trial was registered at clinical trial

92 registry of India (CTRI/2017/12/010922).

93 Participants:

94 Patients aged 40 to 70 years who were diagnosed as primary angle closure suspects (PACS) as

95 defined by International Society of Geographical and Epidemiological Ophthalmology (ISGEO)

96 classification12 were recruited from July 2014 to January 2016 from the Glaucoma Service at

97 Aravind Eye Hospital in Pondicherry, India. Patients with primary angle closure (PAC) or

98 primary angle closure glaucoma (PACG) were excluded as were PACS patients with corneal

99 pathology, with significant cataract obscuring undilated fundus evaluation, or using topical or

100 systemic steroids and/or non-steroidal anti-inflammatory drugs.

101 Clinical Assessment:

102 All patients underwent a baseline interview before iridotomy to collect demographic data, and

103 relevant past ocular and systemic history. Trained technicians measured visual acuity and

104 performed refraction to obtain best-corrected visual acuity. Glaucoma-trained specialists

105 completed slit-lamp examination of the anterior segment and undilated fundus evaluation of the

106 optic disc and macula. IOP was measured in a masked manner in both eyes using Goldmann

107 applanation tonometry (GAT). Before measuring the IOP, a technician adjusted the GAT dial to

108 an arbitrary number between 5 and 25. The ophthalmologist looking through the slit lamp then
 6

109 adjusted the dial to the appropriate IOP measure and the study coordinator recorded the result.

110 Two consecutive readings were taken and averaged. Gonioscopy was performed in a dimly

111 illuminated room using a 1 x 1 mm slit beam. The most posterior structure in each quadrant was

112 initially identified using a Goldmann 2- mirror gonioscopy lens (Ocular, Bellevue, WA USA) in

113 primary gaze. Indentation gonioscopy was performed with a 4-mirror gonio lens (Ocular,

114 Bellevue, WA USA) when necessary to identify synechial closure. Stages of angle closure were

115 defined based on ISGEO classification guidelines.12 PACS was diagnosed if pigmented

116 trabecular meshwork was not visible in ≥ 2 quadrants with normal IOP and optic disc.

117

118 Laser Peripheral Iridotomy:

119 Laser peripheral iridotomy was performed using Neodymium:Yttrium-Aluminium-Garnet (Nd-

120 YAG) laser after pre-treatment with 2% pilocarpine. LPIs were performed in both eyes during

121 the same visit and were confirmed to be patent after the procedure. Given the occasional

122 difficulty in completing LPI in a single setting in our populations due to thick irides, LPIs were

123 placed in the optimal crypt regardless of its position. Intra-operative parameters like initial

124 energy setting per shot in milli Joules (mJ), total number of shots, total energy in mJ and LPI

125 location in clock hour were noted. LPIs were classified as superior when placed between the

126 11 and 1 o’clock positions and nasal/temporal LPIs when placed between the 2 and 4 o’clock

127 positions or the 8 and 10 o’clock positions. All LPIs were performed by one of the two

128 investigators (SK, RV). Investigators aimed to create an LPI size of approximately 250-300

129 microns.

130

131
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132 Post LPI medication:

133 Using binary random number generator, patients were randomized in a 1:1 ratio to either topical

134 prednisolone acetate 1% eye drops (Alconpred, Alcon laboratories, Texas, USA) or topical

135 nepafenac 0.1% eye drops (Nevanac, Alcon laboratories, Texas, USA) to treat inflammation

136 following LPI. To avoid crossover effect of the eye drops, both eyes received the same treatment

137 in patients undergoing bilateral LPI (only one eye was evaluated in the study, though both eyes

138 typically underwent LPI). After LPI, the medication was given to the patient by the study

139 coordinator according to the assigned randomization group. The assigned medication to be used

140 was placed in a sealed envelope (completed by KG), and was opened by the study coordinator

141 only after the LPI was completed. Patients were instructed to use their assigned medication 4

142 times a day for seven days, followed by 2 times a day for additional seven days. As both the

143 study medications are in suspension form, patients were instructed to shake the bottle before

144 every use. The glaucoma consultants performing the LPI and evaluating the patients after LPI

145 were masked regarding the identity of medication used throughout the study.

