CLINICAL NEWS & ANALYSIS
SPECIAL REPORT // RETINA VMA ADVANCES : WET AMD 'BEST RESPONDERS'
March 1, 2013 In This Issue VOL. 38, NO. 5
EDITORIAL 4 Truth be told for Why honesty in the physician-patient Hope patients relationship is not what it seems
GLAUCOMA 12 The next step with late-stage RP in drug delivery How a topical micro-droplet system targets direct application to the ocular surface FDA APPROVAL GENERAL 32 Innovation abounds at OIS Regulatory and investment climate What fosters drug, device opportunities The retinal prosthesis is designed to FOLLOW US ONLINE: bypass the eye structure damaged OphthalmologyTimes.com by RP with electrical stimulation of the retina to induce Refractive visual perception in CAPSULOTOMY blind individuals. When DOES MAKE A Commercial launch planned for later DIFFERENCE this year By Lynda Charters (Photo courtesy of Second Sight)
SALT LAKE CITY :: FEMTOSECOND LASER capsulotomies provide sig- nificantly more predictable effec- Sight Medical Products to market its tive lens positions compared with FDA approval of retinal prosthesis retinal prosthesis (Argus II Retinal manual procedures. Prosthesis System) for patients with Robert J. Cionni, MD, discussed the brings limited sight to individuals late-stage RP. The system is the first superiority of the femtosecond laser for and only retinal prosthesis commer- creating capsulotomies compared with with retinitis pigmentosa cially available anywhere in the world. the conventional manual method and The regulatory agency’s decision re-optimization of lens constants for By Cheryl Guttman Krader comes after the 19 members of the FDA Ophthal- accurate laser refractive lens surgery. Reviewed by Mark S. Humayun, MD, PhD mic Devices Advisory Panel voted unanimously “The capsulotomy does make a dif- in September 2012 to recommend approval. The ference,” said Dr. Cionni, medical di- SYLMAR, CA :: prosthesis has been approved and sold in Europe rector of The Eye Institute of Utah, Salt AFTER 20 YEARS of research and develop- since October 2011. Lake City. He cited a study in which it ment and many clinical trials, patients in the United The retinal prosthesis is designed to bypass the was found that a 4-mm capsulotomy States with retinitis pigmentosa (RP) will now have eye structure damaged by RP with electrical stim- tends to position an IOL slightly more the ability to regain limited vision, allowing them ulation of the retina to induce visual perception in posteriorly compared with a 6-mm to read, have unassisted mobility, and have facial blind individuals. Retinal diseases destroy the light- capsulotomy. recognition. sensing cells, or photoreceptors, in the retina. The ( See story on page 36 ) On Feb. 14, the FDA granted approval to Second ( Continues on page 7 : Prosthesis ) Advertiser Index
Welcome to the March 01, 2013, issue of Ophthalmology Times magazine. This digital edition is brought to you by Advanstar Communications Inc. Below you’ll find an alphabetical index of the advertisers in this issue. If you’d like more information about the advertiser, you can click on the name or the page number to see their ad.
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©2013 Fera Pharmaceuticals, LLC FA-N-001 MARCH 1, 2013 :: Ophthalmology Times contents 3
Advances in imaging technology mean patients may benefi t from Special Report faster image acquisition and disease evaluation. RETINA 16 POINT/COUNTERPOINT Defi ning the 'ideal' DME treatment 18 PROGNOSIS FOR A QUICKER DIAGNOSIS Nonmydriatic ultra-wide-fi eld imaging shows promise for evaluating diabetic retinopathy 20 COMBINATION THERAPY A BOON FOR AMD Phase IIb neovascular AMD study shows robust benefi t for anti-PDGF/anti-VEGF therapy 18 21 INTREPID IDENTIFIES 'BEST RESPONDERS' Fewer anti-VEGF injections among benefi ts Glaucoma Practice Management of stereotactic radiotherapy for wet AMD 37 EXCHANGE-TRADED FUNDS: 22 IMAGING THE CHOROID: THE NEW MUTUAL FUNDS? THE NEW FRONTIER Latest investment vehicle offers structure How OCT assessment of choroidal of a fund, but is traded like stock thickness may prove valuable in the future 24 GENE THERAPY TRIALS IN PROGRESS Researchers turn focus to non-viral and 12 THE NEXT STEP viral vectors to deliver DNA to cells IN DRUG DELIVERY Topical micro-droplet system targets 25 PARADIGM SHIFT direct application to the ocular surface FOR TREATING DME Ophthalmologist uses pattern laser treatment in conjunction with anti-VEGF General 26 NEW KID ON THE BLOCK 32 INNOVATION ABOUNDS Pivotal trial results demonstrate effi cacy of newest anti-VEGF agent in treating CRVO- AT OIS related macular edema Regulatory and investment climate fosters drug, device opportunities 42 REDESIGN PLACES FOCUS 28 HIGH RESOLUTION RATES ON PRACTICE EFFICIENCY SEEN FOR VMA Refractive Improved layout and patient education Ocriplasmin joins observation, lead to increased pass-through rates vitrectomy as treatment options 36 ACCURACY DOES MAKE 29 OPTOGENETICS A NEW A DIFFERENCE Procedure provides signifi cantly more APPROACH TO RP Novel method brings back light perception, predictable effective lens positions possibly vision, to patients
In Every Issue 4 EDITORIAL 6 OPHTHALMIC NEWS 39 MARKETPLACE 4 editorial MARCH 1, 2013 :: Ophthalmology Times
MARCH 1, 2013 ◾ VOL. 38, NO. 5
CONTENT Chief Medical Editor Peter J. McDonnell, MD Group Content Director Mark L. Dlugoss [email protected] 440/891-2703 Content Channel Manager Sheryl Stevenson [email protected] 440/891-2625 Content Specialist Helen Thams [email protected] 440/891-2639 Digital & Interactive Content Manager Brandon Glenn Truth be told Content Coordinator Miranda Hester Group Art Director Robert McGarr Art Director Nicole Davis-Slocum Honesty in the physician-patient relationship not what it seems Anterior Segment Techniques Ernest W. Kornmehl, MD Cataract Corner Richard S. Hoffman, MD and Mark Packer, MD coding.doc L. Neal Freeman, MD, MBA “Every time we’ve done a survey and com- Dispensing Solutions Arthur De Gennaro Grand Rounds Robert Ritch, MD By Peter J. McDonnell, MD pared it with OR records, we’ve found that the Money Matters John J. Grande, Traudy F. Grande, and John S. Grande, CFPs® surgeons claim they are doing three times the Neuro-Ophthalmology Andrew G. Lee, MD director of the Wilmer Eye Institute, Ophthalmic Heritage Norman B. Medow, MD number of procedures they are actually per- Panretinal View Allen C. Ho, MD Johns Hopkins University School of Plastics Pearls Richard Anderson, MD Medicine, Baltimore, and chief medical forming,” he said. “And the complication rate is Tech Talk H. Jay Wisnicki, MD Uveitis Update Emmett T. Cunningham Jr., MD, PhD, MPH editor of Ophthalmology Times. at least twice what my colleagues self-report.” What’s New at the AAO John Gallagher PUBLISHING/ADVERTISING He can be reached at 727 Maumenee Building FUZZY MATH Executive Vice President Georgiann DeCenzo [email protected] 440/891-2778 600 N. Wolfe St. Baltimore, MD 21287-9278 Many doctors do what I was taught as a medi- VP, Group Publisher Ken Sylvia [email protected] 732/346-3017 Phone: 443/287-1511 Fax: 443/287-1514 cal student learning about physical diagnosis; Group Publisher Leonardo Avila E-mail: [email protected] [email protected] 302/239-5665 they double the number of alcoholic beverages Associate Publisher Erin Schlussel [email protected] 215/886-3804 that a patient admits to imbibing. A dentist National Account Manager Rebecca A. Hussain AS A YOUNGSTER, [email protected] 415/932-6332 George Washing- named Sam Weisz reports that he divides in Account Manager, Classifi ed/ Display Advertising Darlene Balzano ton famously chose to tell the truth rather than two the number of times that his patients claim [email protected] 440/891-2779 to prevaricate in the hopes of escaping pun- to floss their teeth. The sobering underpinning Account Manager, Recruitment Advertising Jacqueline Moran [email protected] 440/891-2762 ishment: “Father, I cannot tell a lie. I chopped of these strategies is that, on average, we can- Director, Sales Data Gail Kaye Sales Support Hannah Curis down the cherry tree.” We don’t have many not trust our patients to be honest. Reprints 877-652-5295 ext. 121 / [email protected] Outside US, UK, direct dial: 281-419-5725. Ext. 121 George Washingtons around these days. After a long day in the office, I had com- List Account Executive Renée Schuster [email protected] 440/891-2613 We doctors should probably always think the pleted my usual daily hour-long exercise regi- Permissions/International Licensing Maureen Cannon best of our patients, honoring and respecting men, including 5 miles on the treadmill and [email protected] 440/891-2742 them. But that can be hard sometimes, because 100 sit-ups. After a dinner of tasty salad (or- PRODUCTION Senior Production Manager Karen Lenzen they are a bunch of liars. Does this seem a bit ganic greens) and a glass of pomegranate juice, AUDIENCE DEVELOPMENT harsh to you? Well, a recent review of studies on I flossed my teeth and settled down to ponder Corporate Director Joy Puzzo Director Christine Shappell patient veracity reveals some striking findings: the implications of such shameless mendacity Manager Wendy Bong in the American public. > In a 2009 survey of 2,000 patients and 1,200 In my opinion, there are two major logical physicians, 29% of patients admitted lying to consequences from the fact that the Washingto- Chief Executive Offi cer: Joe Loggia Chief Executive Offi cer Fashion Group, their doctors. nian obsession with truth is largely extinct: Executive Vice-President: Tom Florio Executive Vice-President, Chief Administrative Offi cer & Chief Financial Offi cer: Tom Ehardt > Twenty-eight percent of physicians thought the 1. It is unrealistic of physicians to expect patients Executive Vice-President, Chief Marketing Offi cer: Steve Sturm Executive Vice-President: Georgiann DeCenzo majority of patients lie to them on occasion. to comply fully with long-term medical therapy Executive Vice-President: Chris DeMoulin (pills or drops) for chronic diseases, such as dia- Executive Vice-President: Ron Wall Executive Vice-President, Business Systems: Rebecca Evangelou > Younger patients (25 to 34 years of age) are betes and glaucoma. We should make it a priority Sr Vice-President: Tracy Harris more likely to lie than older patients, and men lie to develop surgical procedures with acceptable Vice-President, Media Operations: Francis Heid Vice-President, Legal: Michael Bernstein twice as much as women. safety and efficacy profiles or sustained-release Vice-President, Human Resources: Nancy Nugent drug platforms that will make frequent drug ad- Vice-President, Electronic Information Technology: J. Vaughn > They lie about smoking, about whether they are ministration over years a thing of the past. Advanstar Communications Inc. provides certain customer contact data (such as customers’ names, addresses, phone numbers, and e-mail addresses) to third parties taking their medicines, about how often they exer- who wish to promote relevant products, services, and other opportunities that may be of interest to you. If you do not want Advanstar Communications Inc. to make your cise, about alcohol intake, and apparently about 2. Anticipating that our internists will multiply by contact information available to third parties for marketing purposes, simply call toll-free 866-529-2922 between the hours of 7:30 a.m. and 5 p.m. CST and a customer service anything that might be embarrassing or they other- two whatever we say, we should divide by four representative will assist you in removing your name from Advanstar’s lists. Outside the U.S., please phone 218-740-6477. wise don’t want included in their medical records. when answering their questions about alcohol Ophthalmology Times does not verify any claims or other information appearing in any Q of the advertisements contained in the publication, and cannot take responsibility for any consumption. losses or other damages incurred by readers in reliance of such content. Doctors also lie. One-tenth of respondents in Ophthalmology Times cannot be held responsible for the safekeeping or return of unsolicited articles, manuscripts, photographs, illustrations or other materials. a survey of 1,800 physicians admit saying un- Ophthalmology Times is a member of the Association of Independent Clinical true things to patients, more than half have Publications Inc. Library Access Libraries offer online access to current and back issues of Ophthalmology given patients unrealistically positive prognoses, Times through the EBSCO host databases. and 20% don’t come clean about mistakes they To subscribe, call toll-free 888-527-7008. Outside the U.S. call 218-740-6477. have made because they fear malpractice suits. A friend of mine, a high-ranking official in a professional medical society, once told me why Reference PRINTED IN his organization had stopped surveying its sur- t ‘I don’t smoke, Doc’ and other patient lies. Health and U.S.A. geons about volumes and complication rates. Wellness section, Wall Street Journal, Feb. 19, 2013. MARCH 1, 2013 :: Ophthalmology Times editorial advisory board 5
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EDITORIAL ADVISORY BOARD Ophthalmology Times Mission Statement Chief Medical Editor Anne L. Coleman, MD Robert K. Maloney, MD Jules Stein Eye Institute/UCLA Los Angeles, CA Ophthalmology Times is a physician-driven publication that disseminates news and information of Peter J. McDonnell, MD Los Angeles, CA Wilmer Eye Institute Joan Miller, MD a clinical, socioeconomic, and political nature in a timely and accurate manner for members of the Johns Hopkins University Allen C. Ho, MD Massachusetts Eye & Ear Infirmary ophthalmic community. Baltimore, MD Wills Eye Institute, Thomas Jefferson Harvard University, Boston, MA University, Philadelphia, PA Randall Olson, MD In partnership with our readers, we will achieve mutual success by: Associate Medical Editors Ernest W. Kornmehl, MD University of Utah, Salt Lake City, UT ◾ Being a forum for ophthalmologists to communicate their clinical knowledge, insights, and discoveries. Dimitri Azar, MD Harvard & Tufts Universities, Boston, MA Robert Osher, MD University of Illinois, Chicago, Chicago, IL University of Cincinnati, Cincinnati, OH ◾ Providing management information that allows ophthalmologists to improve and expand their practices. ◾ Addressing political and socioeconomic issues that may either assist or hinder the ophthalmic community, and reporting those issues and their potential outcomes to our readers. Anterior Segment/Cataract Kuldev Singh, MD Theo Seiler, MD Cornea/External Disease Stanford University, Stanford, CA University Hospital of Zurich, Zurich, Switzerland George L. Spaeth, MD Jonathan H. Talamo, MD Ashley Behrens, MD Wills Eye Institute, Thomas Jefferson University Harvard University, Boston, MA Wilmer Eye Institute, Johns Hopkins University Philadelphia, PA Baltimore, MD George Theodossiadis, MD Robert N. Weinreb, MD Athens, Greece Rubens Belfort Jr., MD Hamilton Glaucoma Center Kazuo Tsubota, MD Federal University of São Paulo University of California, San Diego São Paulo, Brazil Keio University School of Medicine, Tokyo, Japan Elizabeth A. Davis, MD Neuro-Ophthalmology George O. Waring III, MD University of Minnesota, Minneapolis, MN Atlanta, GA Uday Devgan, MD Andrew G. Lee, MD Jules Stein Eye Institute/UCLA Methodist Hospital, Texas Medical Center Retina/Vitreous Houston, TX Los Angeles, CA Mark S. Blumenkranz, MD I. Howard Fine, MD Oculoplastics/ Stanford University, Stanford, CA Oregon Health & Science University Reconstructive Surgery Neil M. Bressler, MD Portland, OR Wilmer Eye Institute, Johns Hopkins University Howard V. Gimbel, MD Richard L. Anderson, MD Baltimore, MD Gimbel Eye Centre, Calgary, Canada Center for Facial Appearances, Salt Lake City, UT Stanley Chang, MD The Steinert* Mini LRI & AK Richard S. Hoffman, MD Robert Goldberg, MD Columbia University, New York, NY Oregon Health & Science University, Portland, OR Jules Stein Eye Institute/UCLA, Los Angeles, CA David Chow, MD Diamond Knife Jack T. Holladay, MD, MSEE, FACS John T. LiVecchi, MD University of Toronto, Toronto, Canada Baylor College of Medicine, Houston, TX St. Luke’s Cataract & Laser Institute Sharon Fekrat, MD Manus Kraff, MD Tarpon Springs, FL Duke University, Durham, NC Northwestern University, Chicago, IL Shannath L. Merbs, MD Stuart Fine, MD Samuel Masket, MD Wilmer Eye Institute, Johns Hopkins University University of Pennsylvania, Philadelphia, PA Baltimore, MD Jules Stein Eye Institute/UCLA, Los Angeles, CA Julia Haller, MD Bartly J. Mondino, MD Wills Eye Institute, Thomas Jefferson University Jules Stein Eye Institute/UCLA, Los Angeles, CA Pediatric Ophthalmology Philadelphia, PA Hilel Lewis, MD Mark Packer, MD Norman B. Medow, MD W Oregon Health & Science University, Portland, OR Manhattan Eye, Ear & Throat Hospital Columbia University, New York, NY ie New York, NY V Walter J. Stark, MD Carmen A. Puliafito, MD p To Wilmer Eye Institute, Johns Hopkins University Jennifer Simpson, MD Keck School of Medicine, USC, Los Angeles, CA D te Baltimore, MD University of California, Irvine ac Carl D. Regillo, MD Retr Irvine, CA Wills Eye Institute, Thomas Jefferson University Glaucoma H. Jay Wisnicki, MD Philadelphia, PA New York Eye & Ear Infirmary, Beth Israel Medical Lawrence J. Singerman, MD Robert D. Fechtner, MD Center/Albert Einstein College of Medicine Case Western Reserve University, Cleveland, OH University of Medicine & Dentistry of New Jersey New York, NY Newark, NJ Lawrence Yannuzzi, MD Manhattan Eye, Ear & Throat Hospital Neeru Gupta, MD Refractive Surgery New York, NY University of Toronto, Toronto, Canada Eric D. Donnenfeld, MD Jeffrey M. Liebmann, MD W e New York University Medical Center Uveitis i Manhattan Eye, Ear & Throat Hospital V New York, NY p New York, NY Emmett T. Cunningham Jr., MD, PhD o Daniel S. Durrie, MD T Richard K. Parrish II, MD Stanford University, Stanford, CA n Kansas City, KS io Bascom Palmer Eye Institute, University of Miami ns Xte Miami, FL Kenneth A. Greenberg, MD Chief Medical Editors- FuLL E Danbury Hospital, Danbury, CT/ New York Harry A. Quigley, MD Emeritus University, New York, NY Wilmer Eye Institute, Johns Hopkins University Baltimore, MD Peter S. Hersh, MD Jack M. Dodick, MD s The Perfect LRI & AK Knife For Either Supine Or Upright University of Medicine & Dentistry of New Jersey New York University School of Medicine Robert Ritch, MD Patients. Newark, NJ New York, NY (1976-1996) New York Eye & Ear Infirmary, New York, NY s 3HORTER (ANDLE !LLOWS )NCISION #REATION !T 4HE 3LIT Ioannis G. Pallikaris, MD David R. Guyer, MD Joel Schuman, MD Lamp. University of Crete, Crete, Greece New York, NY (1996-2004) University of Pittsburgh Medical Center Pittsburgh, PA s !LSO )DEAL &OR 5SE 5NDER !N /PERATING -ICROSCOPE s 5NIQUE $OUBLE &OOTPLATE )NSURES !CCURATE 0RECISE $EPTH 3ETTINGS 2ESULTS Ophthalmology Times Industry Council s 3TEP MM 7IDE "LADE %XTENSIONS OF -ICRONS John Bee Mark Newkirk Daina Schmidt 0LUS &ULL %XTENSION 2ETRACTION Rhein Medical Inc. Reichert Technologies Bausch + Lomb Surgical s 4ITANIUM (ANDLE -ADE )N 4HE 53! !ND !VAILABLE &OR ! 3URGICAL President and CEO Director of Global Marketing and Sales Global Executive Director of Product Strategy %VALUATION 7ITHOUT /BLIGATION William Burnham, OD Giulia Newton Kelly Smoyer Carl Zeiss Meditec Inc. Abbott Medical Optics Inc. Essilor of America Director of Market Development, Americas Head of Commercial Operations Canada and Product Director Alastair Douglas Latin America John Snisarenko #ALL &OR -ORE )NFORMATION Alcon Laboratories Inc. Genentech USA Inc. /R 'O 4O /UR 7EBSITE Director of U.S. Commercial Support Ram Palanki Vice President, Sales & Marketing ThromboGenics, Inc. Bob Gibson Global Head - Marketing & Sales Ramin Valian Topcon Medical Systems Inc. Allergan Inc. Vice President of Marketing Vice President of Marketing
How to Contact Ophthalmology Times Editorial Subscription Services Advertising Production 24950 Country Club Blvd., Toll-Free: 888/527-7008 or 485 Route 1 South 131 W. First St. 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 s 4EL s &AX Suite 200 218/740-6477 Building F, First Floor Duluth, MN 55802-2065 %MAIL )NFO 2HEIN-EDICALCOM s 7EBSITE WWW2HEIN-EDICALCOM North Olmsted, OH 44070-5351 FAX: 218/740-6417 Iselin, NJ 08830-3009 800/346-0085 $EVELOPED )N #OORDINATION 7ITH 2OGER & 3TEINERT -$ 440/243-8100 732/596-0276 FAX: 218/740-7223, 1334 Rev.A Mantegna, Dancing Muse BBBC FAX: 440/756-5227 FAX: 732/596-0003 218/740-6576 6 ophthalmic news MARCH 1, 2013 :: Ophthalmology Times Foreseeing the ( In Brief ) FROM STAFF REPORTS ophthalmologist HEADLINES YOU MIGHT HAVE MISSED. As seen in Ophthalmology Times' of the future weekly eReport. Sign up at http://www.modernmedicine.com/ Innovation, technology will shape the way physicians practice OphthalmologyTimes/enewssignup By Liz Meszaros FUNDUS CAMERA EARNS 510(K) CLEARANCE Optovue has received 510(k) clearance for the iCam Non-Mydriatic compact fundus SAN FRANCISCO :: camera, which includes a variety of func- tions and features that produce high-quality conomic uncertainties and disrup- the IOL, and the excimer laser,” he said. “We’ve image documentation and management of tive innovations, not to mention seen how they changed our practices, as have the ocular health. http://bit.ly/Z0orK2 anticipated and unanticipated advent of new therapies, such as ranibizumab technologies, are likely to shape and bevacizumab [Lucentis and Avastin, Ge- ophthalmology and make future nentech], that pop up on the screen and all of a LASER PLATFORM APPROVED Epredictions difficult. sudden, the entire management of age-related FOR CORNEAL ARCUATE CUTS “It’s hard to find the [crystal] ball . . . [to macular degeneration (AMD) changes.” The Victus Femtosecond Laser Platform see] 20 to 30 years from now,” said H. Dunbar One must also factor in anticipated technolo- from Bausch + Lomb has received 510(k) Hoskins Jr., MD, FACS, former gies—such as information technology (IT) and clearance from the FDA for the creation executive vice president of the telemedicine, therapeutic breakthroughs in AMD, of penetrating arcuate cuts/incisions in the American Academy of Oph- glaucoma, and uveitis, and functioning retinal cornea of patients undergoing cataract surgery or other ophthalmic treatment. thalmology, and who currently prosthesis, for example—when trying to predict http://bit.ly/15TPxcs maintains a glaucoma prac- the future. But just as importantly, there will tice in San Francisco. “Clearly, also be unanticipated technologies, he noted. predictions are hazardous. “For example, when timolol popped up back SYSTEM UPGRADES ALLOW Dr. Hoskins “As Yogi Berra, the great in the 1980s, trabeculectomy dropped dramati- AUTOMATED IOL DELIVERY philosopher, once said: ‘The cally,” he said. “Our inability to predict those The latest hardware and software up- one thing you can’t do is predict the unanticipated technologies will grades for Alcon's Infiniti Vision System future.’ And I’ve learned that over affect what is going to happen are expected to provide surgeons greater and over again,” Dr. Hoskins said. Key trends in the future.” control during cataract surgery, including the What is known is that there FOR Not only innovations, but also Intrepid AutoSert IOL injector, which enables automated delivery of the IOL. will be a few trends, including: health care how they are implemented will http://bit.ly/XFCI1S Reduced compensation per have an effect on predictions and unit of care that will demand actualities in the future. > Reduced ALLERGAN LAUNCHES increased productivity and effi- compensation per “You’ve heard that IT will ciency for practices. unit of care that will change the way we practice in PRESERVATIVE-FREE DROPS Refresh Optive Advanced Preservative-Free Increased consolidation of prac- demand increased the future,” he said. “I predict that Lubricant Eye Drops (Allergan) feature the tices, which is going on already. productivity and by the year 2020 or 2030, it will An increasing team approach. change it dramatically.” same formula as Refresh Optive Advanced, efficiency for “Those trends are obvious,” Dr. In addition, fee-for-care in- but without the use of a preservative. practices. http://bit.ly/13r9R55 Hoskins said. “The main changes stead of fee-for-service is inevi- that will occur, however, will prob- > Increased table, and the number of group ably be a little unpredictable, just consolidation of practices will increase, with ex- TRIAL EVALUATES AFLIBERCEPT like economic impact and the enor- practices, which is panded team activities. FOR DME IN RUSSIA, ASIA mous uncertainties that exist.” going on already. “I predict that by 2020 or 2030, Regeneron Pharmaceuticals Inc. and Bayer we will see hands-on technicians HealthCare have initiated a new phase III > An increasing team DISRUPTIVE and limited license practitioners trial to evaluate the efficacy and safety of approach. INNOVATIONS instead of hands-on doctors,” Dr. aflibercept (Eylea) injection in the treatment Innovations—actual and antici- Hoskins said. “Many of the things of diabetic macular edema (DME) in Russia, pated—will shape the future of ophthalmol- that we now do by ourselves will be turned China, and other Asian countries. http://bit.ly/YCAPyY ogy, Dr. Hoskins continued. over to technicians and other practitioners.” “We’ve all been through phacoemulsification, Continues on page 7 : Future MARCH 1, 2013 :: Ophthalmology Times 7 ophthalmic news
