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jurnal retinopati diabetikum

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   ARTICLE European multicenter trial of theprevention of cystoid macular edema aftercataract surgery in nondiabetics:ESCRS PREMED study report 1 Laura H.P. Wielders, MD, Jan S.A.G. Schouten, MD, PhD, Bjorn Winkens, PhD,Frank J.H.M. van den Biggelaar, PhD, Claudette A. Veldhuizen, MD, Oliver Findl, MD, PhD, Joaquim C.N. Murta, MD, PhD, Willem R.O. Goslings, MD, PhD, Marie-Jos  e Tassignon, MD, PhD, Maurits V. Joosse, MD, PhD, Ype P. Henry, MD, Alexander H.F. Rulo, MD, Jos  e L. G € uell, MD, PhD, Michael Amon, MD, PhD, Thomas Kohnen, MD, PhD, Rudy M.M.A. Nuijts, MD, PhD,on behalf of the ESCRS PREMED Study Group Purpose:  Tocomparetheefficacyofatopicalnonsteroidalantiin-flammatory drug, topical corticosteroid, and a combination of bothdrugs to prevent the occurrence of cystoid macular edema (CME)after cataract surgery in nondiabetic patients. Setting:  Twelve European study centers. Design:  Randomized clinical trial. Methods:  Nondiabetic patients having uneventful cataract sur-gery were included in this study. Patients were randomized toreceive topical bromfenac 0.09% twice daily for 2 weeks or dexa-methasone 0.1% 4 times daily with 1 drop less per day everyfollowing week, or a combination of both. The primary outcomewas the difference in central subfield mean macular thickness6 weeks postoperatively. Secondary outcome measures includedcorrected distance visual acuity as well as the incidence of CMEand clinically significant macular edema (CSME) within 6 weeksand 12 weeks postoperatively. Results:  Thisstudycomprised914patients.Sixweekspostoper-atively,thecentralsubfieldmeanmacularthicknesswas288.3 m m,296.0 m m, and 284.5  m m in the bromfenacgroup, dexamethasonegroup, and combination treatment group, respectively (overall P  Z .006). The incidence of clinically significant macular edemawithin 12 weeks postoperatively was 3.6%, 5.1%, and 1.5%,respectively (overall  P  Z .043). Conclusion: Patientstreatedwithacombinationoftopicalbrom-fenac 0.09% and dexamethasone 0.1% had a lower risk for devel-oping CSME after cataract surgery than patients treated with asingle drug.  J Cataract Refract Surg 2018; 44:429  –  439 Q  2018 ASCRS and ESCRS Supplemental material available at www.jcrsjournal.org. W orldwide, cataract is the leading cause of pre- ventable and treatable blindness. 1 Cataract sur-gery can improve visual acuity in many patientswith mild to severe visual impairment and is consideredone of the most cost-effective of all healthcare interven-tions. 2 Even though improvements in modern cataract Submitted: December 3, 2017 | Final revision submitted: January 19, 2018 | Accepted: January 19, 2018 From University Eye Clinic Maastricht UMC C (Wielders, Schouten, van den Biggelaar, Veldhuizen, Nuijts), Maastricht University Medical Center C , and MaastrichtUniversity (Winkens), Care and Public Health Research Institute (CAPHRI), Department of Methodology & Statistics, Maastricht, Zuyderland Medical Center (Wielders,Schouten, Nuijts), Department of Ophthalmology, Heerlen, Elisabeth-TweeSteden Hospital (Goslings), Department of Ophthalmology, Tilburg, Haaglanden MedicalCenter (Joosse), Department of Ophthalmology, The Hague, VU University Medical Center (Henry), Department of Ophthalmology, Amsterdam, and Eye HospitalZonnestraal (Rulo), Hilversum, the Netherlands; Vienna Institute for Research in Ocular Surgery (Findl), Hanusch Hospital, Vienna, Austria; Centro HospitalarUniversit  ario Coimbra (Murta), Department of Ophthalmology, and Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal; AntwerpUniversity Hospital and University of Antwerp (Tassignon), Department of Ophthalmology, Antwerp, Belgium; Instituto Microcirugia Ocular (G € uell), Barcelona, Spain;Hospital of the Brothers of St. John of God (Amon), Department of Ophthalmology, Vienna, Austria; Goethe University (Kohnen), Department of Ophthalmology,Frankfurt am Main, Germany.Supported by the European Society of Cataract and Refractive Surgeons (ESCRS), Blackrock, Co Dublin, Ireland. The ESCRS was not involved in any part of the studydesign, data analysis, and interpretation; writing of the report; or the decision to submit the article for publication. Bausch & Lomb France SAS supplied the Yelloxeyedrops free of charge.Presented at the XXXV Congress of the European Society of Cataract and Refractive Surgeons, Lisbon, Portugal, October 2017.Corresponding author: Laura H.P. Wielders, MD, University Eye Clinic Maastricht UMC, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, theNetherlands. Email: laura.wielders@mumc.nl. Q 2018 ASCRS and ESCRSPublished by Elsevier Inc.0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2018.01.029 429  surgery techniques have significantly decreased the inci-dence of postoperative complications, cystoid macularedema (CME) remains one of the most important causesof suboptimum visual acuity after otherwise uneventfulsurgery. 3,4 Cystoid macular edema after cataract surgery, also knownas the Irvine-Gass syndrome, was first reported by Ir v ine in 1953 5 and discussed by Gass and Norton in 1966. 6 Sincethen, ophthalmologists have aimed to prevent CME using perioperativetopicalcorticosteroidsand/ornonsteroidalanti-inflammatory drugs (NSAIDs), albeit current practice variesbetween organizations and countries. 3,7 As yet, the optimumapproach in routine cataract surgery cases remains debatablebecause of the high societal costs involved with routine pre-scription of topical NSAIDs in some countries, such as theUnited States of America. 8 An Ophthalmic Technolog y Assessment of the American Academy of Ophthalmology  3 does not support the use of topical NSAIDs because of insuf-ficient high-quality evidence with regard to its long-termbenefittopreventvisionlossfromCME3monthsormoreaf-ter cataract surgery. The Cataract Clinical Committee of theAmerican Society of Cataract and Refractive Surgery, on theother hand, recently published a report on topical NSAIDsas an important adjunctive tool for surgeons performing routine and complicated cataract surgery and emphasizedthe compelling effectiveness of NSAIDs to reduce pain, pre- ventintraoperativemiosis,modulatepostoperativeinflamma-tion, and reduce the incidence of CME. 7 Two recentsystematicreviewsoftheCochraneCollaborationand2inde-pendent European metaanalyses suggest that topical NSAIDsreduce the risk for developing CME after cataract surgery,although none of them found a clinically relevant effect onmean visual acuity. 9 – 12 To further investigate this important clinical question,many ophthalmologists have studied the efficacy of variousNSAIDs and corticosteroids to prevent CME after cataractsurgery. Most studies compared the efficacy of topicalNSAIDs or combination treatment versus corticosteroidsalone; however, few studies directly compared the efficacy of combination treatment versus topical NSAIDs. 9 More-over,thelowaprioriincidence ofCMEdemandslargesam-ples to detect small, yet clinically important, differences.The PREvention of Macular EDema after cataract sur-gery(PREMED) study was arandomized controlled clinicalmulticenter trial designed to directly compare the efficacy of a topical NSAID, a topical corticosteroid, and the combi-nation of both in nondiabetic patients. The study wasfunded by the European Society of Cataract and RefractiveSurgeons (ESCRS). The aim of the ESCRS PREMED study was to provide evidence-based recommendations thatcould serve as a basis for clinical guidelines on the preven-tion of CME after cataract surgery. PATIENTS AND METHODS The