146 Assessment after Laser Peripheral Iridotomy:

147 Patients were re-examined at 2 weeks (primary endpoint) and 4 weeks after LPI, at which times

148 slit lamp bio microscopy of anterior segment was performed. The level of anterior chamber

149 inflammation was assessed by measuring anterior chamber cells and flare using Standardization

150 of Uveitis Nomenclature (SUN) working group grading13, using a high magnification, 1x1 mm

151 beam. GAT was done in a masked manner as described earlier to measure IOP and gonioscopy

152 was repeated to note down the level of angle widening. At the 2 week follow up visit, dilated

153 fundus evaluation was performed after confirming the patency of LPI.
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154 Repeat Laser Peripheral Iridotomy

155 Laser peripheral iridotomies that were found to be occluded or not clearly patent were enlarged

156 or repeated at the 2 weeks post procedure visit and the medication assigned at the initial was

157 continued for additional 2 weeks in the same tapering fashion. These patients were re-examined

158 again at 2 weeks and 4 weeks after repeat LPI and all the above procedures were repeated and

159 documented.

160 Unscheduled Visits

161 When the patients presented for additional visits in between the scheduled follow-ups, the reason

162 for the visit was noted. They underwent slit lamp bio-microscopic examination, IOP

163 measurement with GAT. Randomization could be broken if the inflammation flared up in the

164 study eye during the follow up visits or unscheduled visits and any changes in the treatment was

165 noted in the case report form. The independent investigator (KG) had the authority to break

166 randomization in such settings. None of the patients needed a change of medication or additional

167 medications to control anterior chamber inflammation or intraocular pressure. One patient in the

168 nepafenac group had persistent iritis at 2 week follow-up, and needed one additional week of

169 treatment. Eight patients in the prednisolone group needed an extended duration of medication, 2

170 extra weeks of prednisolone in 4 patients who underwent repeat LPI, and 1 extra week of

171 prednisolone in 4 patients with rebound iritis.

172 STATISTICAL ANALYSIS:

173 Group differences in baseline variables were evaluated using Student t-test for continuous

174 variables and chi-square test for categorical variables. The primary outcome was uncontrolled
 9

175 inflammation, defined as any anterior chamber cell at 2 weeks after LPI or rebound iritis with

176 medication discontinuation, and was evaluated using a non-inferiority test for proportions.

177 Differences between continuous pre and post mean values were measured using paired t-tests,

178 with changes in IOP across medication groups serving as a secondary outcome measure. Linear

179 regression models were used to determine the association between baseline factors and laser

180 parameters with IOP elevation from baseline to 2 weeks after LPI. In an unplanned exploratory

181 analysis, rates of LPI closure were compared across groups, and logistic regression models were

182 used to determine the predictors of LPI closure needing enlargement at 2 weeks follow-up. P-

183 values of less than 0.05 were considered statistically significant. All statistical analysis were

184 performed using statistical software STATA 11.0 (StataCorp, College Station, TX).

185 A sample size of 148 patients was chosen (74 patients in each group) to prove that treatment with

186 nepafenac is non-inferior to prednisolone acetate in controlling inflammation associated with

187 LPI. Sample size was chosen to detect non-inferiority at a margin of 20% difference in success

188 with regards to controlling inflammation between the two study medications with 80% power, a

189 5% level of significance, and an assumption of 40% of eyes demonstrating poor control in the

190 standard (prednisolone) treatment group.

191 Though we collected data from both the eyes of all the patients, only one eye data was analyzed

192 for the primary outcome (inflammation control) and secondary outcome (IOP). In patients with

193 bilateral PACS, right eyes were analyzed, and in patients with asymmetrical disease (4 patients

194 had PAC in fellow eye), the eye with PACS was analyzed. The analysis was done as per

195 intention to treat analysis guidelines.

