Prednisolone and Ketorolac vs Ketorolac Monotherapy or Sub-Tenon Prophylaxis for Macular Thickening in Cataract Surgery: A Randomized Clinical Trial | Anesthesiology | JAMA Ophthalmology | JAMA Network
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Visual Abstract. RCT: Corticosteriod Plus NSAID vs NSAID Monotherapy or Sub-Tenon Prophylaxis for Cataract Surgery.
RCT: Corticosteriod Plus NSAID vs NSAID Monotherapy or Sub-Tenon Prophylaxis for Cataract Surgery.
Figure 1.  Consort Diagram for Flow of Participants
Consort Diagram for Flow of Participants

Preoperative prednisolone plus nonsteroidal anti-inflammatory drug (NSAID) indicates group receiving a combination of prednisolone, 1%, and ketorolac tromethamine, 0.5%, eye drops 3 times per day until 3 weeks after surgery with initiation 3 days before surgery; postoperative prednisolone plus NSAID, group receiving a combination of prednisolone, 1%, and ketorolac, 0.5%, eye drops 3 times per day until 3 weeks after surgery with initiation on the day of surgery; preoperative NSAID, group receiving monotherapy with ketorolac, 0.5%, eye drops 3 times per day until 3 weeks after surgery with initiation 3 days before surgery; postoperative NSAID, group receiving monotherapy with ketorolac, 0.5%, eye drops 3 times per day until 3 weeks after surgery with initiation on the day of surgery; and sub-Tenon, group receiving sub-Tenon depot consisting of 0.5 mL of dexamethasone phosphate, 4 mg/mL. Participants who withdrew did so before surgery and before investigational medicine was administered; for those outside the time frame, postoperative visits took place outside the prespecified 2 to 4 days for the 3-day visit, 14 to 28 days for the 3-week visit, and 60 to 120 days for the 3-month visit. Some participants who attended a visit outside the specified time frame returned for the next postoperative visit within the specified time frame of that visit.

Figure 2.  Mean Central Subfield Thickness (CST) From Baseline to 3 Months After Surgery
Mean Central Subfield Thickness (CST) From Baseline to 3 Months After Surgery

Error bars represent 95% CIs. Only 1 error bar is presented at baseline because estimates per definition are the same for all groups in the constrained linear mixed model with inherent baseline adjustment. Groups are described in the legend for Figure 1.