ESCRS PREMED study was a randomized controlled trial(RCT). The study protocol was approved by the local ethics com-mittees and national authorities of all participating study centers.The study procedures were performed in accordance with thetenets of the Declaration of Helsinki. The study protocol can befound on the U.S. National Institutes of Health Clinical Trialssite. A A data safety monitoring board (members reported inAppendix S1, available at http://jcrsjournal.org ) evaluated the safety of trial participants. Patient Enrolment Patient recruitment started in Maastricht, the Netherlands, in July 2013. Final inclusion took place at study centers in theNetherlands after a decision was made to stop recruitment onFebruary 8, 2016. The trial included nondiabetic patients 21 yearsor older who required regular phacoemulsification cataract sur-geryinatleast1eye.Patientswereincludedin1of12studycentersinvolved in the ESCRS PREMED study located in Austria (Hospi-tal of the Brothers of St. John of God and Vienna Institute forResearch in Ocular Surgery, Vienna), Belgium (Antwerp Univer-sity Hospital, Antwerp), Germany (Goethe University Hospital,Frankfurt am Main), Portugal (Centro Hospitalar Universit  arioCoimbra, Coimbra), Spain (Institute of Ocular Microsurgery, Bar-celona), and the Netherlands (VU University Medical Center,Amsterdam; Zuyderland Medical Center, Heerlen; Eye HospitalZonnestraal, Hilversum; University Eye Clinic Maastricht UMC,Maastricht; Haaglanden Medical Center, The Hague; andElisabeth-TweeSteden Hospital, Tilburg). All patients signed writ-ten informed consent before inclusion.Only 1 eye per patient was included in the study, and patientswere excluded if they had sustained moderate to severe visualimpairment in the other eye according to the definition of the In-ternational Statistical Classification of Diseases and RelatedHealth Problems 10th revision. 13 Patients were excluded if they had previousCME,anymacularpathology that couldinfluence vi-sual acuity, previous intraocular inflammation or uveitis, retinal vein occlusion, posttraumatic cataract, progressive glaucoma,intraocular pressure (IOP) of 25 mm Hg or higher, previoussteroid-induced IOP elevation, pseudoexfoliation syndrome, orFuchs endothelial dystrophy in the study eye. Furthermore, pa-tients were excluded if they had intraocular surgery in the study eye. Patients who used topical NSAIDs, corticosteroids, antiglau-comatous medication, or high-dose systemic corticosteroids atthe time of screening were excluded, as were patients who received Figure1. TheETDRSretinalthicknessmap.  A :Meancentralsubfieldmacular thickness in the central 1.0 mm area.  B : Parafoveal thick-ness in a concentric ring located 1.0 to 3.0 mm around the fovea. C : Perifoveal thickness in a concentric ring located 3.0 to 6.0 mmaround the fovea.  A  to  C : Total macular volume is calculated for the central 6.0 mm area (ETDRS Z Early Treatment Diabetic Reti-nopathy Study). 430  ESCRS PREMED STUDY REPORT 1  Volume 44 Issue 4 April 2018  an intravitreal injection of bevacizumab or ranibizumab in thestudy eye in the previous 6 weeks, an intravitreal injection of afli-bercept in the previous 10 weeks, or an intraocular or periocularcorticosteroid injection in the previous 4 months. Finally, patientswere excluded if there was a contraindication to the use of any investigation drug. Surgical Technique, Patient Allocation, and Treatment All patients had regular phacoemulsification cataract surgery withintraocular lens (IOL) implantation in the posterior segment andreceived perioperative and/or postoperative antibiotics according to the standard of care in the participating study center.Patients were randomly allocated to 1of 3 treatment groups in a1:1:1 ratio. Stratified block randomization was performed per study center by a local