196
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197

198 RESULTS:

199 Randomization into Study Groups and Group Characteristics:

200 A total of 152 patients were recruited to participate in the study. Seventy four patients were

201 randomized to the prednisolone group and 78 were randomized to the nepafenac group. Two

202 patients randomized to nepafenac group refused to participate further. Overall 150 eyes of 150

203 patients, 74 eyes in the prednisolone group and 76 eyes in the nepafenac group, were analyzed as

204 per intention to treat guidelines (Consort flow diagram- Flow chart 1).

205 Both groups were similar with respect to age (p = 0.60), gender (p = 0.80), presence of diabetes

206 (p = 0.70), baseline IOP (p = 0.80), initial laser energy per shot (p = 0.10), total number of shots

207 (p = 0.29), total laser energy (p = 0.40) and LPI location (p >0.10) (Table 1). More females than

208 males were enrolled into the study, with a female to male ratio of roughly 6:1 in both groups.

209 Anterior Chamber Inflammation:

210 Overall, 1 (1.3%) patient in the nepafenac group failed the primary endpoint of inflammation

211 control (1+ cell and minimal flare at 2 weeks follow-up), while 4 (5.4%) patients in the

212 prednisolone group failed the primary endpoint due to rebound iritis after stopping the

213 medication (p <0.001 for nepafenac non-inferiority). The nepafenac-treated patient showed no

214 anterior chamber reaction by 4 weeks, and all cases of rebound inflammation in the prednisolone

215 group resolved by 4 weeks after LPI with one week of additional twice daily prednisolone. No

216 study participants needed any other additional topical or systemic medications to control

217 inflammation.

218
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219 Intraocular pressure:

220 The mean baseline IOP was comparable between the groups, 15.9±3.0 mmHg in the

221 prednisolone group and 15.8±3.0 mmHg in the nepafenac group (p = 0.80). At 2 weeks after the

222 LPI, the mean IOP was significantly higher in the prednisolone group compared to the nepafenac

223 group, (18.5±5.2mmHg vs.16.3±2.9 mmHg, respectively, p = 0.002). However, at 4 weeks after

224 LPI, the mean IOP did not differ between the groups, (16.6±3.9 mmHg in the prednisolone group

225 vs.15.9±2.8 mmHg in the nepafenac group, p = 0.20), (Figure 1).

226 The prednisolone group showed a significant rise of IOP from baseline to 2 weeks as compared

227 to the nepafenac group, (+2.6 mm Hg vs. +0.6 mm Hg, respectively, p= 0.004). The difference in

228 IOP from baseline to 4 weeks after LPI was not significant between the groups, (0.7±3.4 in the

229 prednisolone group vs. 0.1±2.5 in the nepafenac group, p = 0.30) (Table 2)

230 Of note, significantly higher IOP was noted at 2 weeks vs. 4 weeks after LPI in the prednisolone

231 group, (18.5 mm Hg vs. 16.6 mm Hg, p = 0.0001), but not in the nepafenac group (16.3 mm Hg

232 vs. 15.9 mm Hg, p = 0.07), (Figure 1).

233 As these IOP changes were small in magnitude, but may have resulted from a few eyes with

234 significant medication-related IOP changes, additional analyses were conducted to examine the

235 frequency of significant IOP increases across treatment groups. At 2 weeks after LPI, moderate

236 IOP elevation of 6-15 mm of Hg from baseline was seen in more patients on prednisolone when

237 compared to those on nepafenac, though the difference was not statistically significant (20.8%

238 vs. 8.3% respectively; p = 0.10). A significant difference in the frequency of moderate IOP

239 elevation was observed at 4 weeks after LPI (18.2% in the prednisolone group vs. 3% in the

240 nepafenac group, p = 0.045). At 2 weeks after LPI, high IOP elevation of >15 mm of Hg from
 12

241 baseline, was seen in 2 (4.2 %) prednisolone-treated patients but no nepafenac-treated patients (p

242 = 0.20). No eyes showed more than 15 mm Hg of IOP elevation at 4 weeks after LPI (Table 3).