Table 1.  Baseline Characteristics of Included Participants and Use of Phacoemulsification Energya
Baseline Characteristics of Included Participants and Use of Phacoemulsification Energya
Table 2.  Results From Analyses of CST, IOP, and Visual Acuitya
Results From Analyses of CST, IOP, and Visual Acuitya
Table 3.  Subjective Tolerance, Adverse Events, Added Treatment, and Extra Visits
Subjective Tolerance, Adverse Events, Added Treatment, and Extra Visits
1.
Chu  CJ, Johnston  RL, Buscombe  C, Sallam  AB, Mohamed  Q, Yang  YC; United Kingdom Pseudophakic Macular Edema Study Group.  Risk factors and incidence of macular edema after cataract surgery: a database study of 81 984 eyes.   Ophthalmology. 2016;123(2):316-323. doi:10.1016/j.ophtha.2015.10.001PubMedGoogle ScholarCrossref
2.
Shorstein  NH, Liu  L, Waxman  MD, Herrinton  LJ.  Comparative effectiveness of three prophylactic strategies to prevent clinical macular edema after phacoemulsification surgery.   Ophthalmology. 2015;122(12):2450-2456. doi:10.1016/j.ophtha.2015.08.024PubMedGoogle ScholarCrossref
3.
Kessel  L, Tendal  B, Jørgensen  KJ,  et al.  Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review.   Ophthalmology. 2014;121(10):1915-1924. doi:10.1016/j.ophtha.2014.04.035PubMedGoogle ScholarCrossref
4.
Guo  S, Patel  S, Baumrind  B,  et al.  Management of pseudophakic cystoid macular edema.   Surv Ophthalmol. 2015;60(2):123-137. doi:10.1016/j.survophthal.2014.08.005PubMedGoogle ScholarCrossref
5.
Lim  BX, Lim  CHL, Lim  DK, Evans  JR, Bunce  C, Wormald  R.  Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery.   Cochrane Database Syst Rev. 2016;11(11):CD006683. doi:10.1002/14651858.CD006683.pub3PubMedGoogle Scholar
6.
Juthani  VV, Clearfield  E, Chuck  RS.  Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.   Cochrane Database Syst Rev. 2017;7:CD010516. doi:10.1002/14651858.CD010516.pub2PubMedGoogle Scholar
7.
Colin  J.  The role of NSAIDs in the management of postoperative ophthalmic inflammation.   Drugs. 2007;67(9):1291-1308. doi:10.2165/00003495-200767090-00004PubMedGoogle ScholarCrossref
8.
Wielders  LHP, Lambermont  VA, Schouten  JSAG,  et al.  Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.   Am J Ophthalmol. 2015;160(5):968-981.e33. doi:10.1016/j.ajo.2015.07.032PubMedGoogle ScholarCrossref
9.
Donnenfeld  ED, Perry  HD, Wittpenn  JR, Solomon  R, Nattis  A, Chou  T.  Preoperative ketorolac tromethamine 0.4% in phacoemulsification outcomes: pharmacokinetic-response curve.   J Cataract Refract Surg. 2006;32(9):1474-1482. doi:10.1016/j.jcrs.2006.04.009PubMedGoogle ScholarCrossref
10.
Kim  SJ, Schoenberger  SD, Thorne  JE, Ehlers  JP, Yeh  S, Bakri  SJ.  Topical nonsteroidal anti-inflammatory drugs and cataract surgery: a report by the American Academy of Ophthalmology.   Ophthalmology. 2015;122(11):2159-2168. doi:10.1016/j.ophtha.2015.05.014PubMedGoogle ScholarCrossref
11.
Yavas  GF, Oztürk  F, Küsbeci  T.  Preoperative topical indomethacin to prevent pseudophakic cystoid macular edema.   J Cataract Refract Surg. 2007;33(5):804-807. doi:10.1016/j.jcrs.2007.01.033PubMedGoogle ScholarCrossref
12.
Winfield  AJ, Jessiman  D, Williams  A, Esakowitz  L.  A study of the causes of non-compliance by patients prescribed eyedrops.   Br J Ophthalmol. 1990;74(8):477-480. doi:10.1136/bjo.74.8.477PubMedGoogle ScholarCrossref
13.
Dieleman  M, Wubbels  RJ, van Kooten-Noordzij  M, de Waard  PWT.  Single perioperative subconjunctival steroid depot versus postoperative steroid eyedrops to prevent intraocular inflammation and macular edema after cataract surgery.   J Cataract Refract Surg. 2011;37(9):1589-1597. doi:10.1016/j.jcrs.2011.03.049 PubMedGoogle ScholarCrossref
14.
Athanasiadis  Y, Tsatsos  M, Sharma  A, Hossain  P.  Subconjunctival triamcinolone acetonide in the management of ocular inflammatory disease.   J Ocul Pharmacol Ther. 2013;29(6):516-522. doi:10.1089/jop.2012.0208PubMedGoogle ScholarCrossref
15.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle ScholarCrossref
16.
Harris  PA, Taylor  R, Thielke  R, Payne  J, Gonzalez  N, Conde  JG.  Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.   J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010PubMedGoogle ScholarCrossref
17.
Harris  PA, Taylor  R, Minor  BL,  et al; REDCap Consortium.  The REDCap consortium: building an international community of software platform partners.   J Biomed Inform. 2019;95:103208. doi:10.1016/j.jbi.2019.103208PubMedGoogle Scholar
18.
Early Treatment Diabetic Retinopathy Study Design and Baseline Patient Characteristics.  Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS report number 7.   Ophthalmology. 1991;98(5)(suppl):741-756. doi:10.1016/S0161-6420(13)38009-9PubMedGoogle ScholarCrossref
19.
Wielders  LHP, Schouten  JSAG, Winkens  B,  et al; ESCRS PREMED Study Group.  European multicenter trial of the prevention of cystoid macular edema after cataract surgery in nondiabetics: ESCRS PREMED study report 1.   J Cataract Refract Surg. 2018;44(4):429-439. doi:10.1016/j.jcrs.2018.01.029PubMedGoogle ScholarCrossref
20.
Age-Related Eye Disease Study Research Group.  The Age-Related Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report No. 4.   Am J Ophthalmol. 2001;131(2):167-175. doi:10.1016/S0002-9394(00)00732-7PubMedGoogle ScholarCrossref
21.
R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing; 2019. Accessed July 3, 2021. http://www.r-project.org/
22.
Fitzmaurice  GM, Laird  NM, Ware  JH.  Applied Longitudinal Analysis. John Wiley & Sons Inc; 2011. doi:10.1002/9781119513469
23.
Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing.   J R Stat Soc Ser B. 1995;57(1):289-300. doi:10.1111/j.2517-6161.1995.tb02031.xGoogle Scholar
24.
Zafar  S, Wang  P, Schein  OD, Srikumaran  D, Makary  M, Woreta  FA.  Prescribing patterns and costs associated with postoperative eye drop use in Medicare beneficiaries undergoing cataract surgery.   Ophthalmology. 2020;127(5):573-581. doi:10.1016/j.ophtha.2019.11.005PubMedGoogle ScholarCrossref
25.
Ylinen  P, Holmström  E, Laine  I, Lindholm  J-M, Tuuminen  R.  Anti-inflammatory medication following cataract surgery: a randomized trial between preservative-free dexamethasone, diclofenac and their combination.   Acta Ophthalmol. 2018;96(5):486-493. doi:10.1111/aos.13670PubMedGoogle ScholarCrossref
26.
Erichsen  JH, Forman  JL, Holm  LM, Kessel  L.  Effect of anti-inflammatory regimen on early postoperative inflammation after cataract surgery.   J Cataract Refract Surg. 2021;47(3):323-330. doi:10.1097/j.jcrs.0000000000000455PubMedGoogle ScholarCrossref
27.
Lindholm  JM, Taipale  C, Ylinen  P, Tuuminen  R.  Perioperative subconjunctival triamcinolone acetonide injection for prevention of inflammation and macular oedema after cataract surgery.   Acta Ophthalmol. 2020;98(1):36-42. doi:10.1111/aos.14175PubMedGoogle ScholarCrossref
28.
Wielders  LHP, Schouten  JSAG, Winkens  B,  et al; ESCRS PREMED study group.  Randomized controlled European multicenter trial on the prevention of cystoid macular edema after cataract surgery in diabetics: ESCRS PREMED Study Report 2.   J Cataract Refract Surg. 2018;44(7):836-847. doi:10.1016/j.jcrs.2018.05.015PubMedGoogle ScholarCrossref
29.
Laursen  SB, Erichsen  JH, Holm  LM, Kessel  L.  Prevention of macular edema in patients with diabetes after cataract surgery.   J Cataract Refract Surg. 2019;45(6):854-869. doi:10.1016/j.jcrs.2019.04.025PubMedGoogle ScholarCrossref
30.
Shorstein  NH, Myers  WG.  Drop-free approaches for cataract surgery.   Curr Opin Ophthalmol. 2020;31(1):67-73. doi:10.1097/ICU.0000000000000625PubMedGoogle ScholarCrossref
31.
Donnenfeld  ED, Holland  EJ, Solomon  KD.  Safety and efficacy of nepafenac punctal plug delivery system in controlling postoperative ocular pain and inflammation after cataract surgery.   J Cataract Refract Surg. 2021;47(2):158-164. doi:10.1097/j.jcrs.0000000000000414PubMedGoogle ScholarCrossref
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    Original Investigation
    August 12, 2021

    Prednisolone and Ketorolac vs Ketorolac Monotherapy or Sub-Tenon Prophylaxis for Macular Thickening in Cataract Surgery: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark
    • 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
    • 3Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
    JAMA Ophthalmol. 2021;139(10):1062-1070. doi:10.1001/jamaophthalmol.2021.2976
    Key Points

    Question  Is a combination of corticosteroid and nonsteroidal anti-inflammatory drug (NSAID) eye drops superior to NSAID eye drops alone or dropless surgery with a sub-Tenon dexamethasone depot in controlling postoperative central macular thickening after uncomplicated cataract surgery?