chief executive officer of Second Sight, has PROSTHESIS been working on the development of the reti- OphthalmologyTimes.com nal prosthesis for more than 20 years. Value-added web content and news ( Continued from page 1 ) “It is also an incredible day for patients with RP, who no longer have to be told that they prosthesis allows patients with RP with barely have a progressive blinding disease with no to no light perception vision to detect light and option for restoring vision,” Dr. Greenberg told perform tasks, to assist them with their orien- Ophthalmology Times. “Seeing the project to tation, mobility, and letter recognition. fruition and finally having something avail- “The prosthesis stimulates the remaining ret- able to offer patients in the United States is inal neurons, despite the fact that there are no enormously rewarding for me, for the 100 or photoreceptors, and the information from the so employees of Second Sight, many of whom stimulation is sent to the brain, via the optic have been with us since the company’s incep- nerve,” said Mark S. Humayun, MD, PhD, the tion, and for the hundreds of others who have RETINAL PROSTHESIS IN Cornelius Pings Professor of Biomedical Sci- worked with us through part- ACTION Go to http://ow.ly/ijY4j for a video ences, professor of ophthalmology, biomedi- nerships with academic and demonstration of how the retinal prosthesis cal engineering, cell and neurobiology, Keck national laboratories.” works. (Video courtesy of Second Sight) School of Medicine and Viterbi School of En- The retinal prosthesis sys- gineering, University of Southern California, tem features a spectacle- Los Angeles. Dr. Humayun also is the leader mounted video camera for tion, and in vitro tests demonstrate that the de- of the research team for the Argus project. receiving visual input that vice may last much longer, said Dr. Greenberg. “I have dedicated my career to restoring sight Dr. Greenberg is then converted to a stim- Efficacy and safety of the retinal prosthe- to the blind because my grandmother went ulation pattern by an externally worn video sis was investigated in an international trial blind,” said Dr. Humayun in an interview with processor. The processor transmits data and that enrolled 30 patients at 10 centers in the Ophthalmology Times. “Although the Argus was power wirelessly to a 60-electrode epiretinal United States, the United Kingdom, France, and not developed in time to help her, I am happy array implanted, via a pars plana approach, in Switzerland. Eligible subjects had severe-to- that it will be able to provide useful vision to a procedure similar in nature to scleral buck- profound, outer retinal degeneration second- some blind patients. To this day, it is amazing ling with vitrectomy. ary to RP, or related dystrophies with visual how much the otherwise totally blind patients The electronics are packaged to withstand acuity worse than 2.3 logMAR in both eyes. can see with the Argus II.” the intraocular environment with an expected Robert Greenberg, MD, PhD, president and lifetime of at least 5 to 10 years after implanta- Continues on page 8 : Retinal
how physicians are practicing medicine com- weekly surgical day, she will perform 40 cata- FUTURE pared with peers. ract surgeries, with each one lasting 5 minutes Telemedicine will be prevalent locally and to inject and aspirate the nucleus and the cor- ( Continued from page 6 ) beyond the practice area, increased subspe- tex, using an in-the-bag accommodative poly- cialization will be the norm, and the ratio of mer that restores full accommodation. Included The number of physician assistants is in- workers per physician will change dramati- in this work load will also be three glaucoma creasing, especially in rural states, and this cally, Dr. Hoskins continued. implants and one strabismus surgery. will continue, he added. He projects two optometrists, four physi- “She’ll do all of this by using her robotic Another prediction from Dr. Hoskins cen- cian assistants, six technicians, and only one reach from home! And she’ll be finished by ters on whether accountable care organiza- clerk, because IT will replace filers, scribes, noon, so she has time to feed the kids. The tions will survive. billers, and schedulers. retina docs will finish by 1 p.m.,” he said, “I don’t know if they will, but I predict that “This could allow for two to three times the adding, “Or maybe the cataract prevention pill there will be integrated care organizations that current patient volumes per physician and will will come along and we’ll all be playing golf.” will survive, and we will have to react to those be more than adequate to meet the projected Dr. Hoskins’ final prediction is hopeful, by probably having integrated ophthalmic prac- demands, but I don’t know about the needs,” however. tices that allow for one-stop shopping for eye Dr. Hoskins said. “Clearly, it’s going to be a different world,” care,” he said. The typical ophthalmologist in 2040 will be he said. “Economic uncertainties and disrup- a 47-year-old mother of two children and who tive innovations plus disruptive implementa- TYPICAL PRACTICE OF THE will be working 40 hours per week from home tion equal disrupted predictions. FUTURE via Web holograms for consults. Optometrists, “The one certain[ty] is [that] protecting, pre- The prediction of what a typical ophthalmic nurse practitioners, physician assistants, and serving, and restoring vision will always be a practice will be like in 2040 is tough, Dr. Hoskins technicians will see her patients, but she may rewarding and satisfying career,” Dr. Hoskins noted. He suggested, however, that the typical go in to the office for a particularly compli- said. “Nobody thanks you the way patients future practice will be part of a group prac- cated case, Dr. Hoskins predicted. do. So enjoy the future, identify the trends, tice, with electronic medical records and data He predicted that this ophthalmologist of be flexible, be able to move with the waves, analysis systems in place to help understand the future will have one surgical bay, and on a and have a good time.” Q 8 MARCH 1, 2013 :: Ophthalmology Times ophthalmic news
The components The retinal prosthesis consists of a RETINAL surgically implanted 55-electrode, stimulating microelectrode array made up of 200-μm diameter disc electrodes, an inductive coil link ( Continued from page 7 ) used to transmit power and video data to the implant, an external belt-worn video processing unit, and a miniature video camera Of the 30 patients enrolled, 29 had RP and mounted on a pair of glasses. (Images courtesy of Second Sight) one had choroideremia. Visual acuity was bare light perception in 29 patients and no light perception in one individual. Follow-up for patients with the retinal pros- thesis implanted ranged from a minimum of almost 3.5 years to almost 6 years, and cumu- lative subject-years of follow-up exceeds 125 years. The safety and reliability of the system has remained excellent in this cohort. Explantation of the epiretinal array was per- formed in one patient who experienced recur- rent conjunctival erosion. In a second subject, intermittent communications failure with the implant began to occur at 10 months postop- eratively and was believed to be a result of damage to the telemetry coils induced during Outside the United States, the retinal pros- implantation. The epiretinal electrode array thesis is available at a number of centers in has not been explanted. Germany, Italy, the United Kingdom, France, “With increasing improvement in design and and Saudi Arabia. Dr. Greenberg said that pa- also more experience with the procedure, it tients who received the implant at many of is anticipated that the surgical risks will be these sites are enrolled in a post-marketing further reduced,” Dr. Humayun said. “Hav- study, and, as expected, the initial safety re- ing said this, although implanting an Argus sults are even better than those of the pre- II involves a number of routine vitreoretinal marketing trials. steps, which cumulatively can take only about patient tested with the new software achieved 2 hours, it also requires that the surgeon take MORE DATA AND 20/200 visual acuity. some time to understand the few steps that DEVELOPMENTS “It is very encouraging to see this level of vi- are not part of routine vitreoretinal surgery, Currently, researchers are also working on soft- sual acuity achieved without modifying spacing (i.e., use of a retinal tack).” ware modifications that will enhance the ca- of the electrodes,” Dr. Humayun said. “In the pabilities of the existing prosthesis platform. current embodiment, this increase in acuity COMMERCIAL AVAILABILITY “One of the fantastic features of the Argus comes at the expense of visual field, but Second PLANS II is that it is software upgradeable, just like a Sight is working on even more advanced soft- With the FDA approval, Second Sight is work- smartphone,” Dr. Greenberg said. “Therefore, ware that may be able to compensate for this.” ing actively with Medicare (CMS) to establish patients with the device already implanted and While the focus for improving the Argus II reimbursement for the prosthesis and hopes those receiving it now that it is commercially is on software upgrades, researchers at Second that will be completed soon—although it may available in the United States can benefit from Sight are also working on an entirely new ar- not be accomplished before the commercial future improvements.” tificial vision platform that will be placed in launch, planned for later in 2013. The com- He added that changing the software is a the visual cortex area of the brain. pany is also working with private insurers to safer, easier, and more reliable way to im- “We are very excited about this brain-im- make the device available with coverage to prove the prosthesis than introducing hard- planted device because it would represent a patients who are not Medicare beneficiaries. ware modifications. treatment for blindness from all causes, not Upon commercial launch, the retinal prosthe- With regard to upgrades, Second Sight re- just RP, and potentially benefit nearly 8 mil- sis will be available only through 10 to 12 U.S. ports it has been collaborating with research- lion patients,” Dr. Greenberg said. Q centers, including several that were involved ers in Europe to develop software based on in the pre-marketing clinical trial. Those are modulation of the stimulus frequency that located in San Francisco, New York, Los An- allows color perception (the current version For a look at how the retinal geles, Baltimore, Dallas, and Philadelphia. Ad- operates in a black-white-gray scale). In addi- prosthesis works, see page 10. ditional training is already under way at those tion, a modification is being engineered using sites, and the company expects to open four digital zoom techniques for the camera and to six more centers in the United States soon, software to create virtual electrodes that will MARK S. HUMAYUN, MD, PHD although they are not yet identified. increase resolution. E: [email protected] “Our plan is to make the prosthesis available Whereas about 30% of patients with the cur- Dr. Humayun is a consultant and a minority equity/share holder in Second Sight Medi- only through select ‘centers of excellence,’ ” rent model of the Argus II implanted regain cal Products. The Argus II Retinal Prosthesis System (Second Sight Medical Products Dr. Greenberg said. measurable visual acuity (up to 20/1260), a Inc.) is designated as a humanitarian-use device, which refl ects orphan product status. Advertisement not available for this issue of the digital edition
OphthalmologyTimes.com 10 MARCH 1, 2013 :: Ophthalmology Times ophthalmic news Prosthesis team leader outlines components, procedure, follow-up By Mark S. Humayun, MD, PhD; Special to Ophthalmology Times
to the microelectrode array via ap- EDITOR’S NOTE: Mark S. Humayun, MD, PhD, is the team leader Electronics Case plication-specific circuitry and a su- behind the Argus Retinal Prosthesis project. He and his team have been working on the prosthesis for 20 years. In this exclusive article to Ophthalmology Times, Dr. perior-temporally placed inductive Humayun outlines the components of the prosthesis, how the prosthesis works, the radio frequency coil link, allowing surgical procedure, and patient expectations. for wireless forward and reverse te- lemetry between intra and extraoc- ular portions of the system. THE RETINAL PROSTHESIS tion of the visual scene in front of the These pulses are intended to stim- consists of a surgically implanted patient and relays the information ulate the retina’s remaining cells to 55-electrode, stimulating micro- to the VPU. The VPU digitizes the create phosphenes, or perceptions of electrode array made up of 200- signal in real-time, applies a series light. Each electrode activates over- μm diameter disc electrodes, an of image processing filters, and cre- lying cells based on encoded inten- Receiver Electrode Array inductive coil link used to transmit ates a series of stimulus pulses on sity, and collectively the electrodes power and video data to the im- the surface of the retina based on can form an image similar to a gray- (FIGURE 1) The implant is an epiretinal plant, an external belt-worn video pixel brightness values and look-up scale digital scoreboard, resulting in prosthesis surgically implanted in and processing unit (VPU), and a min- tables customized for each subject. perception of patterns of light in the on the eye that includes an antenna, an iature video camera mounted on brain. Patients then learn to inter- electronics case, and an electrode array. a pair of glasses. HOW IT WORKS pret these visual patterns, thereby (Image courtesy of Second Sight) The video camera captures a por- The stimulus pulses are delivered regaining some functional vision. Historical challenges to bioelec- showed meaningful improvements. tronics implants include safe surgi- Reliability also was high. Over the cal implantation and long-term sta- follow-up period of this study, all but bility. We recently published our one device remained implanted and 6 months results (Ophthalmology. the vast majority of electrodes (94.4%) 2012;119:779-788). Three-year follow- remained functional. up data on the Argus II show simi- One of the first cases included lar results and continued to show in the study was a female patient improved visual performance and who had been blind for more than an acceptable safety record.1 30 years due to RP. Her surgery was This multicenter, prospective trial successful with no adverse events. included 30 patients with a mean age The device helps her navigate in of 58 + 10 years, 97% (n = 29) of unfamiliar environments, or if she which had bare light perception and drops something in a known envi- 3% (n = 1) had no light perception at ronment. The device has been stable, baseline. Patients had been followed the electrodes all continue to func- for an average of 3.6 + 1.0 years, with tion nearly 6 years post-surgery, there one device explanted at 14 months has been no infection or bleeding, due to recurrent conjunctival erosion and she is doing remarkably well. and one device failing at 10 months due to communication failure with THE PROCEDURE the implant, but it was left in the eye. The procedure itself is something that Subjects performed statistically most retinal surgeons can perform, better with the system on versus off as it is for the most part a combi- in the following tasks: object local- nation of common techniques. The ization, motion discrimination, and surgery begins with the removal of discrimination of oriented gratings. the lens, via clear corneal incision, Other tests of visual function (ori- in phakic eyes. entation and mobility tasks, and ac- This is followed by a 360° limbal tivities of daily living), and a third- conjunctival peritomy and isolation party assessment of the impact of of the rectus muscles with a scleral the system on quality of life, also buckle. The coil antenna is placed MARCH 1, 2013 :: Ophthalmology Times 11 ophthalmic news
temporally on the globe and the electronics Thus, independently manipulating pulse train package is centered in the superior temporal frequency and amplitude is part of the process OphthalmologyTimes.com quadrant and then sutured to the sclera. of “fitting” the prosthesis to the patient. Dedi- Value-added web content and news Following the placement of the antenna and cated engineers using custom instrumentation hardware, core and peripheral vitrectomies are wirelessly communicate with the implanted part performed, as well as dissection of any epireti- of the device, activating a few electrodes at a nal membrane in the area where the surgeon time and syncing this to the camera to deter- intends to tack the array. Once the vitreous is mine the optimal frequency and amplitude of removed, the electrode array is inserted via a each electrode for an individual patient. After temporal sclerotomy, placed over the macula, fitting is completed, patients work with occu- and micro-tacked to the retina. pational or low-vision rehabilitation therapists Once it is in place on the retina, all of the scle- to help them understand their new vision and rotomies and the conjunctiva are sutured. The how to use it to achieve their goals. eye is injected with postoperative antibiotics. Potential patients must be willing to wear PATIENT TESTIMONIAL Go to the glasses and the VPU (which also houses the http://ow.ly/ijY9M for a video of a patient FOLLOW-UP battery that powers the system). Patients will describing his experience with the retinal prosthesis system. (Video courtesy of Second Sight) While the surgical implantation of the device need to commit to about 3 months of fitting is an accessible skill, the follow-up to surgery and rehabilitation, along with annual clinical is more involved and time-consuming than for follow-up (after the first year). References an average vitreoretinal surgery. The system might not be indicated for every 1. Greenberg R, et al. Results update from Second Sight’s Nanduri and colleagues published their find- patient with severe RP. Refer to the product Argus II Retinal Prosthesis Study. Presented at the annual meeting of the Association for Research in Vision ings that increased stimulation frequency in- insert for contraindications. For the right pa- and Ophthalmology. May 2012, Fort Lauderdale, FL. creases brightness, while increasing stimula- tient, restoring some level of vision and thereby 2. Naduri D, et al. Frequency and amplitude modulation tion amplitude generally affects both size and improving mobility and independence is an have different effects on the percepts elicited by retinal brightness of phosphenes.2 amazing prospect. Q stimulation. IOVS. 2012:53:205-214. ARE YOU SEEING THE FULL PICTURE?
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© 2013 Optos. All rights reserved. Optos, optos and optomap are registered trademarks,200Tx is a trademark of Optos plc. P/N GA-00117 / 1 Registered in Scotland Number: SC139953 optos.com Registered Office: Queensferry House, Carnegie Campus, Dunfermline, Fife KY11 8GR 12 glaucoma MARCH 1, 2013 :: Ophthalmology Times
The next step in drug delivery Topical micro-droplet system targets direct application to the ocular surface By Lynda Charters; Reviewed by Sean Ianchulev, MD, MPH
TAKE-HOME “There is a reason why we have been using The pupils were monitored by digital pu- the conventional eye dropper for more than pillometry at 10, 20, and 60 minutes follow- A new topical micro-droplet delivery 100 years, even though we are well aware of ing dosing. system (Micro-Droplet Piezoelectric its deficiencies,” Dr. Ianchulev said. “The results showed that the micro-droplet Ejection System, Corinthian The micro-droplet piezoelectric ejection sys- ejection system provided similar dilation and Ophthalmic) facilitates depositing tem may overcome these obstacles. The device, pharmacodynamics effect to that achieved to of the drug on the ocular surface. he explained, provides collimated flow in a the drug instilled using the eye dropper—even manner similar to ink-jet printers. though the spray administered one tenth of SAN FRANCISCO :: “This facilitates depositing of the drug on the volume of the eye drop,” Dr. Ianchulev the ocular surface and the result differs mark- said. “This is important because we can re- new topical micro-droplet de- edly from eye dropper instillation or spray,” duce ocular surface exposure to preservatives livery system (Micro-Droplet Dr. Ianchulev said. Piezoelectric Ejection System, The delivery is based on Corinthian Ophthalmic) may the piezoelectric fluid ejec- be an improvement first step tion system, which monitors over the eye dropper to deliver every application of a drug. topical medications. “Using sophisticated ASuch a drug-delivery system might standardize technology, the system is instillation of drugs and prevent over-treatment able to control the dosing and improper instillation, thus aiding patient and ejection of micro-drop- compliance, according to Sean Ianchulev, MD, lets to enable direct appli- MPH, clinical associate professor, University cation on the ocular sur- of California, San Francisco. face,” he said. “It can be Dr. Ianchulev identified some major chal- used across a platform of lenges encountered with the conventional eye topical medications. Glau- dropper, such as overflow, inability to deliver coma, antibiotic, and myd- (FIGURE 1) The micro-droplet piezoelectric ejection system provides inside the eye, and uneven distribution to the riatic drops have been suc- collimated flow of topical medication in a manner similar to ink-jet ocular surface. Even when instilled correctly cessfully sprayed using this printers. (Photo courtesy of Sean Ianchulev, MD, MPH) into the eye, the vast majority of a single eye delivery system.” drop is lost within the first 15 to 30 seconds The technology has a light-emitting-diode op- and for some drugs, such as beta blockers, after instillation, either by lid overflow or via tical targeting system that eliminates the need systemic side effects can be avoided. The re- the nasolacrimal duct system. In stark con- for the patient to tilt his or her head and delivers sults made us very confident about investigat- trast with most other pharmacologic deliv- the spray within less than 30 to 40 ms, which is ing other drugs.” ery methods (e.g., pills, intravenous), there faster than the blink reflex. When a glaucoma drug was tested in a simi- is little control on what amount of drug is ac- lar manner in a canine model, the investiga- tually delivered to the target tissue (i.e., the CLINICAL ASSESSMENT tors achieved the same efficacy curves to those ocular surface) when a physician prescribes A clinical study of the delivery system was per- achieved with eyedropper instillation, he noted. a topical formulation. formed to compare the dilating effect of a topi- The advantage of the ejection system is that To overcome this problem, investigators have cal medication (2.5% phenylephrine and 1% a much lower volume of drug can be ejected attempted to deliver medications by spraying tropicamide) delivered via the micro-droplet onto the ocular surface to achieve the same the drug onto the eye, but initial efforts with ejection device and an eye dropper. The study effect as that using eye drops. Q such systems as atomizer sprays have failed included 102 patients; one eye of each patient due to inability to control droplet size and flow served as the control for which an eye drop- dynamics for consistent and predictable ad- per delivered the drug and the delivery system ministration. Major problems related to the was used to deliver the drug to the fellow eye. SEAN IANCHULEV, MD, MPH physics of droplet ejection, such as dispersion, The patients were randomly assigned to one of E: [email protected] droplet evaporation, drag, and non-collimated three study arms in which 34 patients received Dr. Ianchulev is a scientific advisor and member of the board of directors for Corinthian flow turbulence, have held back such new ap- a 1.5-μl dose, 33 patients received 6 μl, and 35 Ophthalmic. This article was adapted from Dr. Ianchulev’s presentation at the 2012 proaches until recently. patients two doses of 3 μl each. meeting of the American Academy of Ophthalmology. Chronic inflammation associated with non-infectious posterior uveitis requires continuous control1-4
RETISERT® offers continuous control of inflammation1,2
s RETISERT® is the first approved intravitreal implant for chronic non-infectious uveitis affecting the posterior segment designed to deliver corticosteroid therapy for approximately 2.5 years1 s Approximately 80% of patients experienced a 3-year recurrence-free period in 2 pivotal trials1,*
* Two randomized, double-masked, multicenter controlled clinical trials of the 0.59-mg fluocinolone acetonide intravitreal implant in 224 patients.1 Important Risk Information about RETISERT® s 3URGICAL PLACEMENT OF 2%4)3%24® is contraindicated in active viral, bacterial, mycobacterial or fungal infections of the eye. s "ASED ON CLINICAL TRIALS WITH 2%4)3%24®, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT® into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, wound complication, wound site erythema and wound dehiscence. s &OLLOWING IMPLANTATION OF 2%4)3%24®, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. s 5SE OF CORTICOSTEROIDS MAY RESULT IN ELEVATED )/0 ANDOR GLAUCOMA "ASED ON CLINICAL TRIALS WITH 2%4)3%24®, within 3 years post-implantation, APPROXIMATELY OF PATIENTS WILL REQUIRE )/0 LOWERING MEDICATIONS TO CONTROL INTRAOCULAR PRESSURE AND OF PATIENTS WILL REQUIRE lLTERING procedures to control intraocular pressure. s 0ATIENTS SHOULD BE ADVISED TO HAVE OPHTHALMOLOGIC FOLLOW UP EXAMINATIONS OF BOTH EYES AT APPROPRIATE INTERVALS FOLLOWING IMPLANTATION OF RETISERT®. Physicians should periodically monitor the integrity of the implant by visual inspection. s 4HE MOST FREQUENTLY REPORTED OCULAR ADVERSE EVENTS IN CLINICAL TRIALS WITH 2%4)3%24® occurring in 50-90% of patients included: cataract, INCREASED INTRAOCULAR PRESSURE PROCEDURAL COMPLICATIONS AND EYE PAIN 4HIRTY lVE TO FORTY PERCENT OF PATIENTS REPORTED OCULAR conjunctival hyperemia, reduced visual acuity and conjunctival hemorrhage. The most common non-ocular event reported was headache (≥33%). Please see RETISERT® full prescribing information on adjacent pages. References: 1. RETISERT [package insert]. Rochester, NY: Bausch & Lomb Inc; March 2009. 2. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191-1201. 3. Nguyen QD, Callanan D, Dugel P, Godfrey DG, Goldstein DA, Wilensky JT. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina. 2006;(suppl 8):1-16. 4. Jabs DA. Treatment of ocular inflammation [editorial]. Ocul Immunol Inflamm. 2004;12(3):163-168. If you have any questions about RETISERT®, please call 1-800-323-0000 or visit www.retisert.com.