243 Linear regression analyses were performed to determine the confounding factors associated with

244 IOP elevation from baseline to 2 weeks (Table 4). Female gender and use of prednisolone eye

245 drops were associated with significant rise in IOP (p-value 0.03 and 0.02 respectively). There

246 was no association between age, initial laser energy per shot, total laser energy, number of shots,

247 or LPI location with IOP elevation at 2 weeks (p = > 0.06 for all). In multivariable analysis, none

248 of the variables had any association with IOP elevation (p = >0.05 for all)

249

250 Repeat Laser Peripheral Iridotomy:

251 In an unplanned analysis, we noted that at 2 weeks after LPI, 10.8% of prednisolone-treated

252 patients needed repeat LPI (2 patients in the designated study eye, 2 patients in both eyes and 4

253 patients in the fellow eye), while no nepafenac-treated eyes needed such treatment in either the

254 study eye or fellow eye (p = 0.003). Logistic regression analysis were performed to determine

255 baseline parameters predicting LPI closure at 2 weeks follow-up (Table-5). We found that apart

256 from prednisolone (p = 0.04), number of shots (p = 0.03) and total laser energy (p = 0.04) were

257 associated with higher odds of LPI closure. These patients requiring a second procedure had a

258 significant rise in IOP at 4 weeks after repeat LPI compared to baseline (16.9 vs. 15.4; p = 0.03).

259

260

261
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262 DISCUSSION:

263 Our study demonstrates that nepafenac eye drop therapy is non-inferior to prednisolone acetate

264 eye drop therapy in controlling inflammation after LPI in south Indian PACS patients. Of note,

265 5.4% of patients in the prednisolone group presented with rebound iritis as compared to none in

266 the nepafenac treated group, suggesting that nepafenac treatment may have benefits with regards

267 to preventing rebound inflammation. Additionally, none of the patients in the nepafenac group

268 needed steroids or other additional medications to control inflammation. Also, significant

269 increases of IOP were noted only in the prednisolone group over the study period, though these

270 rises were clinically not relevant. These findings argue that nepafenac is a viable alternative to

271 prednisolone in the post-operative treatment of eyes undergoing LPI.

272 Our findings suggest that NSAIDs are sufficient for controlling inflammation after laser

273 iridotomy. At 2 weeks we had only one patient with minimal anterior chamber inflammation in

274 the nepafenac group, and the inflammation completely subsided by 4 weeks after LPI with

275 additional duration of nepafenac eye drops. However, cases of rebound iritis were only found in

276 the prednisolone group (4 vs. 0). As such, we found non-inferior control in the nepafenac group

277 as compared to the prednisolone group; no study group without any anti-inflammatory agents

278 was employed to determine the rate of post-LPI eyes without any treatment. To the best of our

279 knowledge, there are no studies comparing NSAIDS and steroids in controlling inflammation

280 associated with LPI. Of note, however, prior studies have noticed similar levels of inflammation

281 control after other ocular procedures. Keith et al compared the safety and efficacy of bromfenac

282 and prednisolone acetate after cataract surgery, and reported that at two weeks post-surgery

283 persistent minimal inflammation was seen more in bromfenac group (12%) than in prednisolone

284 group (8%).14 Also, in a study by Miyake et al comparing nepafenac with fluorometholone in
 14

285 preventing cystoid macular edema after cataract surgery, nepafenac was found to be more

286 effective than fluorometholone in controlling anterior chamber inflammation associated with

287 cataract surgery.15 Similarly, in a prospective double-blind randomized study, Nagpal et al

288 compared topical nepafenac and prednisolone acetate in controlling post-operative inflammation

289 following a transscleral sutureless vitrectomy and found no significant difference in the

290 inflammatory scores between the groups. They also reported that the patients on nepafenac had