    Findings  In this randomized clinical trial with 470 participants, no differences in central subfield thickness or visual acuity across treatment arms were identified, although approximately half of the group given the sub-Tenon depot received additional anti-inflammatory treatment.

    Meaning  Therapy with NSAID plus corticosteroid eye drops was not superior to NSAID monotherapy or sub-Tenon depot for postoperative central macular thickening after uncomplicated cataract surgery.

    Abstract

    Importance  The choice of anti-inflammatory prophylaxis parallel to cataract surgery is important for patient safety and successful outcome of surgery, but which regimen to choose is contested.

    Objectives  To determine whether a combination of prednisolone and nonsteroidal anti-inflammatory drug (NSAID) eye drops was superior in preventing increased central macular thickness (central subfield thickness [CST]) after uncomplicated cataract surgery compared with NSAID monotherapy and sub-Tenon capsule depot (dropless surgery), and to test whether preoperative initiation of eye drop treatment was superior to initiation on the day of surgery.

    Design, Setting, and Participants  This investigator-driven, single-center, randomized clinical trial with masked statistical analyses enrolled patients at the Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark, from February 1, 2018, to August 15, 2019. Follow-up was completed December 18, 2019. Participants included low-risk patients undergoing phacoemulsification for age-related cataract by an experienced surgeon (1 eye per participant). Data were analyzed from February 17 to June 15, 2020.

    Interventions  Participants scheduled for cataract removal were randomized to 1 of 5 anti-inflammatory prophylactic regimens: eye drops with a combination of prednisolone, 1%, and ketorolac tromethamine, 0.5%, with or without preoperative initiation (preoperative prednisolone plus NSAID [control] and postoperative prednisolone plus NSAID groups), ketorolac monotherapy with or without preoperative initiation (preoperative and postoperative NSAID groups), or sub-Tenon depot of dexamethasone phosphate (sub-Tenon group). Eye drops were administered 3 times per day until 3 weeks postoperatively.

    Main Outcomes and Measures  CST 3 months postoperatively.

    Results  A total of 470 participants (mean [SD] age, 72.2 [7.0] years; 290 women [61.7%]) with 94 participants in each group were included in the analysis. Three months after surgery, the mean CST was 250.7 (95% CI, 247.6-253.7) μm in the preoperative prednisolone plus NSAID group, 250.7 (95% CI, 247.8-253.7) μm in the postoperative prednisolone plus NSAID group, 251.3 (95% CI, 248.2-254.4) μm in the preoperative NSAID group, 249.2 (95% CI, 246.2-252.3) μm in the postoperative NSAID group, and 255.2 (95% CI, 252.0-258.3) μm in the sub-Tenon group. There were no significant differences in CST or visual acuity compared with control and no differences between preoperative and postoperative groups, but 47 of 83 participants (56.6%) in the sub-Tenon group needed additional anti-inflammatory treatment.

    Conclusions and Relevance  No differences in CST or visual acuity were detected between the combination of prednisolone and NSAID eye drops vs NSAID monotherapy or sub-Tenon dexamethasone depot, although more than one-half of patients in the sub-Tenon arm received additional anti-inflammatory treatment. Initiating prophylaxis 3 days preoperatively was not superior to initiation on the day of surgery. Monotherapy with NSAIDs may be preferred in uncomplicated cataract surgery.

    Trial Registration  ClinicalTrials.gov Identifier: NCT03383328

    Introduction

    Pseudophakic cystoid macular edema (PCME) is an important cause of unsatisfactory visual outcome after cataract surgery. It affects visual acuity after approximately 1% of surgical procedures.1,2 There is no common classification of PCME, and therefore estimates differ between studies. A meta-analysis3 reported that 4% to 25% had some degree of macular edema, even when prophylactic treatment was administered. It is believed that PCME is caused by the inflammatory response after cataract surgery, which disrupts the blood-ocular barrier leading to leakage of fluid into the retina.4 To control the inflammatory response and reduce the risk of PCME, prophylactic anti-inflammatory eye drops are prescribed parallel to cataract surgery.

    The choice of anti-inflammatory prophylaxis is contested.5,6 Two types of drugs are available: corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroids inhibit phospholipases and thereby both prostaglandin and lipoxin synthesis,7 and NSAIDs selectively inhibit cyclooxygenase enzymes, which convert arachidonic acids to prostaglandins7; however, meta-analyses3,5,6,8 have found that NSAIDs are more effective in preventing PCME. It has been suggested that preoperative initiation of NSAID prophylaxis is beneficial,9-11 but to our knowledge, evidence from large randomized trials is missing.

    Prophylactic treatment parallel to cataract surgery is traditionally administered as eye drops. Many patients have difficulties using eye drops and need assistance.12 Therefore, several dropless approaches have been suggested, and some studies2,13,14 have found that the effectiveness of these dropless approaches is comparable to corticosteroid eye drop monotherapy. To our knowledge, no studies have compared a dropless approach with NSAID eye drops. The purpose of this study was to determine whether (1) combination of prednisolone and NSAID eye drops is superior in preventing macular thickening after uncomplicated cataract surgery compared with NSAID monotherapy and dropless surgery using a sub–Tenon capsule dexamethasone phosphate depot and (2) preoperative initiation of eye drop treatment is superior to initiating treatment on the day of surgery.