RETISERT is a registered trademark of Bausch & Lomb Incorporated. ©2012 Bausch & Lomb Incorporated. PH4560 4/12 HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS------Surgical placement of RETISERT is contraindicated in active viral, bacterial, mycobacterial and These highlights do not include all the information needed to use RETISERT safely and fungal infections of ocular structures. (4.1) effectively. See full prescribing information for RETISERT. RETISERT (fluocinolone acetonide intravitreal implant) 0.59mg ------WARNINGS AND PRECAUTIONS------Initial U.S. Approval: 1963 Cataract formation: Nearly all phakic patients are expected to develop cataracts and require ------INDICATIONS AND USAGE------cataract surgery. (5.1) RETISERT is a corticosteroid indicated for the treatment of chronic non-infectious uveitis Endophthalmitis: Late onset endophthalmitis has been observed. (5.2) affecting the posterior segment of the eye.(1) Increase in intraocular pressure: Use of corticosteroids may result in elevated IOP and/ ------DOSAGE AND ADMINISTRATION------or glaucoma. (5.3) IOP lowering medications were required in > 75% of patients; filtering RETISERT is surgically implanted into the posterior segment of the affected eye through a surgeries were required in > 35% of patients. (6.1) pars plana incision. (2.1) Separation of implant components: Physicians should periodically monitor the integrity of RETISERT is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 the implant by visual inspection. (5.4) μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over ------ADVERSE REACTIONS------approximately 30 months. (2.1) Aseptic technique should be maintained at all times prior to and during the surgical Ocular adverse events included procedural complications, and eye pain (> 50%). Thirty-five implantation procedure. (2.2) to forty percent of patients reported ocular/conjunctival hyperemia, reduced visual acuity, and conjunctival hemorrhage. (6.1) ------DOSAGE FORMS AND STRENGTHS------The most common non-ocular event reported was headache (≥33%). (6.2) 0.59 mg fluocinolone acetonide intravitreal implant. To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb at 1-800-323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION Revised March 2009 FULL PRESCRIBING INFORMATION: CONTENTS* 6.2 Clinical Trials Experience - Non-Ocular Events 1. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS 2. DOSAGE AND ADMINISTRATION 8.1 Pregnancy 2.1 Dosing Information 8.3 Nursing Mothers 2.2 Handling of Implant 8.4 Pediatric Use 3. DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use 4. CONTRAINDICATIONS 11. DESCRIPTION 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures 12. CLINICAL PHARMACOLOGY 5. WARNINGS AND PRECAUTIONS 12.1 Mechanism Of Action 5.1 Cataract Formation 12.3 Pharmacokinetics 5.2 Endophthalmitis and Surgical Complications 13. NONCLINICAL TOXICOLOGY 5.3 Increase in Intraocular Pressure 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility 5.4 Separation of Implant Components 14. CLINICAL STUDIES 5.5 Other Corticosteroid Induced Adverse Reactions 16. HOW SUPPLIED/STORAGE AND HANDLING 6. ADVERSE REACTIONS 17. PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience - Ocular Events *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION detachment, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of 1 INDICATIONS AND USAGE intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and RETISERT is indicated for the treatment of chronic non-infectious uveitis affecting the wound dehiscence. posterior segment of the eye. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one 2 DOSAGE AND ADMINISTRATION to four weeks post-operatively. 2.1 Dosing Information RETISERT (fluocinolone acetonide intravitreal implant) 0.59 mg is implanted into the 5.3 Increase in Intraocular Pressure posterior segment of the affected eye through a pars plana incision. Prolonged use of corticosteroids may result in elevated IOP and/or glaucoma with damage The implant contains one tablet of 0.59 mg of fluocinolone acetonide. RETISERT is designed to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with to release fluocinolone acetonide at a nominal initial rate of 0.6 μg/day, decreasing over caution in the presence of glaucoma. Patients must be monitored for elevated IOP. the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. Based on clinical trials with RETISERT, within 3-years post implantation, approximately 77% Following depletion of fluocinolone acetonide as evidenced by recurrence of uveitis, of patients will require IOP lowering medications to control intraocular pressure and 37% RETISERT may be replaced. of patients will require filtering procedures to control intraocular pressure. (see 6.1 Clinical Trials Experience - Ocular Events section). 2.2 Handling of Implant Caution should be exercised in handling RETISERT in order to avoid damage to the implant, 5.4 Separation of Implant Components which may result in an increased rate of drug release from the implant. Thus, RETISERT In vitro stability studies show that the strength of the adhesive bond between the silicone should be handled only by the suture tab. Care should be taken during implantation and cup reservoir and the suture tab is reduced with prolonged hydration, indicating a potential explantation to avoid sheer forces on the implant that could disengage the silicone cup for the separation of these components. Physicians should periodically monitor the integrity reservoir (which contains a fluocinolone acetonide tablet) from the suture tab. Aseptic of the implant by visual inspection. technique should be maintained at all times prior to and during the surgical implantation procedure. 5.5 Other Corticosteroid Induced Adverse Reactions RETISERT should not be resterilized by any method. RETISERT should be used with caution in patients with a history of a viral, bacterial, mycobacterial or fungal infection of the cornea and conjunctiva including epithelial herpes 3 DOSAGE FORMS AND STRENGTHS simplex keratitis (dendritic keratitis), vaccinia and varicella. 0.59 mg fluocinolone acetonide intravitreal implant. Use of ocular steroids may prolong the course and may exacerbate the severity of many 4 CONTRAINDICATIONS viral infections of the eye (including herpes simplex). Employment of a corticosteroid 4.1 Viral, Bacterial, Mycobacterial and Fungal Infections of Ocular Structures medication in the treatment of patients with a history of herpes simplex requires great Surgical placement of RETISERT is contraindicated in active viral diseases of the cornea and caution. conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and Prolonged use of corticosteroids may suppress the host response and thus increase the varicella, and also in active bacterial, mycobacterial or fungal infections of the eye. hazard of secondary ocular infections (bacterial, fungal, and viral) . In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. Fungal 5 WARNINGS AND PRECAUTIONS and viral infections of the cornea are particularly prone to develop coincidentally with long- 5.1 Cataract Formation term application of steroids. The possibility of fungal invasion should be considered in any Use of corticosteroids may result in posterior subcapsular cataract formation. persistent corneal ulceration where steroid treatment has been used. Based on clinical trials with RETISERT, during the 3-year post implantation period, nearly all Since resistance to infections is known to be reduced by corticosteroids, simultaneous phakic eyes are expected to develop cataracts and require cataract surgery. bilateral implantation should not be carried out, in order to limit the potential for bilateral post-operative infection. 5.2 Endophthalmitis and Surgical Complications Ocular administration of corticosteroids has also been associated with delayed wound Late onset endophthalmitis has been observed. These events are often related to the healing and perforation of the globe where there is thinning of the sclera. integrity of the surgical wound site. Careful attention to assure tight closure of the scleral The use of steroids after cataract surgery may delay healing and increase the incidence of wound and the integrity of the overlying conjunctiva at the wound site is important. bleb formation. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal 6 ADVERSE REACTIONS arachidonic acid. Arachidonic acid is released from membrane phospholipids by
6.1 Clinical Trials Experience - Ocular Events phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure. The available safety data includes exposure to RETISERT in patients with chronic non- infectious uveitis affecting the posterior segment in two multicenter controlled clinical 12.3 Pharmacokinetics trials. Patients were randomized to dosage regimens of 0.59 mg or 2.1 mg implants. In a subset of patients who received the intravitreal implant, and had blood samples taken The most frequently reported ocular adverse events were cataract, increased intraocular at various times (weeks 1, 4 and 34) after implantation, plasma levels of fluocinolone pressure, procedural complication, and eye pain. These events occurred in approximately acetonide were below the limit of detection (0.2 ng/mL) at all times. Aqueous and vitreous 50 - 90% of patients. Cataract includes aggravated cataract, and posterior capsular humor samples were assayed for fluocinolone acetonide in a further subset of patients. opacification. Procedural complications includes post-op complication, post-op wound While detectable concentrations of fluocinolone acetonide were seen throughout the complication, post-op wound site erythema, and wound dehiscense. observation interval (up to 34 months), the concentrations were highly variable, ranging from below the limit of detection (0.2 ng/mL) to 589 ng/mL. Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all phakic eyes are expected to develop cataracts and require cataract surgery. IOP lowering 13 NONCLINICAL TOXICOLOGY medications to lower intraocular pressure were required in approximately 77% of patients; 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility filtering surgeries were required to control intraocular pressure in 37% of patients. Long-term animal studies have not been performed on RETISERT to evaluate the Ocular adverse events occurring in approximately 10 - 40% of patients in decreasing carcinogenic potential or the effect on fertility of fluocinolone acetonide. order of incidence were ocular/conjunctival hyperemia, reduced visual acuity, glaucoma, Fluocinolone acetonide was not genotoxic in vitro in the Ames test, the mouse lymphoma conjunctival hemorrhage, blurred vision, abnormal sensation in the eye, eye irritation, TK assay, or in vivo in the mouse bone marrow micronucleus assay. maculopathy, vitreous floaters, hypotony, pruritus, ptosis, increased tearing, vitreous hemorrhage, dry eye, eyelid edema, macula edema and visual disturbance. 14 CLINICAL STUDIES Ocular adverse events occurring in approximately 5 - 9% of patients in decreasing order In two randomized, double-masked, multicenter controlled clinical trials, 224 patients of incidence were eye discharge, photophobia, blepharitis, corneal edema, iris adhesions, with chronic (a one year or greater history) non-infectious uveitis affecting the posterior choroidal detachment, diplopia, eye swelling, retinal detachment, photopsia, retinal segment of one or both eyes were randomized to receive a 0.59 mg RETISERT. The primary hemorrhage and hyphema. efficacy endpoint in both trials was the rate of recurrence of uveitis affecting the posterior segment of the study eye in the 34 week pre-implantation period compared to the rate of 6.2 Clinical Trials Experience - Non-Ocular Events recurrence in the 34 week post-implantation period. Uveitis recurrence rates at 1, 2, and 3 The most frequently reported non-ocular adverse event was headache (33%). Other non- year post-implantation were also compared to the 34 week pre-implantation period. ocular adverse events occurring in approximately 5-20% of patients in decreasing order of Detailed results are shown in Table 1 below: incidence were nasopharyngitis, arthralgia, sinusitis, dizziness, pyrexia, upper respiratory Table 1: Uveitis Recurrence Rates tract infection, influenza, vomiting, nausea, cough, back pain, limb pain, and rash. STUDY 1 STUDY 2 8 USE IN SPECIFIC POPULATIONS N=108 N=116 8.1 Pregnancy TIME POINT Pregnancy Category C Uveitis Recurrence Rates1,2 No adequate animal reproduction studies have been conducted with fluocinolone acetonide. N (%) Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Fluocinolone acetonide when administered 34 Weeks Pre-implantation 58 (53.7) 46 (39.7) subcutaneously at a dose of 0.13 mg/kg/day (approximately 10,000 times the daily clinical 34 Weeks Post-implantation 2 (1.8) 15 (12.9) dose of RETISERT), during days 6 to 18 of pregnancy in the rabbit, induced abortion at the end of the third and at the beginning of the fourth gestational week. When administered 1 Year Post-implantation 4 (3.7) 15 (12.9) subcutaneously to rats and rabbits during gestation at a maternal toxic dose of 50 μg/ 2 Years Post-implantation 11 (10.2) 16 (13.8) kg/day (approximately 4,000 times the clinical dose of RETISERT), fluocinolone acetonide 3 Years Post-implantation 22 (20.4) 20 (17.2) caused abortions and malformations in a few surviving fetuses. There are no adequate and well-controlled studies in pregnant women. RETISERT should be 3 Years3 Post-implantation 33 (30.6) 28 (24.1) used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 1 Recurrence of uveitis for all post-implantation time points was compared to the 34 weeks 8.3 Nursing Mothers pre-implantation time point. It is not known whether ocular administration of corticosteroids could result in sufficient 2 2 systemic absorption to produce detectable quantities in human milk. Systemic steroids p-value<0.01 from McNemar’s test. appear in human milk and could suppress growth, interfere with endogenous corticosteroid 3 Results presented include imputed recurrences. Recurrences were imputed when a subject production, or cause other untoward effects. Caution should be exercised when RETISERT is was not seen within 10 weeks of their final scheduled visit. implanted in a nursing woman. 16 HOW SUPPLIED/STORAGE AND HANDLING The implant consists of a tablet encased in a silicone elastomer cup containing a release 8.4 Pediatric Use orifice and a polyvinyl alcohol membrane positioned between the tablet and the orifice. The Safety and effectiveness in pediatric patients below the age of 12 years have not been silicone elastomer cup assembly is attached to a polyvinyl alcohol suture tab with silicone established. adhesive. Each RETISERT is approximately 3 mm x 2 mm x 5 mm. 8.5 Geriatric Use Each implant is stored in a clear polycarbonate case within a foil pouch within a Tyvek No overall differences in safety and effectiveness have been observed between elderly and peelable overwrap. Each packaged implant is provided in a carton which includes the younger patients. package insert. NDC 24208-416-01 11 DESCRIPTION RETISERT® (fluocinolone acetonide intravitreal implant) 0.59 mg is a sterile implant Storage: designed to release fluocinolone acetonide locally to the posterior segment of the eye Store in the original container at 15° - 25°C (59° - 77°F). Protect from freezing. at a nominal initial rate of 0.6 μg/day, decreasing over the first month to a steady state between 0.3-0.4 μg/day over approximately 30 months. The drug substance is the synthetic 17 PATIENT COUNSELING INFORMATION corticosteroid fluocinolone acetonide, represented by the following structural formula: Patients should be advised to have ophthalmologic follow-up examinations of both eyes at appropriate intervals following implantation of RETISERT. As with any surgical procedure, there is risk involved. Potential complications accompanying intraocular surgery to place RETISERT into the vitreous cavity may include, but are not limited to, the following: cataract formation, choroidal detachment, temporary decreased visual acuity, endophthalmitis, hypotony, increased intraocular pressure, exacerbation of intraocular inflammation, retinal detachment, vitreous hemorrhage, vitreous loss, and wound dehiscence. Following implantation of RETISERT, nearly all patients will experience an immediate and temporary decrease in visual acuity in the implanted eye which lasts for approximately one to four weeks post-operatively. C24H30F2O6 Mol. Wt. 452.50 Chemical Name: Pregna-1,4-diene-3,20-dione,6,9-difluoro-11,21-dihydroxy- Based on clinical trials with RETISERT, within 3 years post-implantation, approximately 77% 16,17-[(1-methyl-ethylidene)bis(oxy)]-,(6Į,11ȕ‚ 16Į)-. of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure. (see 6.1 Clinical Fluocinolone acetonide is a white crystalline powder, insoluble in water, and soluble in Trials Experience - Ocular Events section). methanol. It has a melting point of 265-266ºC. Based on clinical trials with RETISERT, during the 3-year post-implantation period, nearly all Each RETISERT consists of a tablet containing 0.59 mg of the active ingredient, Fluocinolone phakic eyes are expected to develop cataracts and require cataract surgery. Acetonide, USP, and the following inactives: microcrystalline cellulose, polyvinyl alcohol, and magnesium stearate. Marketed by: Bausch & Lomb Incorporated 12 CLINICAL PHARMACOLOGY Rochester, NY 14609 12.1 Mechanism Of Action Manufactured by: Corticosteroids inhibit the inflammatory response to a variety of inciting agents and Bausch & Lomb Incorporated probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, Waterford, Ireland leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. U.S. Patent # 6,217,895 There is no generally accepted explanation for the mechanism of action of ocular U.S. Patent # 6,548,078 corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A inhibitory proteins, collectively called lipocortins. It is postulated that ™/® denote trademarks of Bausch & Lomb Incorporated. 2 © Bausch & Lomb Incorporated these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor Based on full prescribing information revised March 2009. 9164000 16 Special Report ) RETINA ADVANCES CONTINUE TO PROGRESS FOR THE TREATMENT AND MANAGEMENT OF RETINAL DISEASE
DEFINING THE ‘IDEAL’ DME TREATMENT POINT Superior effi cacy, safety profi les support anti-VEGF therapy By Cheryl Guttman Krader; Reviewed by Julia A. Haller, MD
PHILADELPHIA :: olid scientific rationale exists for other modalities never measure up to the levels achieved in those treated with anti-VEGF injections,” Dr. Haller said. anti-vascular endothelial growth “In the DRCR network trial, the anti-VEGF treated eyes factor (VEGF) treatment of dia- also won out in analyses of worsening of diabetic reti- S nopathy, and in the DA VINCI trials, eyes treated with af- betic macular edema (DME). libercept (Eylea, Regeneron) benefited with more thinning Results of clinical trials show it has efficacy and safety than those treated with focal laser,” she said. advantages compared with other modalities. Safety data from the controlled trials also show the few- “We know that VEGF is a primary pathological driver of est side effects occurred in eyes in the anti-VEGF treat- DME, and blocking VEGF activity effectively treats DME ment groups, and in the available DME treatment trials and limits the progression of diabetic for ranibizumab and aflibercept, there were no significant retinopathy as well,” said Julia A. Haller, differences in serious adverse event rates MD, ophthalmologist-in-chief, Wills Eye comparing the anti-VEGF and sham groups. Hospital, and professor and chairwoman, “Laser treatment leaves burns that re- PRO Department of Ophthalmology, Jeffer- sult in permanent scotomata, which can son Medical College of Thomas Jefferson spread,” Dr. Haller said. “This effect may anti-VEGF therapy Medical College, Philadelphia. partly explain why eyes treated with laser Dr. Haller “In addition, anti-VEGF therapy has only have the worse visual acuity out- Fewer sight-limiting side fewer side effects than the other avail- comes across the controlled DME studies. effects than other available able treatments for DME, which are laser photocoagula- With steroids, there are risks of glaucoma treatments for DME tion and steroids,” she said. and cataract.” She cited results from the DRCR.net proto- Superior visual acuity WHY ANTI-VEGF? col I study showing that overall 50% of eyes outcomes Discussing the scientific rationale for anti-VEGF treatment treated with triamcinolone experienced IOP of DME, Dr. Haller explained that an alternative name for increase of at least 10 mm Hg from baseline, IOP ≥30 mm VEGF when first described was vascular permeability fac- Hg, and/or required initiation of an IOP-lowering medica- tor because it caused edema. Results of preclinical studies, tion. In parallel treatment arms that did not receive corti- including experiments performed in a guinea pig cheek costeroid treatment, only 7% to 11% of eyes experienced model and in the monkey eye, showed injection of VEGF one or more of the IOP-related adverse events. stimulated vascular leakage. Studies in which vitreous fluid In an interview after the debate, Dr. Haller emphasized was sampled from patients with DME showed increased that her remarks have to be taken in the context of the VEGF immunoreactivity in retinal vessels. format of the program. Briefly reviewing some anti-VEGF clinical treatment “Although in fact anti-VEGFs have become the first line trials, Dr. Haller observed that studies investigating dif- for DME treatment in many cases, laser and steroids do ferent anti-VEGF agents consistently show that intravit- have a role as well, and are key weapons in the armamen- real anti-VEGF injection is an effective treatment for DME tarium used to combat DME,” she said. Q and provides superior anatomic and functional outcomes than the active comparators. “Whether in the DRCR network protocol I trial compar- JULIA A. HALLER, MD ing ranibizumab (Lucentis, Genentech) with deferred or E: [email protected] prompt laser against triamcinolone or laser, or the READ 2 Dr. Haller has been a consultant in the past for Allergan, Genentech, and Regeneron. This article was study comparing ranibizumab alone, laser, or ranibizumab adapted from Dr. Haller’s presentation during Retina 2012 at the annual meeting of the American Academy plus laser, mean reductions in central subfield thicken- of Ophthalmology, where, in an Oxford-style debate, she provided her perspective on whether anti-vascular ing and final visual acuities achieved in eyes treated with endothelial growth factor therapy is the ideal treatment for diabetic macular edema. MARCH 1, 2013 :: Ophthalmology Times 17 Special Report ) RETINA
DEFINING THE ‘IDEAL’ DME TREATMENT COUNTERPOINT Therapy carries cost burden for ongoing monthly injections By Cheryl Guttman Krader; Reviewed by Baruch D. Kuppermann, MD, PhD
IRVINE, CA :: espite the emergence of anti-vas- net study, less than 30% of patients were three-line gainers at the end of year 2.” cular endothelial growth factor Three years of follow-up in RISE and RIDE also indicate that (VEGF) agents as treatment for reduced efficacy in patients with chronic DME is another limita- D tion of anti-VEGF therapy. Patients originally assigned to sham diabetic macular edema (DME), treatment in RISE and RIDE were crossed over to ranibizumab corticosteroid and/or laser treatment is preferred after 2 years years, but had only a meager response, he said. “In contrast, in the study of the fluocino- for many patients. lone acetonide intravitreal insert (Iluvien, “Injection of an anti-VEGF agent is certainly effective for treat- Alimera Sciences), patients with chronic CON ing DME in many patients, but not in all, and efficacy depends DME were the most responsive, with 34% anti-VEGF therapy on the treatment protocol and frequency of re- achieving a three-line improvement,” he said. peat injections,” said Ba r uch D. Kuppermann, Concerns about systemic safety of anti- MD, PhD, professor of ophthalmology and bio- VEGF treatment are heightened in the vas- Reduced efficacy in medical engineering, and chief, Retina Ser- culopathic DME population. In the phase III patients with chronic DME vice, Gavin Herbert Eye Institute, University RISE and RIDE trials that compared rani- Effective alternatives of California, Irvine. bizumab 0.3 and 0.5 mg, the higher dose may be preferred in specific “Additionally, I have concerns about the treat- was associated with more deaths without patients Dr. Kuppermann ment costs, burden, and systemic safety that providing any efficacy advantage compared I think are shared by many others,” he said. with the lower dose. Therefore, ranibizumab “While corticosteroids are not without side effects, they are a was approved for treatment of DME using the 0.3-mg dose. great option for [patients with] pseudophakia and better than “However, patients with bilateral disease will be getting higher anti-VEGF treatment for eyes with chronic DME. Furthermore, doses, and there is concern that these severe systemic side effects we should not forget about laser for focal DME, where it can pro- might be even greater with bevacizumab due to its longer sys- vide very good results for low cost and low treatment burden.” temic half life and the reduction in systemic VEGF levels noted with bevacizumab but not ranibizumab in the IVAN trial for wet AT WHAT COST? AMD,” Dr. Kuppermann said. Reviewing the evidence, Dr. Kuppermann noted that anti-VEGF Discussing alternatives, Dr. Kuppermann noted that in the treatment for DME carries a “huge” treatment and cost burden, DRCR protocol I study enrolling pseudophakic patients, efficacy considering that maximizing the visual acuity improvement outcomes were similar at 1 year in the group that received in- requires ongoing monthly injections. Whereas in the pivotal jections of triamcinolone every 4 months as needed compared trials for exudative age-related macular degeneration, patients with eyes receiving ranibizumab as often as monthly. Visual treated with an anti-VEGF agent achieved rapid vision gains acuity results were also similar in the second year when in- that peaked after 3 monthly injections, in the phase III ranibiz- jections for both agents were only given as needed, but more umab DME trials, visual acuity continued to improve over 2 injections were given in the ranibizumab group. Q years with ongoing monthly anti-VEGF injections. In addition, it appears that a p.r.n. treatment approach may not be that effective for DME. BARUCH D. KUPPERMANN, MD, PHD “Results from ranibizumab clinical trials show you have to E: [email protected] be aggressive when treating DME to achieve good results,” Dr. Dr. Kuppermann is a consultant and clinical investigator with Alimera, Allergan, Genentech, and Regeneron, manufac- Kuppermann said. “With ongoing monthly injections in RISE turers of intravitreal anti-vascular endothelial growth factor therapies (VEGF) and steroid therapies, either approved and RIDE, about 40% of [patients with] DME treated with rani- for diabetic macular edema (DME) or being investigated for DME. This article was adapted from Dr. Kuppermann’s bizumab 0.3 mg gained 3 or more lines of best-corrected visual presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology, where, in an acuity at 24 months. However, using a p.r.n. approach in a DRCR. Oxford-style debate, he provided his perspective on whether anti-VEGF therapy is the ideal treatment for DME. 18 MARCH 1, 2013 :: Ophthalmology Times Special Report ) RETINA
Prognosis for a quicker diagnosis Nonmydriatic ultra-wide-field imaging shows promise for evaluating diabetic retinopathy By Cheryl Guttman Krader; Reviewed by Paolo S. Silva, MD
BOSTON :: ADVANCES IN IMAGING technology mean patients may benefit from faster image acquisition and disease evaluation. Nonmydriatic ultra-wide-field imaging (Optos P200MA, Optos) compares favorably with di- lated ETDRS protocol fundus photography and dilated fundus examination in determining the severity of both diabetic retinopathy (DR) and diabetic macular edema (DME), according to the results of a clinical validation study per- formed by researchers at the Beetham Eye In- stitute, Joslin Diabetes Center, Harvard Medi- cal School, Boston. (FIGURE 2) LEFT: A 30° retinal image centered on the macula. RIGHT: A 200° ultra-wide-field retinal image. The ultra-wide-field retinal imaging sys- The green circle represents the approximate area covered by a 30° retinal image. The system combines tem combines scanning laser (green 532-nm scanning laser ophthalmoscope technology with a large ellipsoidal mirror. (Images courtesy of Paolo S. Silva, MD) and red 633-nm) ophthal- moscope technology with abetic populations, nonmydriatic ultra-wide- eyes were graded as having mild or moderate a large ellipsoidal mirror field imaging may prove to be beneficial in nonproliferative DR (54%). The majority of eyes to image up to 200° (82%) research and clinical settings,” Dr. Silva said. had no DME (57%), and nearly one-fourth were of the retina in a single, “To determine whether additional prognostic determined to have clinically significant DME. 0.25-second scan. A high- information can be obtained from peripheral Results from grading of the ultra-wide-field resolution mode (ResMax, retinal lesions, ultra-wide-field images of dia- 100° images showed exact agreement with the Dr. Silva Optos) scans a 100° area of betic and non-posterior pole will need to be ETDRS, photography-based interpretations in the retina (25%), but offers evaluated carefully over time in a defined pop- 84% of eyes and there was a difference of just increased image resolution (11 μm). ulation. These peripheral findings may or may 1 severity level in another 7%. When com- “Compared with ETDRS 30° color fundus not provide additional prognostic information pared with clinical examination, the readings photography, the new imaging technology has for DR progression.” from the nonmydriatic ultra-wide-field images several advantages as it avoids the need for were an exact match in 70% of eyes and were pupil dilation, offers a wider imaging field, has VALIDATION STUDY within 1 level in 93%. faster acquisition time, and may penetrate bet- The validation study enrolled 103 patients with The ultra-wide-field images had 99% sensitiv- ter through media opacity and smaller pupils,” type 1 or 2 diabetes who were attending a regu- ity for detecting and identifying DR on ETDRS said Paolo S. Silva, MD, lead author of a pub- larly scheduled clinic appointment. At a single photographs and 100% specificity. Sensitivity lished paper on the study [Am J Ophthalmol. visit, each patient underwent imaging of both and specificity for detecting and identifying PDR 2012;154:549-559] and assistant chief, Center eyes, using the nonmydriatic ultra-wide-field on ETDRS photographs using the ultra-wide- for Ocular Telehealth, Beetham Eye Institute. technology (100° and 200° fields), as well as field imaging were 100% and 92%, respectively. “If our findings on its use for evaluating DR dilated ETDRS photography and dilated fun- The researchers also noted that acquisi- are confirmed in larger studies in broader di- dus examination. The nonmydriatic imaging tion of the nonmydriatic ultra-wide-field im- was performed first by a certified imager; the ages took less than half the time needed for ETDRS photographs were acquired by an ETDRS- ETDRS photography, even excluding the time certified photographer; and the dilated fundus for pupil dilation. examination was performed by a retina specialist. Although the ultra-wide-field imaging cap- All of the images acquired were graded in tures peripheral lesions, their implications on masked fashion for DR and DME severity by DR severity are unknown at this time. two independent readers. Any discrepancies “Current knowledge of DR progression rates, between the two readers were adjudicated by along with recommendations for DR manage- a third retina specialist. ment, is based on lesions located within the 7 ETDRS photography was completed for 200 standard 30° fields following the ETDRS imaging eyes and the readings showed the group rep- protocol,” he said. “It is uncertain how peripheral resented the full spectrum of DR from none lesions would [affect] these recommendations.” (FIGURE 1) Optomap image showing diabetic retinopathy. (Photo courtesy of Optos) (12.5%) to proliferative (2.5%); the majority of Continues on page 20 : Imaging Advertisement not available for this issue of the digital edition
OphthalmologyTimes.com 20 MARCH 1, 2013 :: Ophthalmology Times Special Report ) RETINA
Combination therapy a boon for AMD Phase IIb neovascular AMD study shows robust benefit for anti-PDGF/anti-VEGF therapy By Cheryl Guttman Krader; Reviewed by Pravin U. Dugel, MD
PHOENIX :: PATIENTS WITH WET age-related maturation. These pericytes form a protective fied by neovascular membrane size or baseline macular degeneration (AMD) may benefit from armor around the neovascular complex, but are vision, the combination arms were always su- treatment that combines anti-platelet-derived stripped away with the addition of perior to ran i biz u mab monotherapy. growth factor (PDGF)/anti-vascular endothe- an anti-PDGF agent, thereby render- Combination treatment was also lial growth factor (VEGF) therapy. ing the neovascular complex more Study superior to control in an analysis of Results from a large phase IIb randomized vulnerable to anti-VEGF therapy. the disappearance of subretinal hy- clinical trial show combination therapy with The E10030 phase IIb trial of anti- power perreflective material as seen on op- E10030 (Fovista, Ophthotech), an investiga- PDGF combination therapy randomly pointS tical coherence tomography (OCT), tional 50-kD DNA aptamer directed against assigned 449 treatment-naive patients and a comparison of the two com- PDGF-B (subunit B), plus ran i biz umab (Lu- equally into three treatment arms > Designed as bination groups showed a clear and centis, Genentech), is superior to rani bizu mab to receive rani biz umab plus E10030 superiority study predictable dose-related effect. monotherapy for treating neovascular AMD. 0.3 mg, ran i biz umab plus E10030 1.5 “We were especially interested in > “There is no doubt that anti-VEGF monother- mg, or ran ibiz u mab monotherapy. Largest phase II this parameter that was felt to rep- apy treatment is effective for neovascular AMD, “There are two important things superiority study resent the entire lesion and lesion but there is equally no doubt that chronic anti- to note about the study,” Dr. Dugel in retina components,” Dr. Dugel said. VEGF monotherapy treatment induces resistance, said. “It was designed as a superi- When the relationship of OCT and that is why we have to ority study, and it was the largest phase II su- thickness and vision was studied, regardless treat perhaps indefinitely,” said periority study ever done in retina.” of the initial lesion thickness, the combination Pravin U. Dugel, MD, study Both the 0.3-mg and 1.5-mg E10030 combi- arms always proved superior. When fluorescein investigator and managing nation groups met their pre-specified primary angiograms were studied, there was a consis- partner, Retinal Consultants endpoint by achieving superior mean visual acu- tent and predictable relationship between le- of Arizona, Phoenix. ity improvement from baseline to week 24 com- sion regression and vision improvement. “It makes good physiologic pared with rani biz u mab monotherapy. The vision The safety data showed no differences in the Dr. Dugel sense to combine anti-PDGF and improvement at week 24 was 10.6 letters in the rate or type of ocular adverse events or seri- anti-VEGF agents, and this is 1.5-mg E10030 combination group, 8.8 letters in ous systemic adverse events among the three well-supported in the oncology literature,” he said. the 0.3-mg E10030 combination group, and 6.5 study arms, and mean IOP was not signifi- “If the results of the Fovista phase IIb neovascular letters in the rani biz u mab monotherapy group. cantly different even though patients received AMD study are confirmed in a larger pivotal phase “The data for visual acuity improvement two injections in the combination groups. Q III trial, the combined approach has the potential also showed a classic dose response and con- to change dramatically and profoundly our treat- tinued divergence of the efficacy curves over ment model for patients with neovascular AMD.” time,” Dr. Dugel said. PRAVIN U. DUGEL, MD The rationale for the anti-PDGF combination Pre-specified subgroup analyses were per- E: [email protected] is based on evidence that anti-VEGF monother- formed to determine whether any particular pa- Dr. Dugel is a consultant to and minor shareholder in Ophthotech. This article was apy treatment induces PDGF upregulation, peri- tient subgroup(s) drove the superior results for adapted from Dr. Dugel’s presentation at Retina 2012 during the annual meeting of cyte recruitment, and neovascular membrane the combination treatment. With patients strati- the American Academy of Ophthalmology.