291 lesser pain perception as compared to those on prednisolone indicating the additional benefit of

292 nepafenac in addressing the pain apart from the inflammation.6 Wright et al compared the

293 relative anti-inflammatory potency and safety of topical diclofenac–gentamicin with

294 betamethasone– neomycin following strabismus surgery and found that diclofenac was as

295 effective as betamethasone in controlling inflammation at one week and 4 weeks post-surgery.5

296 A recent trial by Groth et al16 comparing the impact of prednisolone vs. ketorolac vs. saline tears

297 on Selective Laser Trabeculoplasty (SLT) efficacy found that NSAIDs were equally efficacious

298 in controlling anterior chamber inflammation following SLT compared to steroids. Together,

299 these studies support the use of NSAIDs as a potential alternative to steroids after a broad range

300 of ocular procedures.

301 About 5.4% of patients in the prednisolone group presented with rebound iritis within 2 or 3 days

302 of stopping the medication, a well-known complication of steroid withdrawal.17,18 No patient

303 presented with such rebound inflammation in the nepafenac group. Patients with rebound iritis

304 require additional medications and follow ups inconveniencing both the patient and the treating

305 physician. As such, nepafenac may be preferable to prednisolone in some respects, reducing

306 medication dosage and number of follow-ups in some patients.

 15

307 Mild IOP changes were observed in the prednisolone group, but not in the nepafenac group,

308 though no clinically meaningful IOP rises were noted in either group. We could see a statistically

309 significant increase in the IOP of about 2.6 mm of Hg from baseline to two weeks in the

310 prednisolone group. Also there was a significant drop of IOP from 2 weeks to 4 weeks once the

311 steroid drops were stopped, suggesting the rise was steroid-related. Similarly, Laurell et al in

312 their study compared the inflammatory response after cataract surgery using dexamethasone,

313 diclofenac or placebo postoperatively and found that there was a significant rise in IOP in the

314 dexamethasone group as compared to the placebo group (p<0.05) as early as 8 days.4 Though in

315 univariate analysis we found an association between IOP elevation and prednisolone acetate use,

316 the same was not held true in multivariable analysis. Though this small rise of IOP in the

317 prednisolone group may not be clinically meaningful, there is a chance of subsequent steroid

318 abuse and consequent adverse events in the form of cataract and glaucoma, particularly in

319 countries where topical steroids can be obtained without a prescription.19

320 We noticed a higher need for repeat LPI in prednisolone-treated eyes as opposed to nepafenac-

321 treated eyes. While looking at the confounding factors we found that apart from prednisolone

322 acetate, higher total laser energy and more number of laser shots were also associated with repeat

323 LPI. Given 8 patients who required repeat LPI and another 4 patients who had rebound iritis, a

324 total of 12 patients out of 74 patients (16.2%) in the prednisolone group needed additional visits,

325 while no nepafenac-treated patients required such additional follow-up. Thus, even though

326 prednisolone acetate eye drops are generally cheaper than nepafenac eye drops, the cost of the

327 additional visits in the prednisolone group may make nepafenac an equally cost-effective drug

328 for controlling inflammation associated with LPI.

 16

329 The strengths of our study include the large sample size, randomized design, masking the

330 investigators to the identity of medication and also recording the intraocular pressure in a masked

331 manner. Our study did have certain limitations. First, we included only PACS eyes. The steroid

332 response in PAC and PACG may be different as they have established structural damage, and the

333 results of this study cannot be generalized to entire primary angle closure disease spectrum. It is

334 possible we would see more aggressive inflammation in PAC and PACG necessitating the use of

335 steroids. We have not done a formal cost assessment of study medications to analyze the cost

336 effectiveness of nepafenac; the price of nepafenac eye drops is 2-3 times higher than

337 prednisolone eye drops which may pose an issue for some patients. Also we did not assess the

338 pain scale and comfort levels with the study medications which would have added value to our

339 research. Though we aimed for a LPI size of 250-300 microns in all the patients, we have not

340 assessed the size of the LPI during the follow-up. Finally, while masking of study group may

341 have been incomplete as the appearance of the nepafenac and prednisolone drops were distinct,

342 such that a knowledgeable patient may have allowed them to discern their treatment group.