investigator using concealed online software B (ALEA, version 3.0, Formsvision BV) and a block size of 15 pa-tients. Trial participants were unblinded for the allocated treat-ment. Patients in the bromfenac group received bromfenac0.09% eyedrops (Yellox) twice daily for 2 days preoperatively and 2 weeks postoperatively. Patients in the dexamethasone groupreceived dexamethasone disodium phosphate 0.1% eyedrops 4times daily for 2 days preoperatively and 1 week postoperatively,with 1 drop less per day every following week. Patients in the com-bination treatment group received topical bromfenac and dexa-methasone in the above-mentioned doses. Topical treatmentsstarted 2 days before cataract surgery because previous studies 14,15 found a lower incidence of CME in patients who started antiin-flammatory treatment preoperatively. No other ocular corticoste-roids or NSAIDs were allowed to be used during the course of thestudy. Outcomes Assessment An extensive ophthalmologic examination, including slitlampevaluation, IOP measurement, and fundoscopy of both eyes, wasperformed at baseline. Cataract was graded according to theLens Opacities Classification System II, 16 and the presence of aqueous cells and flare was graded according to the Standardiza-tion of Uveitis Nomenclature (SUN) classification. 17 Subjective Figure 2.  Consort flow diagramshowing the number of partici-pants who were screened, ran-domized, and analyzed. Table 1. Main baseline characteristics. Parameter Overall(N Z 914)Bromfenac(n Z 307)Dexamethasone(n Z 304)Combination(n Z 303) Mean age (y) G SD 70.45 G 8.87 69.70 G 8.94 71.23 G 8.73 70.41 G 8.91Right eye, n (%) 504/914 (55.1) 182/307 (59.3) 157/304 (51.6) 165/303 (54.5)Female sex, n (%) 478/914 (52.3) 166/307 (54.1) 163/304 (53.6) 149/303 (49.2)White race, n (%) 897/914 (98.1) 300/307 (97.7) 301/304 (99.0) 296/303 (97.7)CME in contralateral eye, n (%) 4/912 (0.4) 0/307 (0.0) 3/302 (1.0) 1/303 (0.3)Previous anti-VEGF, n (%) 2/909 (0.2) 0/306 (0.0) 1/300 (0.3) 1/303 (0.3) Type of cataract, n (%)Nuclear 777/903 (86.0) 267/304 (87.8) 260/299 (87.0) 250/300 (83.3)Cortical 610/903 (67.6) 211/304 (69.4) 203/299 (67.9) 196/300 (65.3)Subcapsular 199/903 (22.0) 72/304 (23.7) 61/299 (20.4) 66/300 (22.0)CME Z cystoid macular edema; VEGF Z vascular endothelial growth factor 431 ESCRS PREMED STUDY REPORT 1  Volume 44 Issue 4 April 2018  refraction and corrected distance visual acuity (CDVA) weremeasured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts. If patients were unable to read any letter on theETDRS chart, hand motion or finger counting at a given distancewere converted to the logarithm of the minimum angle of resolu-tion (logMAR) equivalent. 18 A baseline optical coherence tomography (OCT) was per-formed within 3 months preoperatively using spectral-domainOCT (SD-OCT) devices (3D OCT, Topcon Corp.; Cirrus HD-OCT, Carl Zeiss Meditec AG; OCT-HS100, Canon, Inc.;RTVue-100 Optovue, Inc.; or Spectralis, Heidelberg Engineering,Inc.). Each study center used only 1 type of SD-OCT device forall preoperative and postoperative measurements. Retinal thick-ness was measured in accordance with the ETDRS retinal thick-ness map (Figure 1), which includes the central subfield meanmacular thickness in the central 1.0 mm area, parafoveal thicknessin a concentric ring located 1.0 to 3.0 mm around the fovea, peri-foveal thickness in a concentric ring located 3.0 to 6.0 mm aroundthefovea,andtotalmacularvolumeinthecentral6.0mmarea. 19 If the preoperative OCT was of insufficient quality (eg, because of dense cataract), an alternative baseline measurement was per-formed at 1 day postoperatively because previous studies haveshown no significant differences between preoperative and 1-day postoperative retinal thickness measurements. 