    Methods
    Design and Intervention

    Quiz Ref IDThis study was a randomized clinical trial comparing 5 different regimens for anti-inflammatory prophylaxis parallel to uncomplicated cataract surgery. The trial protocol and statistical analysis plan are found in Supplement 1 and Supplement 2, respectively. The control group received a combination of corticosteroid and NSAID eye drops, initiated 3 days before surgery (preoperative prednisolone plus NSAID group). Comparison groups received a combination of corticosteroid and NSAID drops initiated on the day of surgery (postoperative prednisolone plus NSAID group), NSAID eye drop monotherapy initiated 3 days before surgery or on the day of surgery (preoperative NSAID and postoperative NSAID groups, respectively), and sub-Tenon depot of dexamethasone administered at the conclusion of surgery (sub-Tenon group). Participants in the sub-Tenon group were not given anti-inflammatory drops. Corticosteroid drops were prednisolone acetate, 1% (Pred Forte; Allergan); NSAID drops, ketorolac tromethamine, 0.5% (Acular; Allergan); and sub-Tenon depot, 0.5 mL of dexamethasone phosphate, 4 mg/mL (Dexamethasone Krka [Krka] or Dexavital [Vital Pharma Nordic]). All drops were administered 3 times per day until 3 weeks postoperatively, and adherence was monitored by asking participants, in an unstructured manner, if they were taking their drops; no formal recording of compliance was collected. Ethics committee approval was obtained from the Committee on Health Research Ethics, Capital Region, Denmark. The study was approved by the Danish Medicines Agency and the Danish Data Protection Agency. Accordance with the good clinical practice quality standard was monitored by the good clinical practice unit at Copenhagen University Hospital, Copenhagen, Denmark. The study was conducted in accordance with the Declaration of Helsinki,15 and all participants provided written informed consent. Participants received no incentives or compensation for participation. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Participants and Sample Size

    We recruited participants among patients scheduled for cataract surgery at the Department of Ophthalmology, Rigshospitalet Glostrup, Glostrup, Denmark, from February 1, 2018, to August 15, 2019. Inclusion criteria were age-related cataract, capacity to consent, and consent to participation. In addition, women had to be postmenopausal. Exclusion criteria were known allergy to any content of the pharmaceuticals used; medical history of retinal vein occlusion, epiretinal membrane, uveitis, glaucoma, retinal detachment, diabetes, exudative age-related macular degeneration, or age-related macular degeneration with geographical atrophy; and significant complications of surgery such as posterior capsule rupture/vitreous loss, choroidal hemorrhage, or dislocated lens material. Participants with complications were excluded when complications were detected (Figure 1). Sample size was set at 94 per interventional group, which allowed us to detect a difference of 5 μm in central retinal thickness with a power of 90% at a 5% significance level or a power of 80% at a 1.25% significance level. Five micrometers was chosen at the investigators’ discretion.

    Randomization

    One eye per participant was included using a computerized coin toss to decide which eye to include if both eyes were eligible. Immediately after receiving signed consent for participation, participants were randomized to 1 of the 5 interventional groups (Figure 1) by the same examiner (J.H.E.). We used the randomization instrument in Research Electronic Data Capture (REDCap)16,17 hosted at Capital Region, Denmark. A block-randomized list was created at Sealed Envelope (https://www.sealedenvelope.com/simple-randomiser/v1/lists) and uploaded to REDCap by an independent researcher. The length of the list was 470, and block sizes were 5, 10, and 15 in random order.

    Surgical Procedure

    All surgical procedures were performed by experienced surgeons (including L.M.H.), with experience defined as a minimum of 1000 cataract procedures performed within the 2 previous years. The surgical procedure was phacoemulsification with implantation of a hydrophobic intraocular lens (IOL) in the lens bag. Oxybuprocaine was used as local anesthetic, and eyes were instilled with phenylephrine hydrochloride, 10%, tropicamide, 1%, and ketorolac, 0.5%, before surgery. We used a 2.4-mm main incision and a 1-mm side port incision. Intracameral lidocaine hydrochloride, 1%, and viscoelasticum were instilled, followed by capsulorhexis and hydrodissection. For phacoemulsification, we used a surgical microscope and probe (Infinity Vision System; Alcon) with a miniflared 0.9-mm tip. On conclusion, the anterior chamber was irrigated with 1 mL of cefuroxime, 2.5 mg/mL.

    Examinations and Outcomes

    Follow-up was completed December 18, 2019. Participants were examined at the preoperative visit (baseline) and 3 days, 3 weeks, and 3 months postoperatively. The primary outcome was central macular thickness at the 3-month visit measured by optical coherence tomography (DRI OCT Triton; Topcon Europe Medical BV) using the central 1.0-mm zone (central subfield thickness [CST]) of the ETDRS (Early Treatment Diabetic Retinopathy Study) grid obtained from the built-in software (IMAGEnet 6; Topcon Europe Medical BV).18,19 Secondary outcomes were CST at 3 weeks postoperatively, corrected distance visual acuity (CDVA) in logarithm to the minimal angle of resolution (logMAR) using an ETDRS chart, intraocular pressure (IOP), and subjective tolerance of treatment. Intraocular pressure was measured using a rebound tonometer (iCare Finland) and controlled by Goldmann applanation tonometry if the IOP was greater than 25 mm Hg. Subjective tolerance to treatment was assessed 3 days and 3 weeks postoperatively by asking the participants if they experienced no discomfort or mild discomfort or moderate or severe discomfort. Cataract severity was graded using the Age-Related Eye Disease Study classification.20 Adverse events were defined as events that were not expected as part of routine surgery for cataract or baseline conditions or as events that led to additional treatment. Corneal edema or dryness were not noted as adverse events unless additional treatment was initiated. The decision to institute additional treatment was made by experienced physicians (including J.H.E., L.M.H., and L.K.). Any need for additional topical anti-inflammatory, lubricating, IOP-lowering, or antibiotic treatment was registered. Adverse events with relation to the eyes were grouped as pain/soreness, insufficiently controlled anterior chamber inflammation, cystoid abnormalities on optical coherence tomography, dryness, corneal abrasion, swollen/red externa, elevated IOP of greater than 25 mm Hg, significant corneal edema, or other.