343

344

345 In conclusion, nepafenac is effective and non-inferior to prednisolone acetate in controlling the

346 inflammation associated with LPI, with less of an effect on IOP. Hence it can be considered in

347 the place of topical steroids to treat the inflammation associated with LPI in PACS patients.

348 Further research is warranted in PAC and PACG patients as well as in eyes receiving other

349 ophthalmic procedures.

350

351 Acknowledgements: Mohammed Sithiq Uduman S, Biostatistician for statistical analysis

 17

352 REFERENCES

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355 2. Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal

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358 3. Becker B: Intra ocular pressure response to Topical corticosteroids. Invest Ophthalmol

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361 4. C-G Laurell, C Zetterström. Effects of dexamethasone, diclofenac, or placebo on the

362 inflammatory response after cataract surgery. Br J Ophthalmol 2002;86:1380-84

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364 5. Mark Wright, Zahida Butt, Gawn Mcllwaine, Brian Fleck. Comparison of the efficacy of

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366 1997;81:299–301.

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368 6. Manish Nagpal, Sarang Lambat, Navneet Mehrotra, et al. Topical nepafenac 0.1% alone

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375 8. Ang LP, Aung T, Chew PT. Acute primary angle closure in an Asian population: long-term

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394

395 14. Keith A Walter, Amy J Estes, Samantha Watson ME. Management of Ocular Inflammation

396 following Routine Cataract Surgery-Topical Corticosteroid (Prednisolone) versus Topical Non-
 19

397 steroidal (Bromfenac). Us Ophthalmic Review 2011;4:97–100.

398

399 15. Kensaku Miyake, Ichiro Ota, Goichiro Miyake, Jiro Numaga. Nepafenac 0.1% versus

400 fluorometholone 0.1% for preventing cystoid macular edema after cataract surgery. J Cataract

401 Refract Surg 2011;37:1581–88.

402

403 16. Sylvia L. Groth, Eiyass Albeiruti, Mariana Nunez, et al. SALT Trial: Steroids after Laser

404 Trabeculoplasty: Impact of Short-Term Anti-inflammatory Treatment on Selective Laser

405 Trabeculoplasty Efficacy. Ophthalmology 2019;126(11):1511-6

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407 17. Krupin T, LeBlanc RP, Becker B, et al. Uveitis in association with topically administered

408 corticosteroid. Am J Ophthalmol 1970;3:883–5.

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410 18. Rehab Ismail and Ahmed Sallam. Complications Associated with Cataract Surgery.

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415
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416 Figure legend: Fig 1. Line diagram showing intraocular pressure course from baseline to 2

417 weeks and 4 weeks after laser peripheral iridotomy in nepafenac and prednisolone groups. A

418 significant rise in intraocular pressure from baseline to 2 weeks was noted in the prednisolone

419 group as compared to the nepafenac group (p=0.002); also, we could note a significant fall in

420 intraocular pressure from 2 weeks to 4 weeks in the prednisolone group (p=0.0001).

421

422
 Table 1. Demographic Characteristics and Procedural Details for Primary Angle Closure
Suspects Undergoing Laser Peripheral Iridotomy

Variable Nepafenac Prednisolone p-value*

n=76 n=74
Age (Years), Mean (SD) 51.5 (7.8) 52.1 (7.7) 0.60
Female gender, % 85.5 86.5 0.80
Diabetes mellitus, % 22.4 24.3
0.70
Baseline IOP, Mean (SD) 15.8 (3.0) 15.9 (3.0)
0.80
Initial laser energy per shot (mJ), Mean (SD) 4.9 (0.7) 4.7 (0.8)
0.10
Total number of laser shots, Mean (SD) 28.4 (26.9) 34.8 (35.4) 0.29
Total laser energy (mJ), Mean (SD) 137.7 (124.2) 149.7 (130.8) 0.40
Location of LPI, %
Superior 3.9 10.8 0.10
Nasal 85.5 83.8
0.76
Temporal 10.5 5.4 0.24