motion, and reflections. In addition, the com- “With the 200° image there is good resolu- IMAGING posite color image is based on red and green tion along a central horizontal band that en- wavelengths only. Due to the curvature of the compasses the disc and macula and extends ( Continued from page 18 ) globe and the mirror, in 200° images there is to the temporal and nasal periphery,” Dr. Silva some loss of resolution beyond the superior concluded. Q The imaging technology has some limita- and inferior vascular arcades. Due to the large tions, Dr. Silva noted. The cost is substantially contiguous area of retina that is acquired in higher compared with traditional methods of a single image, it is necessary to zoom in to PAOLO S. SILVA, MD retinal imaging, and there is the potential for sufficient magnification in order to obtain an E: [email protected] imaging artifacts not seen in traditional fun- adequate view necessary to appreciate subtle Dr. Silva discloses no relevant financial interests. Grant funding was provided to the dus photography due to the mirror, lashes, retinal lesions. Joslin Diabetes Center for performance of the study. MARCH 1, 2013 :: Ophthalmology Times 21 Special Report ) RETINA
INTREPID identifies ‘best responders’ Fewer anti-VEGF injections among benefits of stereotactic radiotherapy for wet AMD By Cheryl Guttman Krader; Reviewed by Timothy L. Jackson, PhD, FRCOphth
LONDON :: PATIENTS UNDERGOING stereotactic deemed to require further anti-VEGF therapy, radiotherapy for wet age-related macular de- and had a lesion measuring 6 mm or less. generation (AMD) may experience a reduced A total of 230 patients were randomly assigned Utilizing the need for anti-vascular endothelial growth fac- to three groups to receive radiotherapy with a radiotherapy system tor (VEGF) injections, along 16-Gy dose, 24-Gy dose, or sham exposure. The with visual acuity benefits. radiotherapy was administered as a one-time Findings from post-hoc treatment and patients were seen monthly there- > LOW-ENERGY X-RAY TUBE. Although analyses of data collected after. Need for further anti-VEGF injection (rani- similar to a portable chest X-ray machine, the tube through 12 months in the bizumab; Lucentis, Genentech) was assessed based utilized by the IRay produces a highly collimated, INTREPID trial indicate eyes on predefined re-treatment criteria. narrow beam. It is designed to affect only the with lesions that are actively For the responder analysis, eyes with ac- target area or lesion, with minimal scatter onto Dr. Jackson leaking, fully within the ra- tively leaking lesions were defined as those surrounding healthy tissue. diotherapy treatment zone, with macular volume >7.4 mm2, the macular > and without significant fibrosis achieve the volume which represented the median volume SELF-CONTAINED AUTOMATED greatest benefit. The randomized, for the study population. Within BEAM POSITIONING SYSTEM. The sham-controlled, double-masked this particular subgroup, patients positioning mechanism ensures the precise trial is investigating stereotactic who received stereotactic radio- entry of energy into the eye, avoiding critical radiotherapy using a proprietary take-home therapy had a 45% reduction in the structures, such as the lens and optic nerve. device (IRay, Oraya) in patients The INTREPID trial number of anti-VEGF injections re- > ORAYA THERAPY SOFTWARE. receiving anti-VEGF injections for results showed a ceived during the first 12 months of Specialized software includes treatment planning, exudative AMD. significant benefit INTREPID along with a 5-letter greater treatment monitoring and control, and treatment “These ‘best responders’ rep- of stereotactic gain in best-corrected visual acuity verification. The treatment-planning model uses resent about 25% to 50% of the radiotherapy (BCVA) compared with the sham- axial length of the eye, obtained via immersion enrolled population, depending for reducing the need treated controls. ultrasonography or optical biometry, to calculate on the number of defining crite- for further anti-vascular As a reference in the overall the exact required beam positioning. ria used,” explained Timothy L. endothelial growth study population, stereotactic ra- > I-GUIDE EYE STABILIZATION Jackson, PhD, FRCOphth, consul- factor injections diotherapy significantly reduced DEVICE. This component has been designed tant ophthalmic surgeon, King’s in eyes with active wet the number of anti-VEGF injec- to stabilize and align the eye. It includes a College Hospital, London. “Over- age-related macular tions needed, but by only 32%, sterile, disposable contact lens that uses a all, the data indicate that they can degeneration. and was associated with a 1.6 let- expect to need about 50% fewer ter BCVA benefit, which was not small amount of vacuum to hold the eye in the anti-VEGF injections over the course of a year statistically significant. appropriate treatment orientation. The I-Guide also contains optical reflectors that work with following the radiotherapy and achieve sig- Eyes with both macular volume >7.4 mm2 nificantly better visual acuity improvements and lesion diameter <4 mm represented about the beam positioning system to enable precise than their counterparts receiving anti-VEGF one-fourth of the study population. Within localization and tracking of the eye. monotherapy. this subgroup, the radiotherapy-treated eyes > EYE-TRACKING SYSTEM. The IRay “However, these subset analyses need to be required 54% fewer anti-VEGF injections than system has been designed to monitor movement interpreted with caution and, of course, fur- the sham-treated controls and had close to a of the patient’s eye continuously and enable ther follow-up is needed,” he added. 7-letter greater gain in visual acuity. immediate shut-down of treatment in the event The stereotactic radiotherapy is delivered Among eyes with lesions that were both ac- of excessive eye motion. (Source: Oraya) using a slit lamp-type system. It delivers three tively leaking and that was within the treat- X-ray beams that pass through the inferior sclera ment zone, only 20% of those receiving radio- and overlap at the macula, coalescing over a therapy compared with 70% of controls re- 4-mm zone. ceived four or more anti-VEGF injections over the course of 12 months; while 100% of con- TIMOTHY L. JACKSON, PHD, FRCOPHTH PATIENT ENROLLMENT trol eyes received at least one additional anti- E: [email protected] Patients were eligible to be enrolled in INTREPID VEGF injection after the mandatory baseline Dr. Jackson receives lecture fees and grant support from Oraya. The proprietary if they had exudative AMD diagnosed within treatment, only 33% of the eyes in the radia- stereotactic radiotherapy device is CE marked and investigational in the United the past 3 years, had received at least three tion arm required anti-VEGF re-treatment, Dr. States. This article was adapted from Dr. Jackson’s presentation at Retina 2012 anti-VEGF injections in the prior year, were Jackson noted. Q during the annual meeting of the American Academy of Ophthalmology. BECAUSE THERE ARE NO TIME-OUTS IN MACULAR EDEMA DUE TO RVO*
*Branch or central retinal vein occlusion.
Indication and Usage Retinal Vein Occlusion: OZURDEX® (dexamethasone Patients should be instructed to report any symptoms intravitreal implant) is a corticosteroid indicated for the suggestive of endophthalmitis without delay. treatment of macular edema following branch retinal vein IMPORTANT SAFETY INFORMATION occlusion (BRVO) or central retinal vein occlusion (CRVO). Contraindications Dosage and Administration Ocular or Periocular Infections: OZURDEX® FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY. (dexamethasone intravitreal implant) is contraindicated The intravitreal injection procedure should be carried in patients with active or suspected ocular or periocular out under controlled aseptic conditions. Following the infections including most viral diseases of the cornea intravitreal injection, patients should be monitored for and conjunctiva, including active epithelial herpes elevation in intraocular pressure and for endophthalmitis. simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It may be time for OZURDEX ® (dexamethasone intravitreal implant) 0.7 mg Every case of retinal vein occlusion (RVO) is different Every patient responds differently to therapy Every office visit is an opportunity to assess macular edema due to RVO and treat appropriate patients with OZURDEX®
IMPORTANT SAFETY INFORMATION (continued) Corticosteroids should be used cautiously in patients Contraindications (continued) with a history of ocular herpes simplex. Advanced Glaucoma: OZURDEX® (dexamethasone Risk of Implant Migration: Patients in whom the intravitreal implant) is contraindicated in patients with posterior capsule of the lens is absent or has a tear are advanced glaucoma. at risk of implant migration into the anterior chamber. Aphakic Eyes with Rupture of the Posterior Lens Adverse Reactions Capsule: OZURDEX® is contraindicated in patients The most common ocular adverse reactions who have aphakic eyes with rupture of the posterior reported by greater than 2% of patients in the first lens capsule. 6 months following injection of OZURDEX® for retinal ACIOL and Rupture of the Posterior Lens Capsule: vein occlusion and posterior segment uveitis include: OZURDEX® is contraindicated in eyes with ACIOL intraocular pressure increased (25%), conjunctival (Anterior Chamber Intraocular Lens) and rupture of the hemorrhage (22%), eye pain (8%), conjunctival hyperemia posterior lens capsule. (7%), ocular hypertension (5%), cataract (5%), vitreous detachment (2%), and headache (4%). Hypersensitivity: OZURDEX® is contraindicated ® in patients with known hypersensitivity to any Increased IOP with OZURDEX peaked at approximately components of this product. week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX® required Warnings and Precautions surgical procedures for management of elevated IOP. Intravitreal Injection-related Effects: Intravitreal injections have been associated with endophthalmitis, eye Please see Brief Summary of full Prescribing inflammation, increased intraocular pressure, and retinal Information on adjacent page. detachments. Patients should be monitored regularly following the injection. Potential Steroid-related Effects: Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.
©2013 Allergan, Inc., Irvine, CA 92612 ® marks owned by Allergan, Inc. www.Ozurdex.com APC07BY12 122961 Keep the Opportunity in Sight ® Adverse Reactions Reported by Greater than 2% of Patients in the OZURDEX First Six Months (continued) ( dexamethasone intravitreal implant) 0.7 mg MedDRA Term OZURDEX® Sham Brief Summary—Please see the OZURDEX® package insert for full N=497 (%) N=498 (%) Prescribing Information. Cataract 24 (5%) 10 (2%) INDICATIONS AND USAGE Vitreous detachment 12 (2%) 8 (2%) Retinal Vein Occlusion: OZURDEX® (dexamethasone intravitreal Headache 19 (4%) 12 (2%) implant) is a corticosteroid indicated for the treatment of macular edema Increased IOP with OZURDEX® (dexamethasone intravitreal implant) following branch retinal vein occlusion (BRVO) or central retinal vein peaked at approximately week 8. During the initial treatment period, occlusion (CRVO). ® ® 1% (3/421) of the patients who received OZURDEX required surgical Posterior Segment Uveitis: OZURDEX is indicated for the treatment procedures for management of elevated IOP. of non-infectious uveitis affecting the posterior segment of the eye. Following a second injection of OZURDEX® in cases where a second CONTRAINDICATIONS ® injection was indicated, the overall incidence of cataracts was higher Ocular or Periocular Infections: OZURDEX (dexamethasone intravitreal after 1 year. implant) is contraindicated in patients with active or suspected ocular USE IN SPECIFIC POPULATIONS or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic Pregnancy keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Teratogenic Effects: Pregnancy Category C: Topical dexamethasone ® has been shown to be teratogenic in mice producing fetal resorptions Advanced Glaucoma: OZURDEX is contraindicated in patients with and cleft palate. In the rabbit, dexamethasone produced fetal advanced glaucoma. ® resorptions and multiple abnormalities involving the head, ears, limbs, Aphakic Eyes with Rupture of the Posterior Lens Capsule: OZURDEX palate, etc. Pregnant rhesus monkeys treated with dexamethasone is contraindicated in patients who have aphakic eyes with rupture of sodium phosphate intramuscularly at 1 mg/kg/day every other day the posterior lens capsule. ® for 28 days or at 10 mg/kg/day once or every other day at 3 or 5 days ACIOL and Rupture of the Posterior Lens Capsule: OZURDEX is between gestation days 23 and 49 had fetuses with minor cranial contraindicated in eyes with ACIOL (Anterior Chamber Intraocular abnormalities. A 1 mg/kg/dose in pregnant rhesus monkeys would be Lens) and rupture of the posterior lens capsule. approximately 85 times higher than an OZURDEX® injection in humans Hypersensitivity: OZURDEX® is contraindicated in patients with (assuming 60 kg body weight). known hypersensitivity to any components of this product. There are no adequate and well-controlled studies in pregnant women. WARNINGS AND PRECAUTIONS OZURDEX® (dexamethasone intravitreal implant) should be used Intravitreal Injection-related Effects: Intravitreal injections have during pregnancy only if the potential benefit justifies the potential been associated with endophthalmitis, eye inflammation, increased risk to the fetus. intraocular pressure, and retinal detachments. Nursing Mothers: It is not known whether ocular administration Patients should be monitored regularly following the injection [see of corticosteroids could result in sufficient systemic absorption Patient Counseling Information]. to produce detectable quantities in human milk. Systemically Potential Steroid-related Effects: Use of corticosteroids may produce administered corticosteroids appear in human milk and could suppress posterior subcapsular cataracts, increased intraocular pressure, growth, interfere with endogenous corticosteroid production, or glaucoma, and may enhance the establishment of secondary ocular cause other untoward effects. Caution should be exercised when infections due to bacteria, fungi, or viruses. corticosteroids are administered to a nursing woman. Corticosteroids should be used cautiously in patients with a history Pediatric Use: Safety and effectiveness of OZURDEX® in pediatric of ocular herpes simplex. patients have not been established. Risk of Implant Migration: Patients in whom the posterior capsule Geriatric Use: No overall differences in safety or effectiveness have of the lens is absent or has a tear are at risk of implant migration into been observed between elderly and younger patients. the anterior chamber. NONCLINICAL TOXICOLOGY ADVERSE REACTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility Clinical Studies Experience: Because clinical studies are conducted No adequate studies in animals have been conducted to determine under widely varying conditions, adverse reaction rates observed in whether OZURDEX® (dexamethasone intravitreal implant) has the the clinical studies of a drug cannot be directly compared to rates potential for carcinogenesis. in the clinical studies of another drug and may not reflect the rates Although no adequate studies have been conducted to determine the observed in practice. mutagenic potential of OZURDEX®, dexamethasone has been shown Adverse reactions associated with ophthalmic steroids include to have no mutagenic effects in bacterial and mammalian cells in vitro elevated intraocular pressure, which may be associated with optic or in the in vivo mouse micronucleus test. nerve damage, visual acuity and field defects, posterior subcapsular PATIENT COUNSELING INFORMATION cataract formation, secondary ocular infection from pathogens In the days following intravitreal injection of OZURDEX®, patients including herpes simplex, and perforation of the globe where there is are at risk for potential complications including in particular, but not thinning of the cornea or sclera. limited to, the development of endophthalmitis or elevated intraocular The following information is based on the combined clinical trial pressure. If the eye becomes red, sensitive to light, painful, or develops results from 3 initial, randomized, 6-month, sham-controlled studies a change in vision, the patient should seek immediate care from an (2 for retinal vein occlusion and 1 for posterior segment uveitis): ophthalmologist. Adverse Reactions Reported by Greater than 2% of Patients in the Patients may experience temporary visual blurring after receiving an First Six Months intravitreal injection. They should not drive or use machines until this MedDRA Term OZURDEX® Sham has resolved. N=497 (%) N=498 (%) ©2012 Allergan, Inc., Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc. Patented. See: www.allergan.com/products/patent_notices Intraocular pressure increased 125 (25%) 10 (2%) Made in Ireland Based on 72212US14 Conjunctival hemorrhage 108 (22%) 79 (16%) APC52EA12 Eye pain 40 (8%) 26 (5%) Conjunctival hyperemia 33 (7%) 27 (5%) Ocular hypertension 23 (5%) 3 (1%) MARCH 1, 2013 :: Ophthalmology Times 25 Special Report ) RETINA Paradigm shift for treating DME Ophthalmologist explains his use of pattern laser treatment in conjunction with anti-VEGF By Pravin U. Dugel, MD; Special to Ophthalmology Times
DIABETIC RETINOPATHY (DR) and In addition to better interpretation of ex- delivery, resulting in minimal collateral dam- diabetic macular edema (DME) are the most isting studies of laser photocoagulation, the age while still maintaining clinical efficacy. common causes of blindness among the work- treatment itself is also changing. It was pre- DME can be divided into three different cat- ing-age populations of the developed world. viously thought that laser photocoagulation egories, among which there is significant over- Yet, treatment for these patients represents a provided its therapeutic benefit, via the de- lap. The first categor y is tr ue focal DME, with a large unmet need. struction of microaneurysms. Large and intense very precise location of the leak which is away The Early Treatment Diabetic Ret- laser burns were applied that not from the fovea. The second category is diffuse inopathy Study (EDTRS) set focal/ only caused destruction initially, DME, in which there is widespread leakage, grid laser photocoagulation as the but also tended to expand over even under the fovea. The third category is standard of care for treatment more take-home time, impacting the surround- ischemic DME, characterized by swelling due than two decades ago,1 but the under- ing tissues. to insufficient blood flow. A new technology standing of laser therapy is evolving However, recent studies have (Endpoint Management, and treatment modalities changing. suggested that laser treatment CATEGORIZING PATIENTS Topcon Medical Concurrently, there has been a large can best be used as a stimula- The vast majority of patients can be catego- Laser Systems), when focus on therapy with anti-vascular tor of retinal pigment epithelial rized into the second or third groups, and I combined with Topcon’s endothelial growth factor (VEGF), (RPE) cells, creating a cascade treat with a combination of laser therapy and PASCAL scanning laser, and study results suggest the ben- of events which release chemi- anti-VEGF injections. Anti-VEGF works imme- allows physicians very efits of combined therapy.2 cal factors that then allow the diately and continues to help as long as it is precise management of Numerous studies have shown edema in patients with DME to be administered. However, when treatment stops, two important elements positive results with anti-VEGF in- resolved.3 Consequently, therapy edema recurs, and maintaining frequent in- of laser treatment: jections. In the drcr.net study, pa- is evolving to be less destructive jections is often not sustainable. Laser photo- duration and power, tients were treated every 4 weeks and more precise by manipulat- stimulation is the perfect complement to anti- relates one until week 16, at which point 25% ing the duration and power of the VEGF treatment because it does not provide ophthalmologist. met the criteria not to receive an laser energy applied. an immediate improvement, but rather has a injection. Of those 25% that could Micropulse and subthreshold slow, steady and sustainable positive effect. skip a treatment, 90% had recurrences that laser therapies have been developed that allow For patients who fall into the first category, required future treatment. physicians to provide less destructive treatment, I would treat using only laser therapy. How- Overall, the first time that a patient met the and studies have shown that these modalities ever, focal DME with a distinct round circle of criteria not to be examined every 4 weeks was are at least as effective as the modified EDTRS exudate or a particular microaneurysm tends at week 64. Thus, the requirement is to see pa- recommendations for focal/grid laser photoco- to occur early in the disease state and is seen tients with DME every 4 weeks for more than agulation.4,5 We are on the tip of an evolution only in a minority of patients. a year, which is not sustainable or realistic. that will change the vocabulary from destruc- Laser photostimulation using the software Many patients are young, have jobs and busy tive photocoagulation to photostimulation of technology is much like photocoagulation in lives, and may not be able to be compliant. If RPE cells. that the physician programs a certain percent- patients are not seen every 4 weeks, that may age of treatment effect so that a burn on the compromise the study results. DURATION AND POWER retinal pigment epithelium can barely be visu- In spite of having been the standard of care for One treatment option is a new technology (End- alized. Once that benchmark it set, the treat- decades, there are several misconceptions that point Management, Topcon Medical Laser Sys- ment effect is titrated down by selecting the have marred the reputation of laser treatment. tems) that, when combined with Topcon’s PAS- percentage level of the energy to be delivered. Initial studies showed that laser photocoagula- CAL scanning laser, allows physicians very pre- I currently use the 50% level in my patients tion stabilized patients but did not necessarily cise management of two important elements of and studies. Once I choose my percentage level, improve vision (Original DRS Study in 1980s). laser treatment: duration and power. The soft- the software automatically adjusts both power However, closer analysis of these results show ware uses advanced mathematical algorithms and duration to achieve this energy level. that many patients actually started with suffi- to guide laser output in controlled, repeatable Another capability of Endpoint Management ciently good vision, so that gaining 3 lines of doses as a percentage of the initial settings is the “landmark” patterns, where the edges visual improvement was not possible. Among determined by the physician during titration. of a pattern can be selected to remain barely those patients that did have potential for greater The technology allows user flexibility in a visible and provide reference points, while the than 3 lines of improvement, more than 40% range the desired endpoints from 95% of the remainder of the pattern itself cannot be seen. achieved this. The results for laser treatment titrated lesion down to subvisible treatment lev- These patterns are useful to identify the treated were actually very good, but this finding was els less than 50%. This control capability can zones and prevent overlapping. misunderstood because of the study design. allow RPE cells to get precise, focused-energy Continues on page 26 : DME 26 MARCH 1, 2013 :: Ophthalmology Times Special Report ) RETINA New kid on the block Pivotal trial results demonstrate efficacy of newest anti-VEGF agent in treating CRVO-related macular edema By Cheryl Guttman Krader; Reviewed by Jean-Francois Korobelnik, MD
BORDEAUX, FRANCE :: A NEW OPTION FOR macular edema 71). After 24 weeks, patients were treated as Eighty percent of sham patients completed following central retinal vein occlusion (CRVO) needed according to pre-specified re-treatment follow-up at week 24 as did 91.5% of aflibercept is showing consistent, statistically significant criteria, and after 52 weeks, sham patients be- patients. Mean change from baseline BCVA was treatment benefits. came eligible for treatment with aflibercept. 18 letters for the aflibercept arm versus 3.3 let- Six-month results from a multicenter, ran- ters in the control group. Mean change in CRT domized, double-masked, sham-controlled trial PRIMARY, SECONDARY was more than two-fold greater in the afliber- show that fixed monthly injections of aflibercept EFFICACY ANALYSES cept arm compared with the controls, and the (Eylea, Bayer/Regeneron Pharmaceuticals) 2 mg The proportion of eyes at 24 weeks with a proportion of eyes with a dry retina (CRT <250 in treatment-naïve patients with macular edema BCVA gain from baseline of 3 or more lines μm) was about three-fold higher for the active secondary to CRVO results in was analyzed as the primary efficacy endpoint versus sham group (80% versus 26%). Analyses rapid and sustained gains in and showed a significant difference favoring of time to first sustained 15-letter gain in BCVA visual acuity, said Jean-Fran- the aflibercept arm over the sham-treated con- and time to first sustained dryness were also cois Korobelnik, MD. trols (60% versus 22%). Secondary efficacy out- highly in favor of the aflibercept arm. The efficacy and safety of comes pertaining to functional and anatomic “The most frequent ocular serious adverse aflibercept for the treatment improvements also showed a significant treat- events in the aflibercept arm were macular edema of macular edema second- ment benefit, and adverse event data showed and reduced visual acuity, but these events are Dr. Korobelnik ary to CRVO is being inves- aflibercept had a favorable safety profile. related to the disease being treated rather than tigated in twin international studies—GALI- GALILEO and COPERNICUS studies are the to the anti-VEGF treatment. There were no APTC LEO and COPERNICUS. Dr. Korobelnik, pro- last studies in CRVO with placebo control arms events reported,” Dr. Korobelnik said. Q fessor of ophthalmology, University Hospital in CRVO. In the future, this will not be ethical, as Bordeaux, France, presented outcomes from anti-vascular endothelial growth factor (VEGF) the GALILEO study that enrolled 177 patients agents have demonstrated a strong benefit com- JEAN-FRANCOIS KOROBELNIK, MD at 62 centers in Europe and Asia. pared with natural history, Dr. Korobelnik noted. E: [email protected] Eligible patients had central retinal thick- The two treatment arms in GALILEO were Dr. Korobelnik is a consultant and advisory board member for Bayer. The 6-month ness (CRT) of at least 250 μm and ETDRS best- similar in baseline characteristics. Patients had results of the GALILEO Study were published online in January 2013 (Holz FG, et corrected visual acuity (BCVA) ranging from a mean age of about 60 years and there was a al. VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 20/40 to 20/320. They were randomly assigned slight predominance of men. Mean BCVA was 6-month results of the phase III GALILEO Study. Br J Ophthalmol. 2013 Jan 7. [Epub at baseline 3:2 to receive aflibercept 2 mg every about 52 letters; mean CRT was 639 μm in the ahead of print]). This article was based on Dr. Korobelnik’s presentation at the 2012 4 weeks (n = 106) or sham injection (n = sham arm and 683 μm in the aflibercept patients. meeting of the American Academy of Ophthalmology.