    Statistical Analysis

    Data were analyzed from February 17 to June 15, 2020. All statistical analyses were conducted according to a prespecified analytical plan using the R statistical software, version 3.6.0 (R Program for Statistical Computing)21 and the nlme package (R Program for Statistical Computing). Pairwise comparisons between the control and comparison groups used a constrained linear mixed model with an unstructured covariance pattern and inherent baseline adjustment.22 Dichotomous outcomes were analyzed with Fisher exact test. All hypothesis tests were 2 sided. Primary analyses (change in CST 3 months postoperatively, relative to the control group) were adjusted for multiple testing using Bonferroni correction, resulting in a significance level of .0125. All secondary analyses were corrected for multiple testing using a false discovery rate correction.23 We considered an adjusted P < .05 to indicate statistical significance. Because some participants were excluded after allocation, analyses followed a modified intention-to-treat approach that included all participants who provided baseline data. The constrained linear mixed model implicitly handled missing data by maximum likelihood estimation. We evaluated the sensitivity of our analyses (eTables 1-6 in Supplement 3). An independent researcher masked statistical analyses by renaming the interventional groups. Full masking was not possible because sub-Tenon treatment was recognizable for participants and outcome assessors. After unmasking, we made analyses of the combination of corticosteroid and NSAID eye drops vs NSAID monotherapy and analyses of preoperative vs postoperative initiation of eye drop therapy by pooling relevant groups. As an exploratory post hoc analysis, we counted cases with a CST increase of at least 10%.

    Results

    A total of 470 participants (mean [SD] age, 72.2 [7.0] years; 290 women [61.7%] and 180 men [38.3%]) were included and randomized, with 94 participants in each interventional group (Table 1). After randomization, 14 participants were excluded. Nine of these were excluded owing to surgical complications and 5 were excluded owing to other criteria (eTable 7 in Supplement 3); thus, 456 participants provided baseline data and 429 completed 3 months of follow-up (Figure 1).

    Central Subfield Thickness

    Three months after surgery, the mean CST was 250.7 (95% CI, 247.6-253.7) μm in the preoperative prednisolone plus NSAID group, 250.7 (95% CI, 247.8-253.7) μm in the postoperative prednisolone plus NSAID group, 251.3 (95% CI, 248.2-254.4) μm in the preoperative NSAID group, 249.2 (95% CI, 246.2-252.3) μm in the postoperative NSAID group, and 255.2 (95% CI, 252.0-258.3) μm in the sub-Tenon group. Differences between the control (preoperative prednisolone plus NSAID) and the comparison groups were 0.1 (98.75% CI, −5.4 to 5.5) μm (P = .97) with the postoperative prednisolone plus NSAID group, 0.6 (98.75% CI, −5.0 to 6.2) μm (P = .79) with the preoperative NSAID group, −1.5 (98.75% −7.0 to 4.1) μm (P = .51) with the postoperative NSAID group, and 4.5 (98.75% CI, −1.1 to 10.1) μm (P = .04) with the sub-Tenon group. Results are presented in Figure 2 and Table 2. The numbers of participants with CST increases of at least 10% are presented in eTable 8 in Supplement 3.

    IOP and Visual Acuity

    The mean IOP decreased in all groups postoperatively, but it was lower in groups not receiving prednisolone in the early postoperative period. At 3 months, we found no differences compared with the preoperative prednisolone plus NSAID group (−3.3 [95% CI, −3.8 to −2.8] mm Hg) in the postoperative prednisolone plus NSAID group (0.2 [95% CI, −0.5 to 0.8] mm Hg), the preoperative NSAID group (−0.3 [95% CI, −0.9 to 0.4] mm Hg), the postoperative NSAID group (−0.3 [95% CI, −0.9 to 0.3] mm Hg), and the sub-Tenon group (−0.2 [95% CI, −0.8 to 0.5] mm Hg (Table 2 and the eFigure in Supplement 3). Corrected distance visual acuity improved in all groups 3 months postoperatively with no identified differences compared with preoperative prednisolone plus NSAID group (Table 2).

    Subjective Tolerance

    Moderate or severe discomfort was reported by a total of 32 participants (7.3%) at 3 days postoperatively and a total of 13 (3.0%) at 3 weeks postoperatively. We identified no differences compared with the preoperative prednisolone plus NSAID group (Table 3).

    Adverse Events, Additional Treatment, and Unscheduled Visits

    Adverse events and addition of anti-inflammatory treatment were registered more often in the sub-Tenon group, but no differences were found between the preoperative prednisolone plus NSAID group and the remaining groups. Two participants were treated for elevated IOP in the immediate postoperative period, but no IOP elevations of greater than 25 mm Hg were found at any postoperative visit. In the sub-Tenon group, there were more unscheduled visits, but no differences were found between the remaining groups and the preoperative prednisolone plus NSAID group. Results are presented in Table 3.

    NSAID Monotherapy vs Combination of Topical Corticosteroid and NSAID

    No differences were identified between NSAID monotherapy and the combination of prednisolone and NSAID drops regarding CST or CDVA at any postoperative visit after pooling combination groups (preoperative and postoperative prednisolone plus NSAID) and NSAID monotherapy groups (preoperative and postoperative NSAID). Intraocular pressure was lower for NSAID monotherapy 3 days and 3 weeks postoperatively compared with the combination of prednisolone and NSAID. No differences in IOP were identified 3 months postoperatively (eTable 9 in Supplement 3).