IOP = intraocular pressure, mJ = milli joules, SD = Standard deviation, *p<0.05, statistically

significant
Table 2. Intraocular Pressure Difference Comparison from Baseline to 2 Weeks and 4
Weeks after Laser Peripheral Iridotomy in between the Groups

IOP difference Nepafenac Prednisolone p-value

n=76 n=74
2 weeks vs. Baseline, Mean (SD) +0.6 (2.7) +2.6 (4.8) 0.004
4 weeks vs. Baseline, Mean (SD) +0.1 (2.5) +0.7 (3.4) 0.26

IOP = Intraocular pressure, SD = Standard deviation

Table 3. Comparison of Post-Iridotomy Intraocular Pressure Elevation from Baseline to 2
weeks and 4 weeks Between the Study Groups

IOP elevation Nepafenac Prednisolone p-value

2 weeks n=76 n=74
6-15 mm of Hg 3 (8.3 %) 10(20.8%) 0.10
>15 mm of Hg 0 2 (4.2%) 0.20

IOP elevation Nepafenac Prednisolone p-value

4 weeks n=76 n=74
6-15 mm of Hg 1 (3.0%) 6(18.2%) 0.045
>15 mm of Hg 0 0 NA

IOP = Intraocular pressure, NA = Not applicable

Table 4. Linear Regression Analysis to Identify Factors Associated with Elevation in Intraocular Pressure
at 2 weeks after Laser Peripheral Iridotomy

Univariate Multivariate
Baseline Interval Co-efficient 95% CI p-value* Co-efficient 95% CI p-value*
parameters

Age (years) 1 year older 0.05 -0.06 to 0.15 0.38 0.04 -0.07 to 0.14 0.48
Female vs. Male 2.26 0.14 to 4.37 0.037 2.00 -0.13 to 4.14 0.06

Initial 1mj -0.62 -1.61 to 0.38 0.22 -0.36 -1.39 to 0.67 0.48
laser energy

Number one more 0.02 -0.01 to 0.05 0.14 0.02 -0.03 to 0.07 0.50
of shots shot

Total 1mj 0.003 -0.004 to 0.01 0.39 0.001 -0.01 to 0.01 0.84
laser energy

LPI location
Nasal vs. Superior -3.06 -6.26 to 0.14 0.06 -2.24 -5.58 to 1.09 0.18
Temporal vs. Superior -2.56 -6.51 to 1.40 0.20 -2.39 -6.82 to 2.05 0.28
Prednisolone vs. Nepafenac 1.93 0.30 to 3.56 0.021 1.31 -0.45 to 3.07 0.14

mJ = milli joules, *p<0.05, statistically significant

 Table 5. Logistic Regression Analysis for Predictors of Laser Peripheral Iridotomy Closure

Baseline parameters Interval Odds ratio 95% CI p-value*

Age (years) 1 year older 1.02 0.93 – 1.11 0.74

Female vs. Male 0.33 0.02 – 5.97 0.46
Initial laser energy 1mj 1.50 0.59 – 3.78 0.39
Number of shots one more shot 0.91 0.83 – 0.99 0.03
Total laser energy 1mj 0.98 0.97 – 1.00 0.04
LPI location
Nasal vs. Superior 1.64 0.09 – 30.2 0.74
Temporal vs. Superior 0.92 0.02 – 50.3 0.97
Prednisolone vs. Nepafenac 19.56 1.11 – 345.3 0.04

mJ = milli joules, *p<0.05, statistically significant

Precis: Nepafenac is safe and non-inferior to steroid treatment for controlling inflammation

associated with laser peripheral iridotomy in primary angle closure suspects.