Douglas, Ian J

Krishnan, Bhaskaran

Root, Adrian

Ian J. Douglas

Adrian Root

Bhaskaran Krishnan

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JAMA Ophthalmology

Oral Fluoroquinolone Use and Retinal Detachment

LSHTM Research Online

Douglas, IJ; Root, A; Krishnan, B (2016) Oral Fluoroquinolone Useand Retinal Detachment. JAMA ophthalmology. ISSN 2168-6165DOI: https://doi.org/10.1001/jamaophthalmol.2016.3477Downloaded from: http://researchonline.lshtm.ac.uk/3029298/DOI: 10.1001/jamaophthalmol.2016.3477Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by/2.5/Copyright 2016 American Medical Association. All rights reserved.1. Akuffo KO, Nolan JM, Stack J, et al. The impact of cataract, and its surgicalremoval, onmeasures of macular pigment using the Heidelberg SpectralisHRA+OCTmulticolor device. Invest Ophthalmol Vis Sci. 2016;57(6):2552-2563.2. Mayne ST, Cartmel B, Scarmo S, et al. Noninvasive assessment of dermalcarotenoids as a biomarker of fruit and vegetable intake. Am J Clin Nutr. 2010;92(4):794-800.3. Chew EY, Clemons TE, Sangiovanni JP, et al; Age-Related Eye Disease Study 2(AREDS2) Research Group. Secondary analyses of the effects oflutein/zeaxanthin on age-relatedmacular degeneration progression: AREDS2report No. 3. JAMA Ophthalmol. 2014;132(2):142-149.4. Bernstein PS, Li B, Vachali PP, et al. Lutein, zeaxanthin, andmeso-zeaxanthin: the basic and clinical science underlying carotenoid-basednutritional interventions against ocular disease. Prog Retin Eye Res. 2016;50:34-66.5. Espaillat A, Aiello LP, Arrigg PG, Villalobos R, Silver PM, Cavicchi RW.Canthaxanthine retinopathy. Arch Ophthalmol. 1999;117(3):412-413.6. Sarraf D, Ceron O, Rasheed K, Drenser KA, Casey R. West African crystallinemaculopathy. Arch Ophthalmol. 2003;121(3):338-342.COMMENT&RESPONSEOral FluoroquinoloneUse and Retinal DetachmentTo the Editor We read with interest the recent article byRaguideau et al1 on the association between the use of fluo-roquinolone antibiotics and retinal detachment. The authorschose to use 2 self-controlled study designs to address thisquestion: first, the case crossover method,2 and, second, theself-controlledcase series.3The2methodsappear togive simi-lar answers, suggesting a roughly 50% increased risk of reti-naldetachment followingexposure toa fluoroquinolone.How-ever,wehave someconcerns about themethodunderpinningthe study.First, in the case-crossover study, Raguideau et al1 ex-cluded peoplewhohad been exposed to any fluoroquinoloneduring the intermediate-risk period, and they also excludedall people exposed twice to a fluoroquinolonewithin any 50-dayperiodduring the control period.Webelieve thismayhaveintroduced an important bias, whereby people exposed dur-ing the control periodwere disproportionately excluded. As aconsequence, patients would appear to be more likely ex-posed during the risk period close to the date of retinal de-tachment, potentially creating a spurious association.This ap-proach is analogous to conducting a case-control study andselecting patients based on prior knowledge of the exposureof interest, which can cause serious bias. We note that 331 ofthe 994 fluoroquinolone-exposed cases were excluded fromthe main analysis for this reason, a substantial proportionof the informative cases in this study. It would be helpful tosee the results of an analysis with no exclusions.Second,a recentcohort study4withthesamequestionuseda“control” exposure todemonstrate that aneffect sizeof simi-larmagnitudemay be driven by bias and confounding; the au-thors found that fluoroquinolone and amoxicillin had similarassociationswith the riskof retinaldetachment.Althoughself-controlleddesignsare less susceptible to individual-level time-invariant confounding than traditional cohort studies, otherbiases (in particular, indication bias) are not avoided, and asimilarcontrolexposure,nothypothesizedtobeassociatedwithretinal detachment, would have been helpful in the study