retinal phototherapy: dynamic range of heat shock continues to show that it is a safe and effective DME protein expression. IOVS. 2010;52:1780-1787. modality, we may even see the use expanded 4. Vujosevic S, Bottega E, Casciano M, Pilotto E, ( Continued from page 25 ) as a compliment to other treatment modali- Convento E, Midena E. Microperimetry and fundus ties for diseases such as branch retinal vein autofluorescence in diabetic macular edema: Titration can also be fine-tuned to allow treat- occlusion, central serous choroidopathy and Subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser ment over the entire macula. We are currently other pathologies that involve fluid leakage. Q photocoagulation. Retina. 2010;30:908-916. titrating to 50% energy, but experimentation is 5. Luttrull JK, Sramek C, Palanker D, Spink CJ, Musch still in the early stages, and there is the possibility References DC. Long-term safety, high-resolution imaging, and of greater reductions and going to lower levels. 1. Early Treatment Diabetic Retinopathy Study Research tissue temperature modeling of subvisible diode While it is not at this point yet, there is even po- Group. Treatment techniques and clinical guidelines micropulse photocoagulation for retinovascular macular for photocoagulation of diabetic macular edema. edema. Retina. 2012;32:375-386. tential to be able to treat directly over the fovea. Early Treatment Diabetic Retinopathy Study Report This is a very exciting time in the develop- Number 2. Early Treatment Diabetic Retinopathy Study ment of laser therapy, and there are phenom- Research Group. Ophthalmology. 1987;94:761-774. enal possibilities for the future of combined 2. Diabetic Retinopathy Clinical Research Network. PRAVIN U. DUGEL, MD, is managing partner, Retinal treatment algorithms. The more precision we Randomized trial evaluating ranibizumab plus prompt Consultants of Arizona, Phoenix, and clinical associate professor, or deferred laser or triamcinolone plus prompt have with our laser treatments, the greater laser for diabetic macular edema. Ophthalmology. Department of Ophthalmology, Doheny Eye Institute, University our ability will be to fine tune treatment and 2010;117:1064-1077. of Southern California, Los Angeles. He has no financial interest achieve even better results. If photostimulation 3. Sramek C, Mackanos M, Spitler R, et al. Non-damaging in Topcon Medical Laser Systems. Brien Holden Vision Institute is one of the largest permanent eye care, concern has galvanised into DQGPRVWVXFFHVVIXOQRQSURÀWVRFLDOHQWHUSULVHV action again. To advance the process of addressing in the history of eye care. By applying commercial the challenge, both ICEE and Brien Holden Vision strategies to vision research and product Institute will more closely align, share one common development the Institute has generated income purpose and one name. for research and public health programs that provide quality eye care solutions and sustainable Together, we believe if we harness our efforts and broaden our scope we can achieve much more. vision services for the most disadvantaged people in our world. Together, we aim to drive, innovate, educate, for everyone... The concern for the devastating shortfall in collaborate, advocate and negotiate what is eye care education in developing communities, needed so that hundreds of millions, even billions, especially for correction of refractive error, became of people worldwide can enjoy the right to sight. everywhere action in 1998 for those at the Institute. The lack Whether it’s research to develop the technology of training institutes and educational opportunities to slow the progress of myopia, investment in was creating a human resource gap and a critical new systems for diagnosis of disease, delivery eye care shortage for hundreds of millions of of sustainable access to services or provision of people in need of services. The concern and eye care education in the most marginalised and willingness to address the issue gave rise to the remote communities in the world, the Institute will Share the vision International Centre for Eyecare Education (ICEE). focus on the quality of vision people experience and equity in eye care access worldwide. brienholdenvision.org Almost 15 years later, and acknowledging that 640 million people are still without access to We believe in vision for everyone...everywhere.
The Durban community in South Africa, arrives in hundreds to support the Brien Holden Vision Institute’s initiative Drive for Sight, part of the World Sight Day celebrations in October 2012. All attendees were offered free eye examinations, access to free or affordable low cost spectacles and referrals for further eye care where necessary. Photo by Graeme Wyllie.
Education Research Technology Public Health Brien Holden Vision Institute Foundation (formerly ICEE) is a Public Health Division of Brien Holden Vision Institute 28 MARCH 1, 2013 :: Ophthalmology Times Special Report ) RETINA
High resolution rates seen for VMA Ocriplasmin joins observation, vitrectomy as treatment options for vitreomacular adhesion By Lynda Charters; Reviewed by Subhransu K. Ray, MD, PhD
SAN FRANCISCO :: THE BASELINE FEATURES that are [BCVA] 6 months after treatment,” Dr. Ray said. of patients without ERM had VMA release with positive predictors of pharmacologic resolution “The number of patients who gained 3 or more ocriplamin versus 14.3% with placebo. Once of vitreomacular adhesion (VMA) following lines of BCVA vision was also sustained at the again, though, even in those with an ERM, ocriplasmin treatment (Jetrea, ThromboGen- 6-month time point in those who ocriplasmin resulted in a higher ics) are smaller adhesion base achieved VMA resolution, compared VMA release compared with pla- size, absence of an epiretinal with patients who did not achieve cebo (8.7% versus 1.5%), though membrane (ERM), presence of VMA resolution.” take-home at an overall lower rate. a full-thickness macular hole, The adverse events associated patient age below 65 years, PREDICTIVE FACTORS High success rates with ocriplasmin treatment in- and phakic status. Non-anatomic predictive baseline fac- of vitreomacular clude significant rates of vitre- Subhransu K. Ray, MD, tors were treatment group and age. adhesion release using ous floaters, photopsia, blurred ocriplasmin (Jetrea, Dr. Ray PhD, outlined the results of Analysis showed, not surprisingly, vision, transient visual acuity de- the phase III Ocriplasmin Pro- that treatment with ocriplasmin re- ThromboGenics) are crease, transient visual impair- gram on behalf of the MIVI-Trust Study Group. sulted in a higher rate of VMA release. associated with smaller ment, retinal edema, and macular “Two treatment options are available for symp- Similarly, age below 65 years was adhesion size, absence edema. Many of these might be tomatic VMA: observation or vitrectomy,” said a positive predictor of higher rates of an epiretinal attributed to the process of VMA Dr. Ray, a partner at Bay Area Retina Associ- of VMA resolution. However, even membrane, presence release itself and not specifically ates in northern California, and an associate among the patients who were over 65 of a full-thickness to an unrelated adverse effect of clinical professor of Ophthalmology, Univer- years of age, the rate of VMA release macular hole, patient the drug, Dr. Ray noted. sity of California, San Francisco. was also significantly (p < 0.001) age below 65 years, “When determining whether However, in October 2012, the FDA approved higher among the patients treated with and phakic status. to incorporate this treatment into the use of ocriplasmin to treat symptomatic ocriplasmin compared with placebo your clinical practice, it is im- VMA. The drug targets fibronectin and lam- (22.1% versus 6.2%, respectively). portant to note that ocriplasmin had a posi- inin and induces liquefaction and subsequent Detailed analysis of the anatomic features also tive effect across all VMA subgroups,” he said. release of the VMA, Dr. Ray explained. revealed the impact of ocriplasmin on VMA re- “Specific baseline features were predictive of lease. Ocriplasmin treatment resulted in a rate a higher success rate. MIVI-TRUST STUDIES of VMA release of 50% among patients with a Ocriplasmin was tested clinically in two phase full-thickness macular hole. However, even in III trials (MIVI-006 and MIVI-007) in a total of patients who did not have a full-thickness mac- 652 patients. The patients received either one ular hole, the VMA release rate was higher in vs intravitreal injection of ocriplasmin or a placebo patients treated with ocriplasmin as compared 19.6% 5.0% injection of saline. The primary endpoint was with placebo (19.6% versus 5.0%, respectively). VMA release rate was higher in the effectiveness at 28 days after the injection. “This overall resulted in a four-fold higher patients treated with ocriplasmin The MIVI-Trust Study group then conducted rate of macular hole closure rate in those pa- as compared with placebo additional analyses to determine which base- tients treated with ocriplasmin (40.6% versus line features were predictive of the most suc- 10.6%, respectively),” Dr. Ray said. At 6 months, cessful VMA release rates, Dr. Ray explained. 76.7% of patients with macular hole closure “The positive predictors of VMA resolution had a sustained and significant improvement “Each patient must be evaluated and edu- are adhesion size <1,500 μm, the absence of in visual acuity of at least two lines and 51.2% cated about the relative benefits of the three an ERM, presence of a full-thickness macular had at least a three-line gain in visual acuity. treatment options available for symptomatic hole, patient age below 65 years, and phakic Adhesion size <1,500 μm resulted in VMA re- VMA, namely, observation, ocriplasmin, and status,” he said. lease in 34.7% of treated patients compared with vitrectomy,” Dr. Ray concluded. Q The combined data from both MIVI-Trust 14.6% of those randomly assigned to placebo. studies showed that across all populations, Nevertheless, even in patients with adhesions ocriplasmin treatment induced a higher rate exceeding 1,500 μm, 5.9% achieved VMA release (26.5%) of VMA resolution compared with pla- when treated with ocriplasmin as compared with SUBHRANSU K. RAY, MD, PHD cebo (10.1%). 0% among the placebo-treated patients. E: [email protected] “This corresponded to a significant improve- The absence of an ERM was an overwhelm- Dr. Ray has no financial interest in the subject matter. This article was adapted ment in the number of patients who gained 2 ing positive predictor for successful VMA re- from Dr. Ray’s presentation during Retina 2012 at the annual meeting of the or more lines of best-corrected visual acuity lease following ocriplasmin treatment; 34.7% American Academy of Ophthalmology. MARCH 1, 2013 :: Ophthalmology Times 29 Special Report ) RETINA
Optogenetics a new approach to RP Novel method brings back light perception, possibly vision, to patients By Lynda Charters; Reviewed by Luk H. Vandenberghe, PhD
BOSTON :: A NEW LABORATORY development light, a neuron that expresses one of these may be the key to a new therapy for retini- molecules is triggered.” Potential for light tis pigmentosa (RP). Channelrhodopsin, for example, is a chan- perception for patients Luk H. Vandenberghe, PhD, discussed the nel protein that opens when light hits it and progress in optogenetics. depolarizes the cell, he explained. with RP “In most cases, RP results A few approaches can be used to place in the loss of photorecep- the molecules in the retina. Optogenetics, the brainchild of Botond Roska, from the tors due to a single gene “The sensors can be placed either in ret- Friedrich Miescher Institute for Biomedical Research, defect,” said Dr. Vanden- inal ganglion cells or deeper in the retina Basel, Switzerland, may hold the key to therapy for berghe, a lecturer in oph- which would capture more of the endoge- patients with retinitis pigmentosa. thalmology, Schepens Eye nous retinal processing capacity and may The principal players in this technologic tool set are Dr. Vandenberghe Research Institute, Massa- restore a more natural form of vision,” he the molecules melanopsin, channelrhodopsin, and chusetts Eye and Ear Infirmary, Harvard said. “The molecules can be placed in am- halorhodopsin. All three molecules share the same Medical School, Boston. acrine cells, bipolar cells, or remnant cone activity, that is, when exposed to light, a single molecule “There are two main strategies to address photoreceptors.” can engage the phototransduction cascade in a neuron, RP, i.e., protective means and restorative While this endeavor may sound like sci- according to Luk H. Vandenberghe, PhD. means,” he said. “Ideally, we ence fiction, Dr. Vandenberghe would like to be at the inter- said, “we have proof-of-concept 1. Melanopsin is derived from vertebrates. Retinal ganglion face of the two.” data for at least four strategies cells use this for circadian rhythm and pupillary reflex. Optogenetic therapy for RP, take-home in animal models, several of 2. Channelrhodopsin is derived from algae (Chlamydomonas according to Dr. Vandenberghe, which can restore fairly com- Optogenetic therapy reinhardtii). The molecule, a channel protein, opens when is the re-sensitization of the ret- plex vision.” is the re-sensitization exposed to light and depolarizes the cell. ina to light by the introduction of Optogenetics has a few lim- of the retina to light a genetically encoded molecular itations and hurdles to over- 3. Halorhodopsin is derived from archaebacteria by the introduction of light sensor that is coupled to come that presently prevent ap- (Natronomonas pharaonis). This molecule has a a genetically encoded the neural circuitry of the de- plication in a clinical setting. hyperpolarizing effect. molecular light generated retina for functional These include overcoming the sensor coupled to the Both halorhodopsin and channelrhodopsin have a role restoration of light perception host immune response, creation neural circuitry of the in phototropism, which is the movement of single-cell and ultimately vision. of possible undesirable forms of degenerated retina. organisms toward light. The restorative methods that vision, the sensitivity and dy- have been attempted previously namic range of the molecules Importantly, the deeper into the retina the molecules that are currently in clinical trials involve that require a great deal of light and are are placed, the more retinal processing that can be retinal implants, cell replacement, and gene only active in about one or two orders of captured. The same tools are used as those that have augmentation. magnitudes compared with normal vision been clinically validated in gene therapy trials, that is, “All of these have advantages and disad- that can adapt to seven orders of magnitude, the sensors can be put into retinal ganglion cells by an vantages,” Dr. Vandenberghe said. “Using pupillary reflex, and nystagmus. intravitreal approach, in amacrine cells or bipolar cells optogenetics, we are aiming to overcome Dr. Vandenberghe pointed out that ini- using an intravitreal or subretinal approach, and in residual some of the limitations of these strategies, tially the therapy will be combined with a photoreceptor cells by a subretinal approach. “The hope such as the retinal coupling needed for head-mounted display device that will ac- is to achieve a more natural vision,” he commented. implanted devices, grafting required for tivate the gene therapy in the retina. The Three biotech ventures are interested in this technology photoreceptor cell replacement, and a one patient or a computer will be able to modu- and helping to move it forward: Retro Sense, EOS gene/one drug regimen and a small win- late the increased sensitivities and adapta- Neuroscience, and GenSight. Q dow of intervention associated with gene tion to the surrounding light environment. augmentation.” This technology is presently in the Three molecules—melanopsin, channel- preclinical stage in primate and animal rhodopsin, and halorhodopsin—are studied safety studies. LUK H. VANDENBERGHE, PHD to re-sensitize the retina to light. “We need four fairly developed fields to E: [email protected] “These have created a great deal of ex- come together: retinal gene therapy, reti- Dr. Vandenberghe is a co-founder of GenSight Biologics, which may develop the discussed therapy, and citement in the field of neuroscience,” Dr. nal circuitry, improved optogenetics, and holds patents with GlaxoSmithKline and ReGenX Biosciences. This article was adapted from Dr. Vandenber- Vandenberghe said. “Upon the influx of engineering,” he concluded. Q ghe’s presentation during Retina 2012 at the annual meeting of the American Academy of Ophthalmology. This activity is supported by an unrestricted educational grant from Bausch + Lomb cme Release Date: March 1, 2013 Expiration Date: March 1, 2014 article series Learning Objectives Infection and Inflammation Associated with Select the most appropriate topical ocular anti- LQIHFWLYHRUDQWLLQÁDPPDWRU\DJHQWIRUWKH treatment of ocular infection or post-surgical Ocular Surgery LQIHFWLRQSURSK\OD[LVEDVHGRQULVNEHQHÀWGDWD is a 55-year-old man who has noted a gradual decrease in vision Identify existing as well as emerging treatment in his right eye over the past year. He has no history of any ocular options for pre- and post-ocular surgery disease or systemic health problems, such as diabetes or high prophylaxis and treatment A.L. blood pressure. Slit lamp examination shows a moderate nuclear sclerotic cataract Ophthalmologist Accreditation in his right eye, and vitreous and retinal examinations are within normal limits. The Institute for Continuing Healthcare Education He is interested in cataract surgery. The potential risks of surgery are discussed with is accredited by the Accreditation Council for him as well as any dangerous symptoms that may occur after the procedure, such as Continuing Medical Education to provide continuing decreased vision, red eye, pain, and discharge. These could all be signs of infection medical education for physicians. or other potentially dangerous visual complications. The Institute for Continuing Healthcare Education designates this enduring material for a maximum of Endophthalmitis 0.75 AMA PRA Category 1 Credit(s)™. Physicians Endophthalmitis is a serious and vision-threatening ocular complication that can occur after a surgical should only claim credit commensurate with the procedure, trauma, or a systemic infection.,WLVDQLQÁDPPDWRU\FRQGLWLRQRI WKHDTXHRXVRUYLWUHRXV extent of their participation in the activity. cavities caused by a bacterial or fungal agent; however, noninfectious endophthalmitis can also be .2,3 Optometrist Accreditation caused by toxic agents, pharmacologic treatments, or post-operative retained native lens material While endophthalmitis is always a risk associated with ocular surgery, it is rare and varies with the 7KLVFRXUVHLV&23(TXDOLÀHGIRUKRXURI &( credit. Please check with your state licensing board type of surgery performed VHH7DEOH $VWXG\E\.HD\HWDOIRXQGWKDWWKHRYHUDOOLQFLGHQFHRI to see if this approval counts toward your actual SC HQGRSKWKDOPLWLVLQZDVSHUVXUJHULHV &, DQGGHFUHDVHGWRSHU requirements for relicensure. (COPE-ID # 36478-SP) VXUJHULHV &, LQ4
Claiming Credit 3OHDVHJRWRZZZLFKHHGXH\HWRFODLP$0$RU Table 1. Incidence of Endophthalmitis by Surgical Procedure COPE credit. You will be directed to a host site for further instruction. A complete set of references can Surgical Procedure Incidence also be found online. Aqueous shunt surgery or trabeculectomy5 1% to 3% and 0.3% to 1.8%, respectively Disclosures 6 Relationships are abbreviated as follows: E, Pars plana vitrectomy 0.011% to 0.039% Educational Planning Committee; G, Grant/research 7 support recipient; A, Advisor/review panel member; Cataract Surgery 0.028% C, Consultant/Independent Contractor; SS, Stock 7 shareholder; SB, Speaker bureau; PE, Promotional Penetrating keratoplasty 0.108% Event Talks; H, Honoraria; O, Other. LASIK8 Post-operative infections are rare Faculty Photorefractive keratectomy 9 Rare and usually involves an infectious keratitis, not endophthalmitis Eric D. Donnenfeld, MD, FACS: Allergan Inc., Bausch + Lomb, Alcon/C Mark T. Dunbar, OD, FAAO: Allergan, Carl Zeiss Diagnosing endophthalmitis quickly is important causative organism, if possible, because knowing Meditec, Inc., Alcon Nutritional, ArticDX /A, C, SB; to preserve vision. Obtaining an accurate the causative organism is essential in directing Reed Exposition (Vision Expo)/A, C history – including any surgical procedures or treatment. Since the outcome of endophthalmitis Marc R. Bloomenstein, OD, FAAO: Allergan Inc., LQIHFWLRQVVXFKDVHQGRFDUGLWLV²LVWKHÀUVWVWHS can be poor, prevention before and after the RPS, AMO/A, AOA/E; Bausch + Lomb, Allergan in diagnosis. The course of the condition may surgery often serves as the best defense. Inc., Odyssey/G; Alcon, Bausch + Lomb, ISNA, vary based on the cause of the infection; for Toxic Anterior Segment Syndrome RPS, Odyssey, Reichert/SB example, bacterial causes generally present more Clark Springs, MD: Alcon, Merck/A acutely, while fungal infections may take several Toxic anterior segment syndrome (TASS) days before becoming evident.2 Symptoms of is a post-operative condition caused by an Peer Reviewer HQGRSKWKDOPLWLVLQFOXGHDUHGDQGLQÁDPHGH\H LQÁDPPDWRU\UHDFWLRQWRDQRQLQIHFWLRXV Donald L. Budenz, MD, MPH: Alcon, Santen/A, vision loss, photophobia, eye pain, and ocular substance that enters the eye during a surgical Alcon, Allergan Inc., Alimera/C, Merck, Lumenis/SB discharge. Eyelid swelling and headache may also SURFHGXUH7$66W\SLFDOO\RFFXUVZLWKLQ to 2 days after cataract or anterior segment Medical Writer be present. An ocular examination may show surgery; signs are limited to the anterior Dominique W. Brooks has no relationships to disclose. keratic precipitates, anterior chamber cell and ÁDUHDQGDVLJQLÀFDQWYLWULWLVLQWKHDIIHFWHGH\H segment of the eye. Cultures taken from the Activity Development and Management Team and/or a hypopyon in the anterior chamber. eye are always negative after gram staining, and blurred vision and ocular pain are often Cathy Pagano, CCMEP; Allison A. Muller, Disease progression due to endophthalmitis may Pharm.D, D.ABAT; Scott Kober, MBA, CCMEP; present. On examination, there is usually severe lead to corneal perforation, vision loss or phthisis DQWHULRUVHJPHQWLQÁDPPDWLRQRIWHQZLWKD April Reynolds, MS, ELS; Sandra Davidson; and Tina Chiu, MEd are employees of the Institute bulbi. Treatment depends upon the causative hypopyon and profound corneal edema. The and have no relationships to disclose. organism and may include a diagnostic vitreous iris and trabecular meshwork may also become tap or vitrectromy with intravitreal injections of Off-Label Product Disclosure: permanently damaged in TASS, which may antimicrobial agents. Treatment may also include lead to an irregularly shaped pupil or elevated This educational activity includes discussion V\VWHPLFDQWLELRWLFVVXFKDVRUDOÁXRURTXLQRORQHV intraocular pressure. TASS typically responds to of published and/or investigational uses of YDQFRP\FLQDFHSKDORVSRULQÁXFRQD]ROH aggressive corticosteroid therapy. agents that are not indicated by the U.S. Food or amphotericin B. Treatment should begin and Drug Administration. Please refer to Iritis/Uveitis WKHRIÀFLDOSUHVFULELQJLQIRUPDWLRQIRUHDFK immediately after cultures are obtained depending product for discussion of approved indications, on the suspected cause of the condition.2 If Preexisting or undiagnosed uveitis can be contraindications, and warnings. the condition does not improve after treatment is exacerbated by ocular surgery. Uveitis is initiated, clinicians should obtain repeat anterior LQÁDPPDWLRQRI WKHXYHDOWUDFWZKLFKLQFOXGHV chamber or vitreous samples to determine the the iris, ciliary body, and the choroid. Most Refresher Key Learning Points In the previous article on herpetic keratitis, we learned the following key learning points: s %NDOPHTHALMITIS IS A RARE BUT DEVASTATING CONDITION s 3EVERAL OCULAR CONDITIONS MAY PRESENT LIKE HERPETIC KERATITIS THUS IT IS IMPORTANT TO MAKE THE APPROPRIATE DIAGNOSIS TO DECREASE THE RISK OF OCULAR DAMAGE s 0REVENTION OF ENDOPHTHALMITIS WITH OCULAR SURGERY IS THE BEST PLAN OF ACTION s #ORTICOSTEROIDS MAY WORSEN ACTIVE HERPETIC KERATITIS AND SHOULD BE ADMINISTERED IN CONJUNCTION WITH AN ANTIVIRAL MEDICATION AND CLOSE SUPERVISION s 0ROPHYLACTIC ANTIBIOTICS CAN BE GIVEN TOPICALLY BEFORE AND AFTER OCULAR SURGERY s 4RIFLURIDINE AND GANCYCLOVIR CAN BOTH BE EFFECTIVE TREATMENTS BUT GANCYCLOVIR CARRIES LESS CORNEAL TOXICITY AND MAY BE PREFERABLE FOR LONG TERM USE s &OR SOME SURGERIES SUCH AS CATARACT SURGERY ANTIBIOTICS MAY BE GIVEN INTRACAMERALLY DURING THE PROCEDURE cases are idiopathic, but a thorough history is Endophthalmitis s ,ID SCRUBS CAN LOWER BACTERIAL necessary to ascertain whether further work-up Prevention Strategies is needed. Symptoms of anterior uveitis include CONCENTRATIONS AND MAY BE BENEFICIAL FOR MOST OCULAR PROCEDURES pain, blurred vision, and photophobia. Posterior Since treatment of endophthalmitis may not uveitis is associated with blurred vision and is not yield positive ocular outcomes, prevention before typically associated with pain or photophobia. and after surgery has become a hallmark of 5 Treatment for both types of uveitis consists of ophthalmic treatment regimens. It is commonly corticosteroid use (topical and systemic) and DFFHSWHGWKDWWKHSDWLHQW·VSHUVRQDOÁRUDLV cycloplegics for anterior uveitis. Intravitreal responsible for most cases of postoperative 20 injections of corticosteroids and sustained-release infection. Lid cleaning prior to surgical corticosteroid implants are also available. Other procedures may lower the amount of bacteria immunotherapies, such as anti-TNF alpha agents, available to cause infection, as evidenced in a can also be used. study by Bucci and colleagues that found that a combination of lid scrubs and antibiotics lowered Close-up of the cornea showing large keratic Other Causes of Vision Loss the amount of bacteria around the eye prior to precipitates on the endothelium in a patient with a 4+ anterior chamber reaction due to After Ocular Surgery cataract surgery. Lid hygiene prior to surgery can postoperative endophthalmitis. In the days after an ocular surgery, other EHEHQHÀFLDOLQDOOVXUJLFDOSURFHGXUHVHVSHFLDOO\ FRQGLWLRQVVXFKDVSRVWRSHUDWLYHLQÁDPPDWLRQ if the patient has blepharitis or meibomian gland patterns among clinicians23; however, a large, and vitreous hemorrhage may also present with dysfunction, which may increase the levels of randomized study of the European Society of similar symptoms to endophthalmitis. Surgical bacteria on the eyelids.22,23 Application of both Catraract and Refractive Surgery by Barry and WUDXPDFDQFDXVHDQLQÁDPPDWRU\FDVFDGHWKDW preoperative and postoperative topical antibiotics, colleagues evaluated intraocular antibiotics and JHQHUDWHVSURVWDJODQGLQVZKLFKFDQLQÁXHQFH WKHXVHRI SRYLGRQHLRGLQHLQWKHRFXODU found that intracameral cefuroxime administered intraocular pressure, cause miosis, and increase FXOGHVDFDQGSRYLGRQHLRGLQHRQWKH DWWKHWLPHRI VXUJHU\VLJQLÀFDQWO\ORZHUHGWKH vascular permeability, thereby increasing the levels periocular skin, as well as sterile draping in the risk for developing endophthalmitis after cataract of protein in the aqueous. operating room, are all potential ways to lower the surgery. Other nonrandomized studies have rates of infection.23 3RVWRSHUDWLYHLQÁDPPDWLRQXVXDOO\UHVSRQGVWR also evaluated the effectiveness of intracameral topical ocular corticosteroids and/or nonsteroidal Many clinicians have preferences for antibiotic injections after cataract surgery, and a medications./DUJHDPRXQWVRI LQÁDPPDWLRQ antibiotic use, but newer antibiotics such as survey of cataract surgeons in Sweden suggested ÁXRURTXLQRORQHVPD\KDYHFOLQLFDOEHQHÀWGXH that intracameral cefuroxime may be responsible can be confused with infectious endophthalmitis 32 and may be treated as such. With vitreous to a broader spectrum of action.24 Whatever the for the lower levels of endophthalmitis. hemorrhage, the patient complains of decreased choice, the selected antibiotic should be active Patient Case Conclusion YLVLRQÁRDWHUVSKRWRSKRELDDQGLPDJHVRI DJDLQVWJUDPSRVLWLYHEDFWHULDDQGKDYHVXIÀFLHQW To lower the risk of endophthalmitis cobwebs, but generally no pain; however, since bioavailability for absorption. 0R[LÁR[DFLQ before cataract surgery, we started A.L. on a the patient is postoperative, he or she may actually JDWLÁR[DFLQEHVLÁR[DFLQDQGOHYRÁR[DFLQDOO ÁXRURTXLQRORQHGURSRQHGD\SULRUWRWKH have some discomfort from the procedure not UHGXFHGRFXODUÁRUDEDFWHULDOHYHOVLQQRQFOLQLFDODQG .25,26 cataract surgery. We also started him on a associated with the hemorrhage. On examination, clinical trials %HVLÁR[DFLQPD\SURYLGHDGGLWLRQDO WRSLFDOQRQVWHURLGDODQWLLQÁDPPDWRU\GUXJ the clinician will be able to see hemorrhage in the FRYHUDJHIRURFXODUSDWKRJHQVVXFKDVFLSURÁR[DFLQ 27 (NSAID) and steroid drop to lower the risk posterior chamber. This may not be the complete and methicillin- resistant staphylococci. RI LQÁDPPDWLRQ3ULRUWRWKHSURFHGXUHLQWKH diagnosis in every case, as endophthalmitis may Some clinicians start topical antibiotics at least operating room, povidone-iodine was used to have an unusual presentation (such as vitreous one day before ocular surgery, while others may clean the eyelid skin and was placed in the cul hemorrhage), but there are typically other 28 give multiple drops at the time of the procedure. de sac as well. During the cataract extraction, ÀQGLQJVVXFKDVDSRVLWLYHVPHDURUFXOWXUHWKDW There has been some debate as to whether intracameral cefuroxime was administered, and point to the proper diagnosis. starting antibiotics days before the procedure the surgery was a success. A.L. was instructed HUDGLFDWHVEDFWHULDOÁRUDDVFRPSDUHGZLWKRQO\ WRFRQWLQXHWKHÁXRUTXLQRORQHGURS4,'IRU one day before the surgery or when compared weeks after the procedure in addition to topical with use of povidone-iodine alone. Despite NSAIDs and steroid drops. this debate, many clinicians use topical antibiotics prior to most ocular procedures and continue antibiotic drops after the procedure. Research Claiming Credit has shown that endophthalmitis typically 3OHDVHJRWRZZZLFKHHGXH\HWR occurs within one week after ocular surgery, so claim AMA or COPE credit. A complete antibiotics are often continued for at least that set of references can be found online. long.25 Controlled studies evaluating prophylaxis IRUHQGRSKWKDOPLWLVKDYHEHHQGLIÀFXOWWR This activity is sponsored by Post-surgical endophthalmitis caused by complete partly because of the low incidence gram-positive bacteria. of the condition and the differences in practice 32 general MARCH 1, 2013 :: Ophthalmology Times