20 Postoperative visits were performed 6 weeks and 12 weeks post-operatively and included a full ophthalmologic examination of thestudy eye, as reported above. Postoperative CDVA measurementsand SD-OCT assessments were performed by a local investigatorwho was masked to the allocated study treatment. Study Outcomes Cystoid macular edema usually occurs within 3 months postoper-atively, with a peak incidence 4 to 6 weeks after cataract surgery. 21 Therefore, the primary outcome of this study was the difference incentral subfield mean macular thickness 6 weeks postoperatively compared with the baseline value. Secondary outcomes were thedifference in central subfield mean macular thickness 12 weekspostoperatively, the incidence of CME and clinically significantmacular edema (CSME) within 6 to 12 weeks postoperatively,and CDVA, total macular volume, and parafoveal and perifovealthickness 6 weeks and 12 weeks postoperatively. Furthermore,all adverse events were reported.Cystoid macular edema was defined as an increase in centralsubfield mean macular thickness of 10% or more over baseline,withcysticchangesonSD-OCT.Cystoidchangesandotherretinalpathology were identified by 2 independent and masked retinaspecialists of the University Eye Clinic Maastricht UMC(Appendix S1, available at http://jcrsjournal.org ). CSME was defined as CME with less than a 0.2 logMAR CDVAimprovement compared with the preoperative baseline. Escape Treatment Small studies have shown that a combination of topical corticoste-roids and NSAIDs is more effective than single-drug treatment inpatients with acute CSME after cataract surgery. 22 Patients whodeveloped CSME during the course of this study were thereforetreated withbromfenac 0.09%eyedrops twice dailyand dexameth-asone 0.1% eyedrops 4 times daily for 4 weeks. If CSME resolvedwithin these 4 weeks, bromfenac was stopped and dexamethasoneeyedrops were reduced with 1 drop per day every following week.If CSME persisted after 4 weeks of topical treatment, patientsreceived1intravitrealinjectionof0.05mL(1.25mg)bevacizumab.From 12 weeks postoperatively, CSME was treated in accordancewith the standard of care at each participating study center. Table 2. Differences in macular thickness, TMV, and CDVA (intention-to-treat analysis). Mean ± SD (Patients)Parameter Bromfenac Dexamethasone Combination CSMT ( m m)Baseline 274.18 G 25.48 (294) 275.18 G 27.16 (293) 273.20 G 24.67 (298)6 wk 288.28 G 46.78 (270) 296.04 G 52.46 (265) 284.51 G 36.40 (267)12 wk 283.30 G 28.03 (264) 283.96 G 28.64 (263) 283.30 G 27.38 (262)Parafoveal thickness ( m m)Baseline 325.17 G 19.53 (295) 326.44 G 20.47 (298) 326.84 G 21.75 (298)6 wk 336.50 G 26.95 (270) 342.40 G 25.43 (266) 337.54 G 21.89 (267)12 wk 334.32 G 21.60 (265) 336.87 G 21.10 (263) 336.40 G 21.33 (263)Perifoveal thickness ( m m)Baseline 282.31 G 16.45 (280) 282.48 G 17.22 (288) 282.44 G 18.07 (285)6 wk 290.79 G 21.77 (258) 294.85 G 18.13 (254) 291.19 G 18.44 (257)12 wk 288.57 G 17.48 (256) 291.11 G 17.73 (254) 291.02 G 17.19 (255) TMV (mm 3  )Baseline 8.29 G 0.53 (278) 8.29 G 0.53 (282) 8.28 G 0.51 (277)6 wk 8.52 G 0.70 (256) 8.67 G 0.58 (249) 8.51 G 0.61 (256)12 wk 8.47 G 0.58 (256) 8.55 G 0.55 (250) 8.51 G 0.60 (255)CDVA (logMAR)Baseline 0.29 G 0.23 (299) 0.29 G 0.21 (298) 0.29 G 0.22 (300)6 wk 0.01 G 0.12 (276) 0.02 G 0.14 (274) 0.01 G 0.12 (274)12 wk    0.02 G 0.10 (270)   0.01 G 0.11 (267)   0.01 G 0.11 (271)CDVA  Z corrected distance visual acuity; CI Z confidence interval; CSMT  Z central subfield mean macular thickness; logMAR Z logarithm of the minimalangle of resolution; TMV  Z total macular volume*Treatment effect after correction for center, sex, age, and cystoid macular edema in the fellow eye † Overall effect at that timepoint over all 3 groups 432  ESCRS PREMED STUDY REPORT 1  Volume 44 Issue 4 April 2018
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