    Preoperative vs Postoperative Initiation of Topical Treatment

    Quiz Ref IDWe pooled groups with preoperative initiation (preoperative prednisolone plus NSAID and preoperative NSAID) and those with postoperative initiation (postoperative prednisolone plus NSAID and postoperative NSAID) of treatment. In this analysis, we identified no differences between preoperative or postoperative initiation of treatment for CST, CDVA, or IOP at any postoperative visit (eTable 10 in Supplement 3).

    Sensitivity of Results

    We found that our overall conclusions were not sensitive to handling of missing values, to restriction to the per-protocol population, or to inclusion, exclusion, or truncation of extreme outliers. In addition, postrandomization confounding from sex, age, and phacoemulsification energy was unlikely (eTables 1-6 in Supplement 3). Characteristics of participants with and without complete data are presented in eTable 11 in Supplement 3.

    Discussion

    Quiz Ref IDWe investigated the effect of anti-inflammatory prophylaxis on macular thickening after uncomplicated cataract surgery in a randomized clinical study that evaluated the additive effect of prednisolone to NSAID eye drops in a fashion that allowed us to compare the effect of initiating treatment preoperatively with initiation on the day of surgery. In addition, we evaluated the effect of dropless surgery using a sub-Tenon dexamethasone depot. We found that NSAID plus corticosteroid drops were not superior to NSAID monotherapy or sub-Tenon dexamethasone depot for postoperative central macular thickening after uncomplicated cataract surgery.

    One of the primary purposes of prescribing an anti-inflammatory prophylactic treatment in parallel with cataract surgery is to prevent PCME. Pseudophakic cystoid macular edema is infrequent and heterogeneously defined, which makes it difficult to use the incidence as an outcome in clinical trials. Instead, the CST measured with optical coherence tomography is generally accepted as a measure for comparing efficacy of prophylactic regimens. We did not find differences in CST between groups receiving NSAID monotherapy or a combination of NSAID and prednisolone. A large European multicenter trial19 compared corticosteroid monotherapy (dexamethasone, 0.1%) with NSAID monotherapy (bromfenac, 0.09%) and a combination of both and found no significant differences between the combination of corticosteroid and NSAID and NSAID monotherapy, whereas dexamethasone monotherapy resulted in increased macular thickness 6 weeks postoperatively. However, NSAID monotherapy is still controversial for prophylactic treatment after cataract surgery, especially in the US,24 and NSAIDs are not recommended by the American Academy of Ophthalmology.10

    A main argument for not recommending NSAIDs has been the lack of comparison with prednisolone drops, because they are theoretically more efficient than more potent corticosteroids owing to a greater intraocular bioavailability.10 Another argument was that the increased effect of adding NSAIDs to corticosteroids was likely caused by increased dosing. To address the first argument, we chose prednisolone rather than more potent corticosteroid drops for the combination groups. Our results showed that NSAID monotherapy was comparable to combined prednisolone and NSAID drops, even though the total dose was higher in the combination groups. This outcome corroborates the conclusions from other randomized trials that compared NSAID monotherapy with combinations of corticosteroid and NSAID eye drops; namely, there is no significant additional effect of adding topical corticosteroids to topical NSAIDs parallel to uncomplicated cataract surgery.19,25 It could be argued that a result of no statistical significance is not evidence that there is no difference between groups. However, our study was powered to detect differences between groups as small as 5 μm, which we expected to be within normal variation between 2 measurements. Differences in CST and CDVA between eye drop groups and controls were minimal, and CIs were narrow. Therefore, it is unlikely that a larger sample size would uncover any clinically relevant differences.

    Preoperative initiation of therapy did not result in decreased CST compared with postoperative initiation, even after pooling relevant groups. A previous randomized clinical trial9 concluded that preoperative initiation of ketorolac, 0.4%, was advantageous in the early postoperative period but showed no significant effects on long-term outcomes. No data on central macular thickness were reported, and the groups were small. We found no effect of preoperative initiation on any outcome measures.26

    In the sub-Tenon group, CST was significantly increased 3 weeks postoperatively compared with the preoperative prednisolone plus NSAID group, but the difference was no longer significant 3 months after surgery. More than half of the participants in the sub-Tenon group required additional topical anti-inflammatory treatment during the study period, which might explain why no difference in CST was found at 3 months. Other randomized13 and nonrandomized2,27 studies have found comparable results between dropless surgery and corticosteroid eye drop monotherapy, but we were unable to locate reports comparing dropless surgery with combined corticosteroid and NSAID eye drops or NSAID monotherapy. We used a sub-Tenon depot of a highly potent corticosteroid, dexamethasone phosphate, and refrained from using triamcinolone, which has a much longer period of action, because of fear of sustained IOP elevations.14 Although it was safe to administer the sub-Tenon dexamethasone depot, it was not comparable to NSAID or prednisolone plus NSAID in preventing macular thickening after cataract surgery. In patients with suspected poor adherence with topical treatment, placing a depot of corticosteroid during surgery could serve as adjuvant therapy. However, IOP should be monitored regularly if triamcinolone is used.28

    Intraocular pressure was lower during eye drop treatment in groups who did not use corticosteroid drops compared with those who did. However, the mean IOP in all groups was low in the reference range, and there were no elevations of greater than 25 mm Hg at any postoperative visit. There were no differences in visual acuity at any time point, but adverse events and unscheduled visits were more often encountered in the sub-Tenon group.

    Limitations

    Quiz Ref IDThis study has some limitations. We used a modified intention-to-treat approach for our analyses because some participants were excluded after allocation. We included patients with an expected low risk of complications, including macular edema, after cataract surgery, and the surgeons were experienced. Thus, our results may only apply to such patients and not patients with risk factors (eg, diabetes).28,29 The study did not include a corticosteroid eye drop monotherapy group and therefore did not compare corticosteroid drops with NSAID drops. Prednisolone, 1%, is less potent than other commonly used corticosteroid drops. Other approaches to dropless surgery exist that may prove more efficient than sub-Tenon dexamethasone depot as used in this study.30,31 Follow-up ended 3 months after surgery, and later presentations of PCME may not have been identified. The decision to add anti-inflammatory treatment was made by an unmasked physician.