Innovation abounds at OIS Regulatory and investment climate fosters drug, device opportunities By Peter Sonnenreich, MA, and John Jesitus, MA
TAKE-HOME A favorable regulatory and investment climate in ophthalmology News Makers in Ophthalmology 2012 means that ophthalmologists and patients can expect more expeditious DATE COMPANY PRODUCT NEWS drug and device approvals in 2013 and Sigma-Tau Approved by FDA for corneal 10/12 Cystaran beyond, said speakers at the recent Pharmaceuticals Inc. cystine crystal accumulation Ophthalmology Innovation Summit. 10/12 Sarcode Bioscience SAR 1118 Successful phase III dry eye data
Approved by FDA for diabetic 8/12 Roche Lucentis CHICAGO :: macular edema favorable regulatory and invest- ment climate in ophthalmology 7/12 LuxBio Sciences Luveniq Completed enrollment phase III study means that ophthalmologists and Statistically significant phase IIb patients can expect more expedi- 6/12 Ophthotech Fovista data (REGN dropped 12% on day tious drug and device approvals of data announcement) in 2013 and beyond, said speak- ers at the recent Ophthalmology Approved by FDA for lowering 2/12 Merck Zioptan AInnovation Summit (OIS) held here. of IOP For starters, experts expect recent FDA changes to streamline the drug and device approval Source: Company filings and Wall Street research. process. In late 2012, as part of the FDA Safety and Innovation Act (FDASIA), Congress autho- One executive who welcomes the changes tor of the FDA’s Division of Ophthalmic, Neu- rized the Medical Device User Fee Amendment is Edward Peterson, president and chief exec- rologic, and Ear Nose and Throat Devices, the III and the Prescription Drug User Fee Amend- utive officer (CEO) of AcuFocus Inc., which is FDA received 1,441 submissions, including 447 ment. Both aim to increase FDA funding and developing a device (Kamra) to increase depth for ophthalmic devices. personnel to provide more timely reviews of of focus for patients with presbyopia. Meet- drug and device applications. These measures ings between AcuFocus representatives and CAPTURING VENTURE expire in October 2017. the FDA are always very productive, he said. CAPITAL Afterward, he said, “You know exactly what Overall, the FDA changes aim to increase the you need to do.” accountability, predictability, and transparency However, he said, scheduling a meeting can of the review process. Achieving these goals Ophthalmologists and take 3 to 5 months. will reduce the risk related to FDA submissions “With more staff, the agency could host more and increase the availability of venture capital patients can expect meetings with industry throughout the process,” in ophthalmology and other specialties, said he said. “This kind of interaction between the William Link, PhD, a Versant Ventures man- more expeditious drug industry and the FDA has the potential to im- aging director who specializes in early-stage prove the process dramatically.” medical device investments. For example, Peterson said, being able to Quinton Oswald, CEO of SARcode Biosci- and device approvals work collaboratively throughout the investi- ence, added that how potential investors view gational device exemption and premarket ap- early-stage drug and device companies hinges in 2013 and beyond. proval submission process with the FDA’s input largely on the predictability of the FDA. upfront would improve the quality of submis- To that end, “For the FDA to provide earlier sions and could further expedite the process. and more frequent feedback is very helpful for The FDA also has pledged to make specific Also, simply increasing the number of FDA a company like mine,” he said. changes in areas ranging from staff levels and reviewers likely will help the agency process Moreover, Dr. Link and Oswald said they training to how it communicates with appli- applications faster, he added. hope that increased funding especially will ben- cants—from pre-submission to post-marketing. In 2012, said Malvina Eydelman, MD, direc- Continues on page 34 : Innovation %XLOGLQJWKH2SKWKDOPLF7HFK¶V&RPPXQLW\RI3UDFWLFH PRGHUQPHGLFLQHFRPL7HFK 5HVRXUFH&HQWHUIRU7HFKQLFLDQ(GXFDWLRQ
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weight in gold — highly Communications is pleased to present skilled, knowledgable and a series of educational offerings that motivated ophthalmic you will hopefully eagerly bring to the OCULAR technicians. MD attention of your technicians. These will Peter McDonnell,We all know that there is a help with learning new skills, refining and improving upon previously learned ALLERGIES winter nationwide shortage of trained information, instructional case studies, ophthalmic technicians. We also know and pearls on how to work effectively that excellent technicians have major The incredibly mild with their doctors to enhance the 2 benefits in our practices. When we that much of the United States Page practice. And, coming soon, an online partner with skilled technicians, we experienced may mean that community will afford the opportunity can%URXJKWWR\RXE\ help more patients in less time, our ophthalmic technicians are going to connect with and share best practices patient satisfaction scores are higher, and to be on the front line helping with colleagues. to manage a wave of patients we finish our work days happier and less In my opinion, these materials help fatigued. We do more things that our with ocular allergies. address an important unmet need for years of specialized training permit us to our technicians. Aware that they are
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ogy, added Anthony J. Gib- INNOVATION ney, managing director, East Coast biopharma at Leerink ( Continued from page 32 ) Swann LLC. Ophthalmology Sales It offers healthy profit mar- CURRENT vs. PROJECTED efit the FDA device review process—because gins, the ability to launch its funding has fallen in recent years, while drugs effectively with its complexity and duration have increased. smaller sales forces, and Compared with drug approvals, Oswald noted, a generally consistent FDA IN 2011 IN 2017 the device process seemed to be “a moving evaluation process, which target. Every time people would try to satisfy builds confidence in clini- Drug sales Drug sales are the FDA, something else—such as a need for cal trial data, he explained. totalled projected to hit additional data—popped up.” Accordingly, he said, the It’s too soon to tell whether beefier budgets receptivity of investors, $486 BILLION $563 BILLION are facilitating smoother device reviews, Dr. merger/acquisition experts, OF THAT OF THAT Link said. But already, as several of his com- and even regulators to oph- panies interact with Dr. Eydelman and her thalmology creates very fer- $10 BILLION $13 BILLION staff, “I’m seeing improved responsiveness,” tile ground for innovation. were from will be from The global drug and he noted. ophthalmology ophthalmology Since the FDASIA passed, added Richard L. medical device market is Lindstrom, MD, “The FDA and its representa- expanding modestly, with drug sales drug sales tives are much more available, responsive, and sales growth expected to helpful in giving guidance to companies who match the rate of popula- THAT'S 2% THAT'S 2.3% are trying to create clinical trials, or nearing tion increase (15.8%) through submission of clinical trial data. We are start- 2017, Gibney said. ing to see some more rapid approvals as well.” Meanwhile, ophthalmol- A PROJECT INCREASE OF 0.3% As founder and attending surgeon at Minne- ogy’s share of this market Source: Cowen Therapeutic Categories Outlook research report. sota Eye Consultants, and adjunct clinical pro- will grow from 2% presently fessor emeritus at the University of Minnesota, to 2.3%, he predicted. Department of Ophthalmology, Dr. Lindstrom Ophthalmology’s modest market share high- treatments are largely biologics. Regarding frequently consults with early-stage ophthal- lights the specialty’s many untapped oppor- stock activity, he said, “It was a breakout year mology companies. tunities—namely, diseases that remain un- for Regeneron, which posted a 166% jump in treatable because treatments have not been its stock price in 2012. The vast majority of the UNTAPPED OPHTHALMIC approved or, in some cases, even attempted, growth came from [aflibercept].” OPPORTUNITIES Gibney said. Such indications one day may Elsewhere, he said, the most commercially Regarding financing, large pharmaceutical and dwarf wet age-related macular degeneration relevant data to emerge in 2012 involved Fo- device companies, along with public share- (AMD), which represents nearly half of oph- vista (Ophthotech), which, in combination with holders, would like more access to ophthalmol- thalmology sales, he said, because wet AMD rani bizu mab (Lucentis, Genentech) showed significantly better visual gain over ran i biz- umab alone in a phase IIb study in wet AMD. Fovista’s active ingredient blocks platelet-de- rived growth factor-B. Don’t miss these opportunities Among products under development, SAR 1118 (SARcode) successfully completed a phase III dry eye study. Conversely, voclosporin (Lu- 2ND ANNUAL OPHTHALMOLOGY 5TH ANNUAL OPHTHALMOLOGY veniq, Lux Biosciences) failed in its phase III INNOVATION SUMMIT INNOVATION SUMMIT trial for noninfectious uveitis. Q AT THE ASCRS MEETING AT THE AAO MEETING DISCLOSURES APRIL 18, 2013 IN SAN FRANCISCO NOVEMBER 14, 2013 IN NEW ORLEANS Dr. Lindstrom is medical director of Sightpath Medical and Refractec, and chief medical officer of TLCVision. He serves The Ophthalmology Innovation Summit The purpose of OIS is to create an on the board of directors of AcuFocus, Encore, Refractec, (OIS) unites leaders in the development ecosystem of clinical, technology, and RevitalVision, TearLab, TLCVision, and Wavetec. of ophthalmic products, drugs, and business. www.oisaao.com In addition to being president and CEO of AcuFocus, Peterson serves on the board of directors for Accelerated devices. www.oisascrs.com For an executive summary on Vision Group and AqueSys. For $100 off the registration fee, use the 2012 OIS AAO meeting, see Dr. Link's Versant investments include AcuFocus, Cameron Health, ForSight, Glaukos, Inogen, LenSx, NeoVista, the discount code OISOPT ophthalmologytimes.com/ois Neurotech Pharmaceuticals, Rox Medical, Second Sight, and Wavetec. EYETHECAR COMPLETEE EVENT
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Femtosecond laser capsulotomy: Accuracy does make a difference Procedure provides significantly more predictable effective lens positions, study finds By Lynda Charters; Reviewed by Robert J. Cionni, MD
TAKE-HOME (Haag-Streit). Dr. Cionni used a refractive ver- re-optimization of the A-constant, he noted. gence formula (Jack Holladay, MD) to calcu- This was also true at the 6-month evaluation. Femtosecond laser capsulotomies late the predicted ELP and then compared that “It was interesting that the manual group provide significantly more predictable with the true lens position. had improved predictability and was close to effective lens positions compared When he compared the mean absolute error, the target refraction at 6 months,” Dr. Cionni with manual procedures. he pointed out that he had used a personal- said. “This demonstrated that there was a shift ized lens constant in both groups; however, in the lens position that was greater in the further optimization of the lens constant was manual group than the laser group.” SALT LAKE CITY :: needed for both groups. He also compared the When he compared the ACDs preoperatively emtosecond laser capsulotomies regression of the preoperative anterior cham- and 1 month postoperatively, there was good provide significantly more pre- ber depth (ACD) with the true postoperative correlation in the laser group but not in the dictable effective lens positions ACD at both time points. manual group (87%, R2 = 0.76, p < 0.000 ver- (ELPs) compared with manual sus 12%, R2 = 0.0142, p = 0.56, respectively). procedures. GOOD CORRELATION The results were similar at 6 months. Robert J. Cionni, MD, discussed At 1 month postoperatively, the femtosecond the superiority of the femtosecond laser group had good correlation between the laserF for creating capsulotomies compared with predicted ELP and the true postoperative lens the conventional manual method and reopti- position, Dr. Cionni noted. There was poor cor- mization of lens constants for accurate laser relation between the two in the manual group. 77% vs 54% refractive lens surgery. The results at 6 months were similar; there was “The capsulotomy does make a difference,” slightly less variability in the manual group at 6 More patients were within 0.25 D said Dr. Cionni, medical director of The Eye In- months compared with the manual group at 1 of the intended target in the laser stitute of Utah, Salt Lake City. He cited a study month. However, the high correlation was seen only in which it was found that a 4-mm capsulotomy in the femtosecond laser group (89%, R2 = 0.80, group compared with manual group tends to position an IOL slightly more posteri- p < 0.000 versus 41%, R2 = 0.17, p = 0.09). orly compared with a 6-mm capsulotomy. When “The mean absolute error was better in the performing manual cases, the capsulotomies laser group compared with the manual group In terms of the uncorrected visual acuity, the will vary and so, too, will the (0.26 ± 0.16 versus 0.34 ± 0.21, respectively),” laser group fared better at all time points than spherical refractive results. Dr. Cionni said. “Significantly more patients the manual group. At 1 month, 73% and 46%, Dr. Cionni also discussed a were within 0.25 D of the intended target in respectively, achieved 20/20 or better, and 82% non-randomized prospective the laser group compared with manual group and 54% achieved 20/25 or better. The results study in which he performed (77% versus 54%, respectively).” were similar at 6 months, although Dr. Cionni all surgeries between March When he evaluated the A-constant sepa- noted some improvement in the manual group. and June 2011. One IOL (Acry- rately, he found that the laser group had a “The ELP is more predictable and more highly Dr. Cionni Sof SN60WF, Alcon Laborato- mean 0.05 increase in the A-constant and the correlated with the postoperative ACD in laser ries) was implanted in 48 pa- manual group had a 0.05 decrease. capsulotomy compared with manual capsulot- tients, for 26 of whom he created a manual cap- omy,” he concluded. “Optimization of the lens sulotomy and for 22 a laser capsulotomy using MORE VARIABILITY constant is essential for better predictability of the LenSx femtosecond laser system (Alcon). In “This shows that in the manual group even the ELP, which means better refractive accu- the manual group, he used a 5.75-mm Mastel though the target is a 5-mm capsulotomy in racy. The lens constant for laser cases should marker to guide a 5-mm capsulorhexis. each case, there is more variability with some be optimized separately from manual cases.” Q Patients were followed up at 1 and 6 months capsulotomies smaller or larger than 5 mm postoperatively and the targeted refractions and and some as large as 6 mm,” he said. the uncorrected visual acuities were compared The calculated new prediction error at 1 month ROBERT J. CIONNI, MD between the two groups. He also measured still showed favorable results and predictability Dr. Cionni is on the LenSx medical advisory board and a consultant to Alcon Labo- the true lens position in all patients using an that favored the laser group. Some improvement, ratories. This article was adapted from Dr. Cionni’s presentation during Refractive all-in-one optical biometer (LenSTAR LS 900, however, was seen in the manual group with Surgery 2012 at the annual meeting of the American Academy of Ophthalmology. MARCH 1, 2013 :: Ophthalmology Times practice management 37
Are exchange-traded funds the new mutual funds? Latest investment vehicle offers the structure of a fund, but is traded like stock Money Matters By John J. Grande, CFP; Traudy F. Grande, CFP; and John S. Grande, CFP
TAKE-HOME ror the performance of an index. Those indexes ETFs may be more tax-efficient than ac- Investors are shifting assets to may reflect exposure to domestic or interna- tively managed funds. ETFs may create and passively managed vehicles. For tional markets; equity, fixed income, commod- redeem their shares in kind, rather than in many, exchange-traded funds (ETFs) ity or currency markets; or a broad or narrow cash, which can help them avoid distributing have become the vehicle of choice. exposure to those markets. year-end capital gains the way many mutual ETFs are investments that trade Unlike mutual funds, however, ETFs trade funds do. This is particularly true for more on exchanges, and are designed to on exchanges and can be bought and sold at seasoned and liquid ETFs. mirror the performance of certain market prices throughout the day during mar- But like any powerful tool, ETFs need to be market indexes, so they tend to be ket hours, like stocks. ETFs typically list their handled carefully. In particular, investors should passively managed. current holdings on a daily basis, whereas understand exactly what a given ETF holds and mutual funds generally disclose their hold- how its underlying index really works during ings every quarter. particular market environments. “This transparency and trading flexibility “For example, investors must understand n investment sea change has are important to investors been occurring in the past who want to know how much few years: Mutual fund inves- an ETF costs and what it is tors have been shifting some or investing in before they buy Investors should understand all of their assets to passively or sell shares,” Bush pointed managed vehicles.1 For many, out. “These advantages can exactly what a given ETF holds exchange-traded funds (ETFs) be particularly critical in Ahave become the vehicle of choice. highly volatile markets, and how its underlying index “An increasing number of investors are turn- since investors can place ETF ing to ETFs to gain exposure to specific mar- trades using limit and stop kets or to complement other holdings in their orders to potentially mitigate really works during particular portfolios,” said Mariana F. Bush, CFA, a senior risk and minimize losses.” analyst with Wells Fargo Advisors. ETFs can also offer an easy market environments. Many of those investors have found plenty way to gain exposure to par- to like in the rapidly maturing field of ETFs. ticular areas of the market. Since the first ETF was launched in 1993, the “Some investors just want to integrate a broad the different return components of futures- field has grown to nearly 1,200 different ETFs, mix of stocks, such as those included in the based ETFs,” Bush cautioned. “The way fu- with combined assets of $1.193 trillion as of S&P 500 index,” explained Bush. “Others are tures contracts work is different from how March 31, 2012, according to the Investment interested in taking a targeted—but still cost- stocks behave. The same goes for ETFs that Company Institute.2 efficient—approach to an investing theme, such involve leverage. They can magnify or min- as the potential for a region, country or indus- imize market movements, and the mecha- TRADED LIKE A STOCK try to outperform the market. ETFs can offer nisms for how they do that can be complex. ETFs are a type of exchange-traded product a way for an investor to achieve potentially Investors must understand the drivers of per- (ETP), which is essentially what it sounds like: diverse exposure to that particular segment formance (or causes of underperformance) an investment that trades on exchanges. ETFs of the market.” with those more complicated ETFs.” are generally designed to mirror the perfor- You should take the time to understand ex- mance of certain market indexes, so they tend OTHER USES—AND actly what you’re buying and how it’s likely to be passively managed. A few actively man- CONSIDERATIONS to behave under different conditions. Work- aged ETFs ex ist, but when most people discuss Another advantage of ETFs is that the invest- ing with your financial advisor to select ap- ETFs, they’re referring to the index-based type. ment minimum is one share.3 This makes it propriate ETFs is likely to involve more than Like mutual funds, most ETFs are registered easy for investors to try out investment themes just a review of performance and expenses. investment companies. And like index mutual or create targeted allocations without a signifi- Among other things, you’ll want to look at an funds, passively managed ETFs attempt to mir- cant investment of capital. Continues on page 38 : ETF 38 MARCH 1, 2013 :: Ophthalmology Times practice management
ing them a cornerstone of an individual’s port- References ETF folio,” Bush said. 1. Tom Lydon, “Are Shifting Demographics Driving ETF Shares of ETFs are bought and sold at Growth?” Yahoo! Finance, 10 May 2012, http://finance. ( Continued from page 37 ) market price which may differ significantly yahoo.com/news/shifting-demographics-driving-etf- from the ETF’s net asset value and are not growth-133555434.html. 2. Investment Company Institute, “Exchange-Traded Fund individual ETF’s exposure and how it fits into individually redeemed from the fund. Only Assets, March 2012,” 24 April 2012, http://www.ici.org/ the rest of your portfolio. “authorized participants” can purchase and etf_resources/research/etfs_03_12. You’ll also want to examine a given ETF’s redeem directly in the funds creation units, 3. NYSE Euronext. ETFs FAQ, 2009, http://www.amex.com/ liquidity. This tends to be less of an issue for typically consisting of a block of 50,000 shares. etf/FAQ/et_etffaq.htm#4 popular, heavily traded ETFs, but less liq- Ordinary brokerage commissions for pur- uid ETFs may be thinly traded and difficult chases and sales may apply which could to trade at a price that makes sense for your reduce returns. investment strategy. Your financial advisor, Index-based ETFs seek investment results JOHN J. GRANDE, CFP®; TRAUDY F. GRANDE, CFP®; AND JOHN S. GRANDE, CFP®are co-editors of Money Matters. They are owners who has access to the traders, can guide your that, before expenses, generally correspond Grande Financial Services Inc., Oakhurst, NJ, and registered principals of Wells trading execution. to the price and yield of a particular index. Fargo Advisors Financial Network Inc., member FINRA/SIPC. ETFs may be an attractive option if you want There is no assurance that the price and The Grandes lecture at Johns Hopkins University School of Medicine, and they to diversify your portfolio with exposure to yield performance of the index can be fully advise ophthalmologists across the country on a diverse range of investment additional asset classes and market sectors, matched. Q and financial matters. Readers may submit their financial questions to them at but it’s important for you to understand their 800/722-1258 or e-mail [email protected] unique characteristics. Readers also may access the Grande’s website at www.grandefinancialservices.com When asked directly whether she believes EDITOR’S NOTE: ETFs are subject to risks similar to those of stocks. Investments in securities and insurance products are: Not FDIC-insured/not ETFs are the new mutual funds, Bush answered bank-guaranteed/may lose value. [PCG / ISG:] Wells Fargo Advisors, LLC, Member with a qualified, “yes.” Investment returns may fluctuate and are subject to market volatility, so that an investor’s shares, when SIPC, is a registered broker-dealer and a separate non-bank affiliate of Wells Fargo “For investors who take the time to under- redeemed, or sold, may be worth more or less than & Co. Investment products and services are offered through Wells Fargo Advisors stand what ETFs can and can’t do and what their original cost. Financial Network, LLC (WFAFN), Member SIPC. Grande Financial Services Inc. is a they hold, ETFs offer benefits that justify mak- separate entity from WFAFN.