byRaguideau et al1 to help exclude such biases.Finally, the detailedmethods used for the self-controlledcase series arenotpresented in the studyor theonline supple-mentary material. Correctly implementing this design re-quires a careful choice of observation and risk periods.5 Is itpossible for the authors to provide further details on how theself-controlled case-series analysis was performed? This ad-ditional informationwould be helpful in the interpretation ofthe conclusions.Ian J. Douglas, PhDAdrian Root, MBBSBhaskaran Krishnan, PhDAuthor Affiliations:Department of Non-Communicable Disease Epidemiology,London School of Hygiene and Tropical Medicine, London, England.CorrespondingAuthor: Ian J. Douglas, PhD, Department of Non-CommunicableDisease Epidemiology, London School of Hygiene and Tropical Medicine, KeppelStreet, LondonWC1E 7HT, England (ian.douglas@lshtm.ac.uk).Published Online:October 20, 2016. doi:10.1001/jamaophthalmol.2016.3477Conflict of Interest Disclosures: All authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Krishnan reportsreceiving grants fromWellcome Trust, the Royal Society, the National Institutefor Health Research, the Medical Research Council, the Michael J FoxFoundation, the British Heart Foundation, and the Royal National Institute forthe Blind. No other disclosures are reported.1. Raguideau F, Lemaitre M, Dray-Spira R, Zureik M. Association between oralfluoroquinolone use and retinal detachment. JAMA Ophthalmol. 2016;134(4):415-421.2. Maclure M. The case-crossover design: a method for studying transienteffects on the risk of acute events. Am J Epidemiol. 1991;133(2):144-153.3. Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics:the self-controlled case series method. Stat Med. 2006;25(10):1768-1797.4. Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associatedsevere adverse events: a longitudinal cohort study.BMJOpen. 2015;5(11):e010077.5. Douglas IJ, Langham J, Bhaskaran K, Brauer R, Smeeth L. Orlistat and the riskof acute liver injury: self controlled case series study in UK Clinical PracticeResearch Datalink. BMJ. 2013;346:f1936.In ReplyOurmain analysis focusedon the immediate acute ef-fects of fluoroquinolones.Therefore, as isusuallydone,weex-cluded patients exposed during the intermediate risk period.Because the intermediate risk period is not associatedwith anincreased risk, this exclusion is unlikely to have affected theoddsratio. Individualswitha fluoroquinoloneprescriptiondur-ing the 10 days preceding retinal detachment (RD) and ex-posed during the intermediate risk period (ie, during the 50prior days) were not considered exposed during the risk pe-riod. Consistently, individuals with 2 fluoroquinolone pre-scriptionsdispensedwithin50days in the control periodwerenot considered exposed either.In a complementary analysis, we included the 331 pa-tients exposed during the intermediate risk period. As antici-pated, the results were unchanged; exposure to fluoroquino-lones remained significantly associated with the occurrenceof RDduring the 10-day risk period,with an adjusted odds ra-tio of 1.46 (95% CI, 1.17-1.81).A potential confounding bias of the systemic disease forwhich fluoroquinolonesmay be prescribed is possible. Otherstudies1-5 previously managed this issue using another anti-biotic as reference. The cohort study performed by Kuo et al2reported, contrarily to the one performed by Daneman et al,1Letters1448 JAMAOphthalmology December 2016 Volume 134, Number 12 (Reprinted) jamaophthalmology.comDownloaded From:  by a London Sch of Hygiene & Tropical Medicine User  on 01/19/2018Copyright 2016 American Medical Association. All rights reserved.a significant association of fluoroquinolone usewith RD afterthey compared the prescriptions of patients in the fluoroqui-nolone cohortwith those of propensity score–matched adultstreated with amoxicillin. Moreover, the study design that weusedensures theminimizationof confusionby