    Conclusions

    In this randomized clinical trial, we found that a combination of prednisolone and NSAID eye drops was not superior to NSAID monotherapy and that initiating prophylactic treatment 3 days before surgery was not superior to initiating treatment on the day of surgery in preventing thickening of the central subfield after uncomplicated cataract surgery. In addition, we found that dropless surgery with a sub-Tenon dexamethasone depot was inferior to a combination of prednisolone and NSAID eye drops and that anti-inflammatory eye drops were required in a substantial number of participants in the sub-Tenon dexamethasone depot group. Intraocular pressure was higher in groups that used prednisolone eye drops compared with NSAID monotherapy and sub-Tenon dexamethasone depot in the first 3 weeks postoperatively. Therefore, NSAID monotherapy with initiation on the day of surgery may be preferred as an anti-inflammatory prophylactic regimen in uncomplicated cataract surgery.

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    Article Information

    Accepted for Publication: June 23, 2021.

    Published Online: August 12, 2021. doi:10.1001/jamaophthalmol.2021.2976

    Correction: This article was corrected on October 21, 2021, to correct a typographical error in the title of the Visual Abstract.

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Erichsen JH et al. JAMA Ophthalmology.

    Corresponding Author: Jesper Høiberg Erichsen, MD, PhD, Department of Ophthalmology, Rigshospitalet Glostrup, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark (jesper.h.erichsen@dadlnet.dk).

    Author Contributions: Drs Erichsen and Kessel had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Erichsen, Holm, Kessel.

    Acquisition, analysis, or interpretation of data: Erichsen, Forslund Jacobsen, Forman, Kessel.

    Drafting of the manuscript: Erichsen, Holm.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Erichsen, Forman.

    Obtained funding: Erichsen, Kessel.

    Administrative, technical, or material support: Erichsen, Holm, Forslund Jacobsen, Kessel.

    Supervision: Holm, Forman, Kessel.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was supported by grant DFF–7016-00161 from Independent Research Fund Denmark (Dr Erichsen), by Fight for Sight Denmark (Dr Erichsen), and by the Henry og Astrid Møllers Fond (Dr Erichsen).

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 4.