HIPAA rules complicate compliance, could up fines
The stakes are even higher for security breaches of health THE FINAL RULE: information, according to new rules for the Health Insurance > makes business associates of covered entities directly Portability and Accountability Act of 1996 (HIPAA). liable for compliance with certain requirements; > strengthens limitations on the use of personal health In fact, the U.S. Department of Health OCR Director Leon Rodriguez says information for marketing and fundraising purposes; and Human Services (HHS) recently the rules “strengthen the ability of > prohibits the sale of a patient’s personal health information unveiled these rules in the Federal my office to vigorously enforce the without specific individual authorization to do so; Register, which are described as the HIPAA privacy and security protections, > expands patients’ rights to request and receive electronic most sweeping changes to HIPAA since regardless of whether the information copies of their personal health information; and its birth more than 15 years ago. Slated is being held by a health plan, a health- broadens patients’ ability to restrict, in some instances, to take effect March 26 and with a care provider, or one of their business disclosure of their personal health information to health compliance deadline of Sept. 23, the associates.” insurance plans; rules are thought to make compliance The final omnibus rule is based on > requires modification to, and redistribution of, a covered for physicians more difficult while entity’s notice of privacy practices; statutory changes under the HITECH expanding the government’s latitude Act and the Genetic Information > simplifies reporting requirements of child immunizations in levying fines to providers from $100 Nondiscrimination Act of 2008, which to schools; to $1.5 million. clarifies that genetic information is > expands the Health Information Technology for Economic The move by government regulators protected under the HIPAA privacy rule and Clinical Health (HITECH) Act to address enforcement within HHS’s Office of Civil Rights (OCR) and prohibits most health plans from due to willful neglect; and is focused on protecting and expanding using or disclosing genetic information > adopts changes to increase and tier civil monetary penalties. individual rights covered by HIPAA. for underwriting. MARCH 1, 2013 :: Ophthalmology Times 39 marketplace
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or conventional emission modes by our sup- because of its ergonomically friendly design and EFFICIENCY port staff, depending on the patient’s pathology. the reduction in patient movement resulting By utilizing the exam room in this manner, from its use in our dual-purpose exam rooms. ( Continued from page 42 ) not only is there an additional laser available The changes we made to our patient educa- to aid with the workflow, but not having to tion and practice layout, coupled with the capital ring either during or after treatment.1 It is move the patient to a different location for investment in additional laser equipment, have likely that continued research will find this treatment results in significant time savings greatly improved our patient pass-through rates. treatment modality to be optimal for an ex- as well. Typical patients in a retina practice We plan to continue in our quest for greater panding number of retinal diseases. are fairly elderly and often use walkers, wheel- efficiency this year with the adoption of elec- chairs, or some other assistance to get from tronic medical records. As we all str uggle with point A to point B, and they truly appreciate cost containment, it is important to remem- not having to move back and forth as much. ber that revenue enhancement should not be A check list for your We chose this laser because of its ergonomics, overlooked as a means of improving practice practice redesign versatility, and small footprint. As our knowl- profitability, and we have found that to be the edge of micropulse laser applications grows, case with our recent updates. Q we are finding that we have many more pa- PATIENT EDUCATION. Audio visual tients that may benefit from laser treatment, Reference aids are an effective means of educating and that this method of treatment may ease t Luttrull JK, Sramek C, et al. Long-term safety, high-resolution imaging, and tissue temperature patients about their disease pathology and case management and improve patient out- modeling of subvisible diode micropulse treatment. An update to our exam lanes included comes. The more laser procedures that are photocoagulation for retinovascular macular edema. adding 32-inch, flat-screen monitors on each done, the greater the demand for efficiency Retina. 2012;32:375-386. wall that allow projection of optical coherence from the treatment modality. tomography and angiograpic images, as well The laser can be placed on a typical arm ap- as educational images. paratus in an exam room and the treatment set- tings can be quickly adjusted. The integration PATRICK J. CASKEY, MD, is senior partner at North Bay PATIENT FLOW. Create a circular flow of the laser into our practice has significantly Vitreoretinal Consultants, Santa Rosa, CA. He has no fi nancial throughout the office, where patients check in improved our overall laser treatment efficiency disclosures or consulting relationships relevant to this article. at one location and check out at another. Keep walkways wheelchair- and walker-friendly. Have a staff member stationed at the exam door and Advertiser Index ready to escort patients to the check-out desk. This enables the staff member to address additional Advertiser Page Advertiser Page questions or concerns, while the physician moves on to the next patient. Alcon Laboratories Inc. 9-10, 19 Marco CV4 Tel: 800/862-5266 Tel: 800/874-5274 ADDITIONAL LASER TREATMENT Internet: www.alcon.com Internet: www.marco.com CAPABILITY. Avoid a bottleneck for patients Allergan Inc. 22-24* Optos 11 waiting to be moved from the exam lane to Tel: 714/246-4500 Internet: www.optos.com the laser room. One option is to design exam Customer Service: 800/433-8871 Fax: 714/246-4971 Regeneron Pharmaceuticals 6A-B* rooms to accommodate lasers directly into the Internet: www.allergan.com Tel: 914/345-7400 exam lanes. By utilizing the exam room in this Bausch + Lomb 13-15 Internet: www.regeneron.com matter, there is an additional laser available to Tel: 800/227-1427 Rhein Medical 5 aid with the workflow. In addition, significant Customer Service: 800/323-0000 Tel: 800/637-4346 Internet: www.bausch.com time savings result from not having to move Internet: www.rheinmedical.com patients to a different location for treatment. Brien Holden Vision Institute 27 ThromboGenics CV3 Tel: 612/9385-7441 Tel: 732/590-2900 Internet: www.brienholdenvision.org Internet: www.thrombogenics.com In our practice of four physicians, there was Fera Pharmaceuticals Inc. CV2 This index is provided as an additional service. often a bottleneck created by patients waiting Tel: 414/434-6604 Fax: 414/434-4603 The publisher does not assume any liability for errors to be moved from the exam lane to the laser Internet: www.ferapharma.com or omissions. room to receive treatment. To address this, ICHE 30-31 *Indicates a demographic advertisement. we designed three of our twelve exam rooms Internet: www.bizmedicine.org to accommodate lasers (IQ 577, Iridex Corp.) directly into the exam lanes. We initially in- OPHTHALMOLOGY TIMES (Print ISSN 0193-032X, Digital ISSN 2150-7333) is published semi-monthly (24 issues yearly) by Advanstar Communications Inc., 131 W First Street, Duluth, MN stalled two lasers and we are anticipating add- 55802-2065. Subscription rates: $200 for one year in the United States & Possessions, Canada and Mexico; all other countries $263 for one year. Pricing includes air-expedited service. Single copies (prepaid only): $13 in the United States & Possessions, Canada and Mexico; $20 all other countries. Back issues, if available are $25 in the U.S. $ Possessions; $30 in Canada ing a third in the near future. and Mexico; $35 in all other countries. Include $6.50 per order plus $2 per additional copy for U.S. postage and handling. If shipping outside the U.S., include an additional $10 per order plus $5 per additional copy. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to OPHTHALMOLOGY TIMES, P.O. Box The lasers are mounted on a swing arm that 6009, Duluth, MN 55806-6009. Canadian G.S.T. number: R-124213133RT001, Publications Mail Agreement Number 40612608. Return undeliverable Canadian addresses to: Pitney Bowes allows the physician to treat the patient either PO Box 25542 London, ON N6C 6B2 CANADA. Printed in the U.S.A. ©2013 Advanstar Communications Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including in the sitting position or with the chair reclined. by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by Advanstar Communications Inc. for libraries and other users registered with the Copyright Clearance Center, 222 The laser console is positioned and the laser out- Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www.copyright.com online. For uses beyond those listed above, please direct your written request to put settings are adjusted to either micropulse Permission Dept. fax 440-756-5255 or email: [email protected]. 42 MARCH 1, 2013 :: Ophthalmology Times practice management
Redesign places focus on practice efficiency Improved layout and patient education lead to increased pass-through rates By Patrick J. Caskey, MD; Special to Ophthalmology Times
hile the future is never certain, inescapable in- fluences bear down on the field of ophthalmol- ogy. Perhaps most cer- tain is that fewer num- bers of ophthalmologists willW have to treat an ever-growing population. The first of the baby boomers are just start- ing to reach the age of needing glaucoma, cat- aract, and retinal treatments, and many more are on their heels. In addition, there is steady pressure from health-care reform to treat a greater number of patients at a lower level of reimbursement. When my partners and I remodeled our practice last year, it was with an eye toward efficiency in preparation for what is to come.
AUDIOVISUAL UPDATES Patient education is an essential task that also has the potential to eat up a lot of physician time. However, an effective means of educat- ing patients about retinal difficulties can help the patient understand the pathology better, as well as save the physician valuable chair time. Audio visual aids in one form or another In our practice of four physicians, there was often a bottleneck created by patients waiting to be moved from the exam lane to the laser room to receive treatment. To address are incredibly helpful in that regard. There- this, we designed three of our twelve exam rooms to accommodate lasers directly into the exam fore, the update to our exam lanes included lanes. The lasers are mounted on a swing arm that allows the physician to treat the patient either in adding 32-inch, flat-screen monitors on each the sitting position or with the chair reclined. The laser console is positioned and the laser output wall that allow projection of optical coherence settings are adjusted to either micropulse or conventional emission modes by our support staff, tomography and angiographic images as well depending on the patient’s pathology. (Photo courtesy of Patrick J. Caskey, MD) as educational materials. The quick and seamless display of patient diagnostic images allows the physician to ex- the daily examination and treatment of patients. ADDED LASER CAPABILITY plain to both the patient and the family mem- One component of this was creating a circular An important addition to our office was addi- bers what pathology is present and what treat- flow throughout the office where patients check tional laser treatment capability. Retinal photo- ment options are available. The use of images in at one location and check out at another. coagulation can be used to treat a variety of increases patient understanding significantly, All walkways are wheelchair- and walker- ischemic, inflammatory, and degenerative reti- reducing the time physicians spend on educa- friendly. A crisp and pleasant end to the pa- nal diseases. tion while increasing patient knowledge and tient encounter is created by stationing a staff In addition, the science behind micropulse overall satisfaction. member at the exam door ready to escort the laser technology has introduced the concept patient to the check-out desk. The staff mem- of providing a positive treatment benefit while PATIENT FLOW ber is then able to provide answers to any ad- avoiding visible intraretinal damage or scar- The remodel to our practice also had to address ditional questions or concerns, while the phy- patient flow concerns and eliminate gridlock in sician smoothly moves on to the next patient. Continues on page 41 : Efficiency (ocriplasmin) Intravitreal Injection, 2.5 mg/mL
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® *Data based on national averages. CME MONOGRAPH Visit http://www.MedEdicus.com/ for online testing and instant CME certificate. Expert Consultations in Diseases of the Aging Eye Glaucoma, Ocular Surface Disease, and Beyond Highlights from a CME Symposium held during the American Academy of Ophthalmology 2012 meeting
Original Release: March 1, 2013 Last Review: February 15, 2013 Expiration: March 31, 2014
Learning Method and Medium Program Chair This educational activity consists of a supplement and ten (10) study questions. The participant should, in order, read the learning objectives contained at the Richard K. Parrish II, MD beginning of this supplement, read the supplement, answer all questions in the 662&,$7(($1)255$'8$7((',&$/'8&$7,21 post test, and complete the Activity Evaluation/Credit Request form. To receive 52)(66252) 3+7+$/02/2*< credit for this activity, please follow the instructions provided on the post test University of Miami Miller School of Medicine and Activity Evaluation/Credit Request form. This educational activity should $6&20 $/0(5<(167,787( take a maximum of 1 hour to complete. Miami, Florida Content Source This continuing medical education (CME) activity captures content from a CME symposium held on November 10, 2012, in Chicago, Illinois. Faculty Activity Description Brian A. Francis, MD, MS The management of patients with ocular hypertension or glaucoma increases in complexity as comorbid conditions such as ocular surface disease and $/3+$1'1*(/<1 ,))(1%85*+ 52)(66252)/$8&20$ cataract present. The goal of this program is to improve the knowledge 2+(1<<(167,787( and clinical performance of glaucoma specialists and comprehensive Keck School of Medicine ophthalmologists by disseminating new information on ocular surface health University of Southern California in patients on glaucoma therapy, and providing expert clinical insight on the Los Angeles, California management of challenging cases. Target Audience Cindy M.L. Hutnik, MD, PhD This educational activity is intended for glaucoma specialists and 52)(6625(3$570(1762) 3+7+$/02/2*< $7+2/2*< comprehensive ophthalmologists. &+8/,&+ &+22/2)(',&,1((17,675< Learning Objectives Ivey Eye Institute Upon completion of this activity, participants should be better able to: St. Joseph’s Health Center ='(17,)<2&8/$5685)$&(',6($6(,17+(,53$7,(176:,7+*/$8&20$ "1,9(56,7<2)#(67(51 17$5,2 or ocular hypertension 21'21 17$5,2$1$'$ =(6&5,%(7+(())(&762)35(6(59$7,9(6,1*/$8&20$0(',&$7,216 on ocular health Steven L. Mansberger, MD, MPH = /$1())(&7,9(0(',&$/5(*,0(16)253$7,(176:,7+*/$8&20$252&8/$5 Senior Scientist, Legacy Health hypertension and complex presentations including ocular surface disease ,5(&7252)/$8&20$ (59,&(6 Accreditation Statement (9(56<(167,787( This activity has been planned and implemented in accordance with the 257/$1' 5(*21 66(17,$/5($6$1' 2/,&,(62)7+(&&5(',7$7,21281&,/)25217,18,1*(',&$/ Education through the joint sponsorship of The New York Eye and Ear Infirmary Stephen C. Pflugfelder, MD and MedEdicus LLC. The New York Eye and Ear Infirmary is accredited by the 52)(66252) 3+7+$/02/2*< ACCME to provide continuing medical education for physicians. James and Margaret Elkins Chair AMA Credit Designation Statement Baylor College of Medicine The New York Eye and Ear Infirmary designates this enduring material for a Houston, Texas maximum of 1.0 AMA PRA Category 1 Credit> +<6,&,$166+28/'&/$,021/<7+( credit commensurate with the extent of their participation in the activity. Grantor Statement This continuing medical education activity is supported through an Jointly sponsored by The New York Eye and Ear Infirmary and MedEdicus LLC. unrestricted educational grant from Merck & Co, Inc. Disclosure Policy Statement It is the policy of The New York Eye and Ear Infirmary that the faculty and anyone in a position to control activity content disclose any real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). The New York Eye and Ear Infirmary has established This continuing medical education activity is supported through policies in place that will identify and resolve all conflicts of interest prior an unrestricted educational grant from Merck & Co, Inc. to this educational activity. Full disclosure of faculty/planners and their commercial relationships, if any, follows.
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This CME symposium was not affiliated with the official program of the AAO/APAO Joint Meeting. Disclosures Brian A. Francis, MD, MS, had a financial agreement or affiliation during the Introduction past year with the following commercial interests in the form of Speakers Bureau: Merck & Co, Inc. For patients with glaucoma or ocular hypertension, the end goal is Cindy M.L. Hutnik, MD, PhD, has no relevant commercial relationships to disclose. preserving vision by medically and/or surgically lowering intraocular Steven L. Mansberger, MD, MPH, had a financial agreement or affiliation during the past year with the following commercial interests in the form of pressure (IOP). An underappreciated factor than can affect treatment Consultant/Advisory Board: Alcon, Inc; Allergan, Inc; and Santen Pharmaceutical outcomes is preexisting or concurrent ocular surface disease (OSD). Co, Ltd; Speakers Bureau: Merck & Co, Inc; Contracted Research: Allergan, Inc; American Glaucoma Society; Centers for Disease Control and Prevention; and Recently, 5 leading ophthalmologists convened at a continuing medical Merck & Co, Inc. Richard K. Parrish II, MD, had a financial agreement or affiliation during the education (CME) symposium to present complex clinical cases focusing on past year with the following commercial interests in the form of Consultant/ the intersection of IOP management and ocular surface health. This CME Advisory Board: Aerie Pharmaceuticals, Inc; Alimera Sciences, Inc; Allergan, Inc; activity summarizes highlights from the case presentations and includes AqueSys, Inc; Bausch + Lomb Incorporated; Glaukos Corporation; InnFocus, Inc; Innovia LLC; and Merck & Co, Inc. panel discussion in 2 of the cases, to share with you the particular debate Stephen C. Pflugfelder, MD, had a financial agreement or affiliation during and varied perspectives those cases engendered. We hope the evidence the past year with the following commercial interests in the form of presented and the panel’s insight on this topic will be helpful to you in Consultant/Advisory Board: Allergan, Inc; Bausch + Lomb Incorporated; and GlaxoSmithKline; Contracted Research: Allergan, Inc; and GlaxoSmithKline. managing patients with glaucoma or ocular hypertension.