indication. In-deed, theself-matcheddesign implies that time-invariantmul-tiplicative confounders arenecessarily adjusted for.Given theshort observation period of our study (180 days), the clinicalsituations of the patients may be considered fixed during thecontrol and risk periods. Therefore, the prescription of fluo-roquinolones for an underlying respiratory, inflammatory, orinfectiousdiseasemayoccur inanondifferentialmannerwithincontrol or risk periods. In addition, in our study, we excludedall patients who had been hospitalizedwithin 6months priorto the RD. This likely resulted in excluding patients with se-vere chronic diseases, including inflammatory diseases, andthus minimizing confounding by indication. Lastly, tocontrol for potential residual bias, we conducted a sensitivityanalysis excluding patients with long-term infectious or in-flammatory conditions and respiratory failure. Exposure tofluoroquinolones remained significantly associated with theoccurrenceofRDover the 10-dayperiod,withanadjustedoddsratio of 1.43 (95% CI, 1.11-1.84).In the self-controlled case series design,we also looked atfirst event, and we used the same short observation period.Theriskperiodwasdefinedas the10-dayperiodaftereachfluo-roquinolone prescription had been dispensed, whereas therisk-freeperiod includedall other periodswhenpatientswereconsidered to be at baseline risk. Individuals exposed to fluo-roquinolones during the intermediate risk period (11-60days)were excluded.The incidence rate ratio and its 95%CIswere estimatedbycomparing the incidence of RD during the risk and risk-freeperiods using a conditional Poisson regression model with alogarithmic link function, taking the duration of the differentstudy periods into account. Given the study observation pe-riod (180 days), age and comorbidities were considered to be“fixed”during the studyperiod. Corticosteroid treatmentwastaken into account as a time-dependent variable.Fanny Raguideau, PharmD, MScRosemary Dray-Spira, MD, PhDMahmoud Zureik, MD, PhDAuthor Affiliations:Department of Epidemiology of Health Products,The French National Agency for Medicines and Health Products Safety,Saint-Denis, France.Corresponding Author: Fanny Raguideau, PharmD, MSc, Department ofEpidemiology of Health Products, French National Agency for Medicines andHealth Products Safety, 143-147 Blvd Anatole France, F-93285 Saint-Denis,France (fanny.raguideau@ansm.sante.fr).Published Online:October 20, 2016. doi:10.1001/jamaophthalmol.2016.3479Conflict of Interest Disclosures: All authors have completed and submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.1. Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associatedsevere adverse events: a longitudinal cohort study.BMJOpen. 2015;5(11):e010077.2. Kuo SC, Chen YT, Lee YT, et al. Association between recent use offluoroquinolones and rhegmatogenous retinal detachment: a population-basedcohort study. Clin Infect Dis. 2014;58(2):197-203.3. Eftekhari K, Ghodasra DH, Haynes K, Chen J, Kempen JH, VanderBeek BL.Risk of retinal tear or detachment with oral fluoroquinolone use: a cohort study.Pharmacoepidemiol Drug Saf. 2014;23(7):745-752.4. Kapoor KG, Hodge DO, St Sauver JL, Barkmeier AJ. Oral fluoroquinolonesand the incidence of rhegmatogenous retinal detachment and symptomaticretinal breaks: a population-based study.Ophthalmology. 2014;121(6):1269-1273.5. Fife D, Zhu V, Voss E, Levy-Clarke G, Ryan P. Exposure to oralfluoroquinolones and the risk of retinal detachment: retrospective analyses oftwo large healthcare databases. Drug Saf. 2014;37(3):171-182.Lettersjamaophthalmology.com (Reprinted) JAMAOphthalmology December 2016 Volume 134, Number 12 1449Downloaded From:  by a London Sch of Hygiene & Tropical Medicine User  on 01/19/2018

Oral Fluoroquinolone Use and Retinal Detachment.

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Oral Fluoroquinolone Use and Retinal Detachment.

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