    References
    1.
    Chu  CJ, Johnston  RL, Buscombe  C, Sallam  AB, Mohamed  Q, Yang  YC; United Kingdom Pseudophakic Macular Edema Study Group.  Risk factors and incidence of macular edema after cataract surgery: a database study of 81 984 eyes.   Ophthalmology. 2016;123(2):316-323. doi:10.1016/j.ophtha.2015.10.001PubMedGoogle ScholarCrossref
    2.
    Shorstein  NH, Liu  L, Waxman  MD, Herrinton  LJ.  Comparative effectiveness of three prophylactic strategies to prevent clinical macular edema after phacoemulsification surgery.   Ophthalmology. 2015;122(12):2450-2456. doi:10.1016/j.ophtha.2015.08.024PubMedGoogle ScholarCrossref
    3.
    Kessel  L, Tendal  B, Jørgensen  KJ,  et al.  Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review.   Ophthalmology. 2014;121(10):1915-1924. doi:10.1016/j.ophtha.2014.04.035PubMedGoogle ScholarCrossref
    4.
    Guo  S, Patel  S, Baumrind  B,  et al.  Management of pseudophakic cystoid macular edema.   Surv Ophthalmol. 2015;60(2):123-137. doi:10.1016/j.survophthal.2014.08.005PubMedGoogle ScholarCrossref
    5.
    Lim  BX, Lim  CHL, Lim  DK, Evans  JR, Bunce  C, Wormald  R.  Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery.   Cochrane Database Syst Rev. 2016;11(11):CD006683. doi:10.1002/14651858.CD006683.pub3PubMedGoogle Scholar
    6.
    Juthani  VV, Clearfield  E, Chuck  RS.  Non-steroidal anti-inflammatory drugs versus corticosteroids for controlling inflammation after uncomplicated cataract surgery.   Cochrane Database Syst Rev. 2017;7:CD010516. doi:10.1002/14651858.CD010516.pub2PubMedGoogle Scholar
    7.
    Colin  J.  The role of NSAIDs in the management of postoperative ophthalmic inflammation.   Drugs. 2007;67(9):1291-1308. doi:10.2165/00003495-200767090-00004PubMedGoogle ScholarCrossref
    8.
    Wielders  LHP, Lambermont  VA, Schouten  JSAG,  et al.  Prevention of cystoid macular edema after cataract surgery in nondiabetic and diabetic patients: a systematic review and meta-analysis.   Am J Ophthalmol. 2015;160(5):968-981.e33. doi:10.1016/j.ajo.2015.07.032PubMedGoogle ScholarCrossref
    9.
    Donnenfeld  ED, Perry  HD, Wittpenn  JR, Solomon  R, Nattis  A, Chou  T.  Preoperative ketorolac tromethamine 0.4% in phacoemulsification outcomes: pharmacokinetic-response curve.   J Cataract Refract Surg. 2006;32(9):1474-1482. doi:10.1016/j.jcrs.2006.04.009PubMedGoogle ScholarCrossref
    10.
    Kim  SJ, Schoenberger  SD, Thorne  JE, Ehlers  JP, Yeh  S, Bakri  SJ.  Topical nonsteroidal anti-inflammatory drugs and cataract surgery: a report by the American Academy of Ophthalmology.   Ophthalmology. 2015;122(11):2159-2168. doi:10.1016/j.ophtha.2015.05.014PubMedGoogle ScholarCrossref
    11.
    Yavas  GF, Oztürk  F, Küsbeci  T.  Preoperative topical indomethacin to prevent pseudophakic cystoid macular edema.   J Cataract Refract Surg. 2007;33(5):804-807. doi:10.1016/j.jcrs.2007.01.033PubMedGoogle ScholarCrossref
    12.
    Winfield  AJ, Jessiman  D, Williams  A, Esakowitz  L.  A study of the causes of non-compliance by patients prescribed eyedrops.   Br J Ophthalmol. 1990;74(8):477-480. doi:10.1136/bjo.74.8.477PubMedGoogle ScholarCrossref
    13.
    Dieleman  M, Wubbels  RJ, van Kooten-Noordzij  M, de Waard  PWT.  Single perioperative subconjunctival steroid depot versus postoperative steroid eyedrops to prevent intraocular inflammation and macular edema after cataract surgery.   J Cataract Refract Surg. 2011;37(9):1589-1597. doi:10.1016/j.jcrs.2011.03.049 PubMedGoogle ScholarCrossref
    14.
    Athanasiadis  Y, Tsatsos  M, Sharma  A, Hossain  P.  Subconjunctival triamcinolone acetonide in the management of ocular inflammatory disease.   J Ocul Pharmacol Ther. 2013;29(6):516-522. doi:10.1089/jop.2012.0208PubMedGoogle ScholarCrossref
    15.
    World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle ScholarCrossref
    16.
    Harris  PA, Taylor  R, Thielke  R, Payne  J, Gonzalez  N, Conde  JG.  Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support.   J Biomed Inform. 2009;42(2):377-381. doi:10.1016/j.jbi.2008.08.010PubMedGoogle ScholarCrossref
    17.
    Harris  PA, Taylor  R, Minor  BL,  et al; REDCap Consortium.  The REDCap consortium: building an international community of software platform partners.   J Biomed Inform. 2019;95:103208. doi:10.1016/j.jbi.2019.103208PubMedGoogle Scholar
    18.
    Early Treatment Diabetic Retinopathy Study Design and Baseline Patient Characteristics.  Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS report number 7.   Ophthalmology. 1991;98(5)(suppl):741-756. doi:10.1016/S0161-6420(13)38009-9PubMedGoogle ScholarCrossref
    19.
    Wielders  LHP, Schouten  JSAG, Winkens  B,  et al; ESCRS PREMED Study Group.  European multicenter trial of the prevention of cystoid macular edema after cataract surgery in nondiabetics: ESCRS PREMED study report 1.   J Cataract Refract Surg. 2018;44(4):429-439. doi:10.1016/j.jcrs.2018.01.029PubMedGoogle ScholarCrossref
    20.
    Age-Related Eye Disease Study Research Group.  The Age-Related Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS report No. 4.   Am J Ophthalmol. 2001;131(2):167-175. doi:10.1016/S0002-9394(00)00732-7PubMedGoogle ScholarCrossref
    21.
    R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing; 2019. Accessed July 3, 2021. http://www.r-project.org/
    22.
    Fitzmaurice  GM, Laird  NM, Ware  JH.  Applied Longitudinal Analysis. John Wiley & Sons Inc; 2011. doi:10.1002/9781119513469
    23.
    Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing.   J R Stat Soc Ser B. 1995;57(1):289-300. doi:10.1111/j.2517-6161.1995.tb02031.xGoogle Scholar
    24.
    Zafar  S, Wang  P, Schein  OD, Srikumaran  D, Makary  M, Woreta  FA.  Prescribing patterns and costs associated with postoperative eye drop use in Medicare beneficiaries undergoing cataract surgery.   Ophthalmology. 2020;127(5):573-581. doi:10.1016/j.ophtha.2019.11.005PubMedGoogle ScholarCrossref
    25.
    Ylinen  P, Holmström  E, Laine  I, Lindholm  J-M, Tuuminen  R.  Anti-inflammatory medication following cataract surgery: a randomized trial between preservative-free dexamethasone, diclofenac and their combination.   Acta Ophthalmol. 2018;96(5):486-493. doi:10.1111/aos.13670PubMedGoogle ScholarCrossref
    26.
    Erichsen  JH, Forman  JL, Holm  LM, Kessel  L.  Effect of anti-inflammatory regimen on early postoperative inflammation after cataract surgery.   J Cataract Refract Surg. 2021;47(3):323-330. doi:10.1097/j.jcrs.0000000000000455PubMedGoogle ScholarCrossref
    27.
    Lindholm  JM, Taipale  C, Ylinen  P, Tuuminen  R.  Perioperative subconjunctival triamcinolone acetonide injection for prevention of inflammation and macular oedema after cataract surgery.   Acta Ophthalmol. 2020;98(1):36-42. doi:10.1111/aos.14175PubMedGoogle ScholarCrossref
    28.
    Wielders  LHP, Schouten  JSAG, Winkens  B,  et al; ESCRS PREMED study group.  Randomized controlled European multicenter trial on the prevention of cystoid macular edema after cataract surgery in diabetics: ESCRS PREMED Study Report 2.   J Cataract Refract Surg. 2018;44(7):836-847. doi:10.1016/j.jcrs.2018.05.015PubMedGoogle ScholarCrossref
    29.
    Laursen  SB, Erichsen  JH, Holm  LM, Kessel  L.  Prevention of macular edema in patients with diabetes after cataract surgery.   J Cataract Refract Surg. 2019;45(6):854-869. doi:10.1016/j.jcrs.2019.04.025PubMedGoogle ScholarCrossref
    30.
    Shorstein  NH, Myers  WG.  Drop-free approaches for cataract surgery.   Curr Opin Ophthalmol. 2020;31(1):67-73. doi:10.1097/ICU.0000000000000625PubMedGoogle ScholarCrossref
    31.
    Donnenfeld  ED, Holland  EJ, Solomon  KD.  Safety and efficacy of nepafenac punctal plug delivery system in controlling postoperative ocular pain and inflammation after cataract surgery.   J Cataract Refract Surg. 2021;47(2):158-164. doi:10.1097/j.jcrs.0000000000000414PubMedGoogle ScholarCrossref
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