Peer Review Disclosures —Richard K. Parrish II, MD Ted Gerszberg, MD, has no relevant commercial relationships to disclose. Editorial Support Disclosures Evaluating the Ocular Surface in Patients With Derek Dore, PharmD; Cynthia Tornallyay, RD, MBA, CCMEP; Kimberly Corbin, CCMEP; Barbara Aubel; and Barbara Lyon have no relevant commercial Glaucoma or Ocular Hypertension relationships to disclose. —Stephen C. Pflugfelder, MD Disclosure Attestation The contributing physicians listed above have attested to the following: Case 1: The patient is a 64-year-old female with a several-year history 1) that the relationships/affiliations noted will not bias or otherwise influence of eye irritation and intermittent tearing that worsens upon their involvement in this activity; 2) that practice recommendations given awakening. Glaucoma was diagnosed a year ago and she is currently relevant to the companies with whom they have relationships/affiliations will being treated with generic latanoprost preserved with benzalkonium be supported by the best available evidence or, absent evidence, will be chloride (BAK). Over the past 3 months, redness and burning have consistent with generally accepted medical practice; and 3) that all reasonable been noted throughout the day, with worsening after evening clinical alternatives will be discussed when making practice recommendations. latanoprost instillation. Off-Label Discussion This activity does not include off-label discussion of any agents. Please refer to The patient’s tear break-up time (TBUT), as measured by standard the official prescribing information for each product for discussion of approved fluorescein testing, is 3 seconds. She has inferior corneal fluorescein indications, contraindications, and warnings. staining and poorly expressible meibomian glands with ductal keratinization and posterior lid margin neovascularization. External For Digital Editions System Requirements: examination with lissamine green dye finds lid parallel conjunctival If you are viewing this activity online, please ensure the computer you plan to folds, which is indicative of conjunctivochalasis. (Figure 1A) Anterior use meets the following requirements: segment optical coherence tomography (OCT) shows her tear ● Operating System: Windows or Macintosh meniscus height centrally to be 378 μm, approximately 50% higher ● Media Viewing Requirements: Flash Player or Adobe Reader than the normal height of 250 μm. (Figure 1B) ● Supported Browsers: Microsoft Internet Explorer, Firefox, Google Chrome, Safari, and Opera ● A good Internet connection The New York Eye and Ear Infirmary Privacy & Confidentiality Policy http://www.nyee.edu/website-privacy.html CME Provider Contact Information 378 μm For questions about this activity, call 212-979-4383. To Obtain AMA PRA Category 1 Credit™ To obtain AMA PRA Category 1 Credit™ for this activity, read the material in its entirety and consult referenced sources as necessary. Complete the evaluation form along with the post test answer box within this supplement. Remove the Activity Evaluation/Credit Request page from the printed supplement or print the Activity Evaluation/ Credit Request page from the Digital Edition. Return via Figure 1A. External examination of Figure 1B. Increased tear meniscus mail or fax to Kim Corbin, Director, ICME, The New York Eye and Ear Infirmary, Case Patient 1 showing lid parallel height in Case Patient 1 visualized 310 East 14th Street, New York, NY 10003 or fax to (212) 353-5703. Your certificate conjunctival folds. by OCT. will be mailed to the address that you provide on the evaluation form. Please Photos Courtesy of Stephen C. Pflugfelder, MD allow 3 weeks for mailed/faxed forms to be processed.There are no fees for participating and receiving CME credit for this activity. Alternatively, we offer instant certificate processing and support Green CME. What are the factors contributing to this patient’s Please take this post test and evaluation online by going to www.MedEdicus.com, presentation of ocular surface signs and symptoms? Educational Activities tab, and clicking the Post-Test & CME Certificate button. Upon passing, you will receive your certificate immediately. You must score 70% There are several factors that may be contributing to the patient’s or higher to receive credit for this activity, and may take the test up to 2 times. presentation: preexisting and persistent OSD, deleterious effects of Upon registering and successfully completing the post test, your certificate will BAK, and abnormal tear dynamics and delayed tear clearance. be made available online and you can print it or file it. Preexisting and Persistent OSD Disclaimer The views and opinions expressed in this educational activity are those of the Prior to the initiation of ocular hypotensive therapy, the patient’s faculty and do not necessarily represent the views of The New York Eye and Ear several-year history of eye irritation and tearing is consistent with Infirmary; MedEdicus LLC; Merck & Co, Inc; or Ophthalmology Times. OSD. Her current signs and symptoms—reduced TBUT, corneal
This CME activity is copyrighted to MedEdicus LLC ©2013. All rights reserved. 2 fluorescein staining, meibomian gland dysfunction, redness and burning in the eyes—indicate persistent OSD. Dr Pflugfelder’s Ocular Surface Assessment Deleterious Effects of BAK on the Ocular Surface 1. Inquire about ocular irritation symptoms: BAK, the most commonly used preservative in ocular medications, is a Although there are many validated questionnaires available, their quaternary ammonium chloride compound with surfactant and administration can be quite cumbersome and time consuming. I detergent properties.1 The toxicity of BAK has been studied extensively. have found a single question to be just as valuable as a set of BAK disrupts corneal epithelial tight junctions,1-3 leading to many questions. Identifying OSD can be as simple as asking your accelerated desquamation, or loss of the apical corneal and patients 1 question, “Are you experiencing eye irritation?” conjunctival epithelium.3,4 BAK can trigger apoptosis at concentrations of 0.01% and necrosis at concentrations of 0.05%.5 BAK also has been 2. Examine the ocular surface: 42'#( ." */( .)." 3"0 '),-. ()-#- found to be proinflammatory, increasing expression of inflammatory 42'#( ." &# ',!#(-)." 3*, - (.1#."' # )'#( markers on the ocular surface epithelial cells,6 promoting gland disease, ectropion, or conjunctival injection or inflammatory cell infiltration6 and goblet cell loss.7,8 The disruption of chalasis? I have found chalasis to be prevalent in patients both goblet cell mucin production and meibomian gland secretion of aged older than 45 years, and I have become much attuned the lipid component of tears results in an unstable tear film and to its presence. increased tear film evaporation, and thereby contributes to the dry eye 9 4" %. ,-. #&#.31#." &/), - #((-.#&& &/), - #( often seen in patients with glaucoma. BAK has been detected in the 1#. 1- )( - -%." *.# (..) &#(%( ." ( corneal and conjunctival tissues for 7 days following instillation of a check the TBUT. 1 single 30-μL drop. Chronic use of BAK may lead to an increased risk of 4)(-# , 2'#(#(!." #( ,#),. ,' (#- /-(-.#&&#(! 3 10 corneal complications such as punctate epitheliopathy, a decrease in in the eye makes it fairly simple to examine the meniscus functional vision, and may affect tasks that require extended ( 1#&&#( # . # ." . ,' (#- /-#-&)1(),'& 11 concentration, such as reading. BAK-induced toxicity may lead to elevated, or blocked by conjunctivochalasis. 12 decreased productivity and overall quality of life. 4)(-# ,' -/,#(!. ,*,) / .#)( 4'), -)*"#-.# . **,) "#-.)' -/, . , Abnormal Tear Dynamics and Delayed Tear Clearance )-')&,#.3" , #-()1 )'' , #&&30#& & This patient has conjunctivochalasis, a condition that increases with osmometer to measure tear osmolarity. The clinical value 13 age. Conjunctivochalasis can compartmentalize the tear film in the ) ."#-. -.#--.#&&/(%()1( ")1 0 , &# 0 .".#(." center of the eye, which results in pooling and stagnation of the context of prescribing ocular hypotensive therapy, it may be central tear meniscus.13 Her abnormal tear dynamics is increasing quite valuable. If a patient consistently has a tear osmolarity BAK’s concentration in the precorneal tear layer, which is likely #(." ,(! ) '-'),"#!" ,1"# "#-!, . ,."( responsible for the finding of punctate epitheliopathy of the inferior the range of 308 to 316 mOsm/L that has been found to be a cornea. The conjunctivochalasis also is causing delayed tear sensitive predictor of dry eye disease,15,16 then that patient clearance, resulting in retention of the ocular hypotensive in the -")/& *, - ,# () /&,"3*). (-#0 1#.")/. precorneal tear meniscus. Glaucoma and OSD Recognizing the Issue of Poor Adherence in This case is representative of the common problem of coexisting OSD Patients Treated With Ocular Hypotensives in patients with glaucoma. Leung and colleagues found that 59% of patients with glaucoma or ocular hypertension complained of —Steven L. Mansberger, MD, MPH 14 symptoms of OSD. In addition, they found that for each additional Case 2: The patient is an 85-year-old female who reports that she is BAK-preserved ocular hypotensive used, there were approximately “doing fine.” IOP in both eyes is 10 mm Hg (her baseline IOP in both 2 times higher odds of showing abnormal results on corneal and 14 eyes before beginning IOP-lowering therapy was 18 mm Hg). Her conjunctival lissamine green staining. medication regimen includes timolol twice daily, brimonidine 3 times Identifying patients at risk for ocular hypotensive toxicity daily, and dorzolamide 3 times daily. Fundoscopy finds evidence of disc hemorrhage inferiorly. (Figure 2) It is prudent to perform an ocular surface assessment in patients with glaucoma in order to determine if the condition of their ocular surface places them at greater risk for ocular surface toxicity with the use of ocular hypotensives. (See Sidebar.) Figure 2. Inferior disc Managing patients with glaucoma and OSD hemorrhage in Case Patient 2. First, I switch the patient to a BAK-free ocular hypotensive. If the Photo Courtesy of Steven L. Mansberger, MD, MPH patient’s OSD is not improved, I initiate an ocular hypotensive drop holiday, and treat the patient’s glaucoma with an oral carbonic anhydrase inhibitor. I consider instituting dry eye therapy with a preservative-free, low-dose ocular steroid, such as dexamethasone 0.01%, which can be compounded by a specialty pharmacy. Other dry eye therapies to consider include ocular cyclosporine A 0.05%; low- dose oral doxycycline (20 mg twice a day or 40 mg once daily), which Disc hemorrhage in patients with glaucoma inhibits desquamation in the corneal epithelium17,18; or punctal There should be concern when disc hemorrhage is observed in the occlusion plugs (only after the patient has discontinued the BAK- setting of good IOP readings. Just as hemoglobin A1C may be used as preserved ocular hypotensive). For ocular hypotensive-naïve patients, an indicator of glucose control in patients with diabetes, the presence the decision to avoid ocular hypotensives containing BAK can of disc hemorrhage in patients with glaucoma may indicate poor mitigate the risk of developing ocular surface problems. Rossi and adherence with ocular hypotensives. Disc hemorrhages persist, on colleagues found that initiating IOP-lowering therapy with a average, for 3 to 6 months, and can be a sign that either patients are preservative-free ocular hypotensive in ocular hypotensive-naïve poorly adherent to their medications or that their glaucoma is patients resulted in no new cases of OSD and maintained the quality worsening. The finding of a disc hemorrhage should prompt of life of treated patients.19 ophthalmologists to ask patients about adherence.
3 How adherent are patients with their prescribed 2) Modifiable factors: perceived severity of disease, perceived benefits ocular hypotensives? of adherence, perceived barriers to adherence, and perceived susceptibility to blindness. This category includes “Cues to Action” Examining Adherence Patterns and Persistency of Adherence that refer to the external reminders some patients may need to When analyzing adherence patterns of patients with their ocular help them remember to use their medication. hypotensives, researchers find that patients typically are most adherent immediately after their ophthalmologist appointment and By identifying and addressing the following factors, patient then immediately before they return for another office visit. Therefore, adherence may be improved. the level of adherence to medications is lower in between visits.20 One BPatient Demographic Features: Elderly patients often have poor way to combat this dip in adherence, especially in patients with corneal sensation. Refrigerating their ocular hypotensive may suspected poor adherence, is to increase the frequency of office visits. make the drop more obviously felt when hitting their eye, allowing them to know that they were successful in drop We also know that with time, we can expect a considerable decrease in administration. our patients’ adherence to their ocular hypotensives. Reardon and BSocial Supports: Patients should consider inviting family colleagues examined the persistency of patients with glaucoma in members into the examination room. Having a family member adhering to their ocular hypotensive regimens over time. When they in the room both reinforces the severity of the disease and looked at latanoprost refill records, they found that only approximately provides an opportunity to enlist family members’ help with 50% of patients were refilling their medications at 6 months.21 remembering the counseling relevant to medication adherence. Therapy adherence and visual function BPerceived Barriers to Adherence: Barriers to ocular hypotensives Stewart and colleagues assessed factors associated with decreased or include medication adverse effects and inconvenience of drop 23 stable visual function in patients with glaucoma and end-stage administration. Medication adverse effects are a common 23 cupping of the optic disc. Grading patients as either poorly adherent reason for poor adherence ; thus, switching to ocular or adherent to glaucoma treatment, the researchers found that of hypotensives that are gentler to the eye, such as those without those who were adherent, approximately 90% were graded as stable BAK, may improve adherence. Decreasing the frequency of drop 21 in their disease progression, whereas only approximately 50% of administration, by using once-daily prostaglandin analogs, or 24 the poorly adherent group were stable.22 Consequences of poor by using fixed-combination drops, also could improve adherence in these patients can be worsening of the visual field or adherence. the requirement of surgical intervention to manage IOP. BPerceived Susceptibility to Blindness and Perceived Severity of Disease: If patients neglect their ocular hypotensives because Determining adherence to ocular hypotensive therapy they perceive there is a low risk of vision loss, adherence may be If patients admit they are poorly adherent, they probably are, and improved through education. Also, patients may be poorly interventions should be employed to improve adherence. But what adherent when they do not have a measure for, and therefore about patients who claim they never miss a drop? The finding of disc cannot quantify, the degree of their susceptibility to blindness. hemorrhage in this patient may suggest poor adherence to ocular These 2 scenarios may be addressed by keeping patients hypotensive therapy despite a stable IOP reading at the office visit. informed of the results of their glaucoma assessments. To obtain a more accurate history, I have found it effective to help BCues to Action: Consider providing patients with cues to action; patients admit to poor adherence by suggesting an overestimate of suggest they set their container of ocular hypotensive near their nonadherence in a “safe” environment. For example, you might say, toothbrush to help them remember to instill their drops in much “It can be difficult to use eye drops every day. How often do you miss the same routine as brushing their teeth. your drops? …about half the time?” By suggesting this high rate of poor adherence, patients may be more comfortable discussing their In summary, poor adherence to ocular hypotensives is common; difficulty with drop administration. recognizing and managing the issue may improve patient outcomes. Improving adherence to ocular hypotensive therapy Recognizing Subtle Ocular Surface Disease A useful tool for determining the factors related to patient adherence Before Management of Intraocular Pressure to ocular hypotensives is the Health Belief Model. (Figure 3) The factors are broadly classified into 1 of 2 groups: —Cindy M.L. Hutnik, MD, PhD 1) Factors that affect individual perception: the patient/doctor Case 3: A 68-year-old male without a significant medical history is relationship, patient demographic features, social supports, patient referred by an optometrist who had been following him for elevated personality, and patient knowledge of the disease. IOP and was concerned about his recent optic disc changes. The patient felt he was doing well, had no visual or ocular complaints, and was still phakic. Individual Perception Modifiable Factors The ocular examination showed the following: OD OS Perceived Cues to Action: Severity of ( # " IOP (mm Hg) 24 22 Disease ( $# CCT (microns) 553 550 Patient/Doctor BCVA 20/25 20/25 Perceived Relationship, Angle III III Demographic Benefits— Features, Perceived BCVA=best corrected visual acuity; CCT=central Barriers to Social Supports. corneal thickness; IOP=intraocular pressure. Adherence Personality, Likelihood of Knowledge Adherence The patient’s visual fields were noncontributory, but he was Perceived diagnosed with open-angle glaucoma based on IOP elevation, optic Susceptibility to disc changes, and open angles on gonioscopy. Imaging revealed a thin Blindness ' retinal nerve fiber layer consistent with the diagnosis.
He was started on a BAK-preserved prostaglandin analog. Five days Figure 3. Health Belief Model (developed by the US Public Health Service after initiation of therapy, the patient reported discontinuing the in the 1950s). ocular hypotensive because of eye discomfort. He admitted that prior
4 Dr Mansberger: I would ensure the patient is properly hydrated, Figure 4. External examination drinking at least 8 to 12 cups of water per day, because dehydration of Case Patient 3 showing may be contributing to dry eye. My tendency is to avoid using a numerous collarettes on eyelash steroid unless there are no options remaining. I also would suggest bases, inspissation of meibomian the patient take nutritional supplements, and switch him to a glands, and lower lid laxity. preservative-free ocular hypotensive. Photo Courtesy of Cindy M.L. Hutnik, MD, PhD What are the BAK-free ocular hypotensive options available in the United States? In the United States, there are 2 commercially available to starting the BAK-preserved ocular hypotensive, his eyes were “a bit non–BAK-preserved ocular hypotensives and 3 preservative-free teary,” but after starting therapy he complained his eyes were “very ocular hypotensives. (Table 1) scratchy and uncomfortable,” and worsened when he read. He Comparative ocular surface effects of ocular hypotensives described the discomfort as “unbearable.” without BAK vs BAK-preserved ocular hypotensives Neither a switch to another prostaglandin analog nor a switch to Nakagawa and colleagues compared the effects of travoprost with another class of ocular hypotensives helped relieve his eye discomfort. sofZia™ to latanoprost with BAK and to phosphate-buffered saline Selective laser trabeculoplasty was offered as an early therapeutic controls on human corneal epithelial cells. The cell cultures exposed option; the patient, however, refused this procedure. to travoprost with sofZia and those of the controls both exhibited 100% viability at 6 hours, whereas the BAK-exposed cells had 0% At the 3-month office visit (after multiple ocular hypotensive trials), a viability (P<.05 vs control).29 full ocular surface workup was ordered. The clinical test findings were diagnostically borderline of OSD, demonstrating few superficial Removing BAK from ocular hypotensives has also been found to be punctate erosions, an equivocal 9-second TBUT in each eye, 14 mm clinically beneficial. Horsley and Kahook evaluated patients’ ocular Schirmer test in each eye, and some reflex tearing. External surface signs and symptoms during latanoprost with BAK therapy, examination showed numerous collarettes on his eyelash bases, and then reevaluated the patients 8 weeks after switching from inspissation of his meibomian glands with minimal expression upon latanoprost with BAK to travoprost with sofZia. The authors found compression, and lower lid laxity. (Figure 4) improvements in TBUT, inferior corneal staining, and OSDI (OSD index) scores after patients switched to travoprost with sofZia.30 (Table 2) Treating the patient with equivocal OSD findings Likewise, Janulevi ien and colleagues found that switching patients Dr Pflugfelder: I would attempt to quickly rehabilitate the ocular from latanoprost with BAK to preservative-free tafluprost led to surface with a topical corticosteroid and preservative-free artificial normalization of tear osmolarity, improved ocular comfort and TBUT, tears, and also to implement longer-term treatment with nutritional and decreased corneal staining.31 (Figure 5, Table 3) supplementation: fish oil (omega-3 fatty acid)25,26,27 and gamma- 28 linolenic acid (omega-6 fatty acid). Another option is to treat with Table 2. Mean TBUT, Inferior Corneal Staining Score, and OSDI Score on doxycycline. Doxycycline and other tetracyclines are potent anti- Latanoprost With BAK and at 8 Weeks After Switch to Travoprost With sofZia inflammatory agents, protease inhibitors, and metalloprotease (P<.001) in a Prospective, Open-label, Single-center Study Involving 20 Patients inhibitors.17,18 Doxycycline is dosed at 20 mg twice daily in the generic (40 Eyes)30 strength, or 40 mg once daily in the branded product. I typically treat patients with doxycyline at these dosages for a month, reassess, and Latanoprost Travoprost With P value then perhaps reduce the dose if improvement is observed. With BAK sofZia (8 weeks (8 weeks after switch) after switch) Dr Francis: I would treat the patient’s blepharitis with warm TBUT (seconds) 2.02 ± 0.71 6.34 ± 1.31 <.001a compresses and his dry eye with artificial tears, and also take the patient off BAK-preserved drops. Inferior corneal 2.40 ± 0.87 1.38 ± 0.59 <.001a staining Table 1. Ocular Hypotensives Without BAK Available in the United States OSDI score 26.31 ± 8.25 16.56 ± 6.19 <.001a Generic Name Brand Name Medication Class
Non–BAK-Preserved BAK=benzalkonium chloride; OSDI=ocular surface disease index; TBUT=tear break-up time. Brimonidine tartrate Alphagan® P Alpha-adrenergic aStudent’s t-test ophthalmic solution receptor agonist with Purite 0.1% or 0.15% 320 Travoprost ophthalmic Travatan Z® Prostaglandin analog solution with sofZia® 315 (boric acid, propylene glycol, sorbitol, zinc 310 mOsm/L) chloride) 0.004% (
Preservative-Free 305
Dorzolamide Cosopt® PF Carbonic anhydrase 300 hydrochloride/timolol inhibitor/Beta- maleate ophthalmic adrenergic receptor 295 solution 2%/0.5% antagonist Mean Osmolarity P<.001 vs baseline 290 Tafluprost ophthalmic Zioptan™ Prostaglandin analog Baseline Week 2 Week 6 Week 12 solution 0.0015%
Timolol maleate Timoptic® in Ocudose® Beta-adrenergic Figure 5. Mean osmolarity at baseline (latanoprost with BAK) and at 2 weeks ophthalmic solution receptor antagonist (P=.002 vs baseline), 6 weeks (P<.001 vs baseline), and 12 weeks (P<.001 vs 0.25% or 0.5% baseline), after changing medication to preservative-free tafluprost in a prospective, observer-masked study involving 30 patients (60 eyes).31 BAK=benzalkonium chloride. Adapted from Janulevi ien I et al. Clin Ophthalmol. 2012;6:103-109.
5 Table 3. Patients’ Dry Eye Complaints, Mean TBUT, and Abnormal Corneal Fluorescein Staining at Baseline (Latanoprost With BAK), and at 2, 6, and 12 Weeks After Changing to Preservative-free Tafluprost in a Prospective, Observer-masked Study Involving 30 Patients (60 Eyes)31
Baseline Week 2 Week 6 Week 12 P value (12 weeks vs baseline)
Dry eye 30 (100%) 19 (63.3%) 11 (36.7%) 11 (36.7%) <.05a complaints (n= 30, patients)
TBUT (seconds) 3.7 ± 1.1 4.1 ± 1.0 5.2 ± 1.5 6.5 ± 1.5 <.001b Figure 6. External examination (n= 60, eyes) of Case Patient 4 showing advanced OSD and eyelid Abnormal 45 (75.0%) 35 (58.3%) 21 (35%) 7 (12%) <.005a disease (lagophthalmos), fluorescein preventing closure of the eyes. staining of Photos Courtesy of the cornea Brian A. Francis, MD, MS (n= 60, eyes)
TBUT=tear break-up time. aMcNemar test bPaired t-test Adapted from Janulevi ien I et al. Clin Ophthalmol. 2012;6:103-109. procedure, her ocular surface and eyelids need time to heal, and her IOP could be managed with ocular antihypertensives The results of the study by Janulevi ien and colleagues emphasize without BAK or with an oral carbonic anhydrase inhibitor while the importance of setting realistic expectations for patients about awaiting the procedure. when they should expect to see improvements in OSD symptoms after switching from a BAK-preserved to a preservative-free ocular Dr Mansberger: This patient has a high chance of going blind, based hypotensive. Improvements in all OSD measures began to appear at on her presentation of uncontrolled IOP and visual decline. I have not week 2, although significant improvements were not seen until week found trabeculoplasty to be effective in patients with implanted 12. (Table 3) Indeed, in this patient, after the recognition and anterior chamber lenses. Trabeculectomy also may not be a good treatment of his subtle OSD, he was started on a preservative-free option, given the patient’s poor lid closure and conjunctival ocular hypotensive, which he has tolerated well. inflammation. Switching ocular hypotensives may be effective, but I would not choose this option because the patient’s visual field has Managing Advanced Glaucoma and been declining despite various attempts at maximal medical therapy. Severe Ocular Surface Disease Minimally invasive glaucoma surgery (MIGS) also may not reduce pressures sufficiently. Most of these procedures will lower IOP to the —Brian A. Francis, MD, MS high teens, which is not that different from the patient’s current IOP. I would likely consider implanting a tube, a Baerveldt tube or an Case 4: The patient is a 79-year-old female with a chief complaint of Ahmed valve implant. decreasing vision. She has a history of primary open-angle glaucoma, OSD, non-neovascular age-related macular degeneration, and Dr Francis: This patient has reached the end of the line in terms of cataract extraction with intraocular lens implantation in each eye. glaucoma medical treatment. I would avoid trabeculectomy in this Her visual fields have progressively worsened over the last 3 years. Her case because there is a high risk that the procedure would be medications, the only 2 ocular hypotensives she can tolerate, include associated with poor outcomes because of her considerable OSD.32 branded latanoprost with BAK at bedtime and dorzolamide twice Baudouin and colleagues found that long-term use of ocular daily in each eye. She is also using artificial tears during the day and hypotensives, particularly BAK-preserved ocular hypotensives, induces an artificial tear ointment at night. considerable histopathologic and inflammatory changes in the ocular surface and also in the trabecular meshwork. In addition, the The ocular examination finds the following: researchers found that as the number of ocular hypotensives OD OS increased, so did the inflammatory markers and disruption of the IOP (mm Hg) 12 20 normal conjunctival architecture.33 I would avoid MIGS-based BCVA 20/50 20/100 procedures because of potentially insufficient IOP lowering. RAPD + Instead of these surgical options, it was decided to manage this Gonioscopy 3+ SS 3+ SS with PAS temp patient with an aqueous tube shunt (Baerveldt implant) because of BCVA=best corrected visual acuity; IOP=intraocular pressure; its efficacy in lowering IOP and the minimal need for postoperative PAS=peripheral anterior synechiae; RAPD=relative afferent ocular hypotensive use or additional surgical interventions following papillary defect; SS=scleral spur. its implantation.34 Fundoscopy finds obvious advanced cupping and optic nerve damage in both eyes. She also has conjunctival injection bilaterally. External Conclusion examination finds advanced OSD and eyelid disease: considerable It is important to be mindful of the deleterious effects of BAK on lagophthalmos, which prevents complete closure of the eyes. She also ocular tissues and its potential to limit medical and surgical has exposure keratopathy and pannus inferiorly in the cornea. (Figure 6) interventions in patients with glaucoma or ocular hypertension. Identifying preexisting or coexisting OSD in patients with glaucoma How should this patient with advanced glaucoma and can assist clinicians in determining the therapeutic options that can severe OSD be managed? effectively and safely manage IOP, without compromising ocular Dr Hutnik: Certainly, this patient must become less dependent on surface health. Today, the ophthalmologist's toolbox has expanded to ocular anithypertensives, particularly agents with BAK. A surgical include non–BAK-preserved and preservative-free IOP-lowering option may need to be considered. Before undergoing a surgical therapies that effectively treat patients with or at risk for glaucoma.
6 References CME Post Test Questions
1. Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular surface To obtain AMA PRA Category 1 Credit™ for this activity, complete the CME Post Test by writing disease in glaucoma patients. Clin Ophthalmol. 2011;5:1575-1583. the best answer to each question in the Answer Box located on the Activity Evaluation/ 2. Pauly A, Meloni M, Brignole-Baudouin F, Warnet JM, Baudouin C. Multiple endpoint Credit Request form on the following page. Alternatively, you can complete the CME Post Test analysis of the 3D-reconstituted corneal epithelium after treatment with benzalkonium online at http://www.MedEdicus.com, Educational Activities tab, and click the Post-Test & chloride: early detection of toxic damage. Invest Ophthalmol Vis Sci. 2009;50(4):1644-1652. CME Certificate button. 3. Kaur IP, Lal S, Rana C, Kakkar S, Singh H. Ocular preservatives: associated risks and newer options. Cutan Ocul Toxicol. 2009;28(3):93-103. See detailed instructions at To Obtain AMA PRA Category 1 Credit™ at page 2. 4. Denoyer A, Ossant F, Arbeille B, et al. Very-high-frequency ultrasound corneal imaging as a new tool for early diagnosis of ocular surface toxicity in rabbits treated with a preserved 1. What is the prevalence of OSD symptoms in patients with glaucoma or ocular glaucoma drug. Ophthalmic Res. 2008;40(6):298-308. hypertension? 5. De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C. Effects of a. 29% benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest b. 39% Ophthalmol Vis Sci. 1999;40(3):619-630. c. 49% 6. Baudouin C, Riancho L, Warnet JM, Brignole F. In vitro studies of antiglaucomatous d. 59% prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost. Invest Ophthalmol Vis Sci. 2007;48(9):4123-4128. 2. Which of the following is likely the LEAST efficient method of identifying a patient who is 7. Liang H, Baudouin C, Labbe A, Riancho L, Brignole-Baudouin F. Conjunctiva-associated at risk for ocular hypotensive toxicity? lymphoid tissue (CALT) reactions to antiglaucoma prostaglandins with or without BAK- a. Examine the puncta preservative in rabbit acute toxicity study. PLoS One. 2012;7(3):e33913. b. Administer an ocular surface assessment questionnaire 8. Yalvaç IS, Gediko lu G, Karagöz Y, et al. Effects of antiglaucoma drugs on ocular surface. c. Examine the lid margin Acta Ophthalmol Scand. 1995;73(3):246-248. d. Administer a tear film stability test with fluorescein 9. Bron AJ, Tiffany JM, Gouveia SM, Yokoi N, Voon LW. Functional aspects of the tear film lipid layer. Exp Eye Res. 2004;78(3):347-360. 3. Which of the following is FALSE about BAK? 10. Liang H, Pauly A, Riancho L, Baudouin C, Brignole-Baudouin F. Toxicological evaluation of a. BAK can cause clinically significant IOP elevation preservative-containing and preservative-free topical prostaglandin analogues on a b. BAK can trigger apoptosis at concentrations of 0.01% and necrosis at concentrations three-dimensional-reconstituted corneal epithelium system. Br J Ophthalmol. 2011; of 0.05% 95(6):869-875. c. BAK has been found in corneal and conjunctival tissues for 7 days following 11. Ishida R, Kojima T, Dogru M, et al. The application of a new continuous functional visual acuity measurement system in dry eye syndromes. Am J Ophthalmol. 2005;139(2):253-258. instillation of a single 30-μL drop 12. Skalicky SE, Goldberg I, McCluskey P. Ocular surface disease and quality of life in patients d. BAK-induced toxicity can cause decreased patient quality of life with glaucoma. Am J Ophthalmol. 2012;153(1):1-9.e2. 4. Which of the following is consistent with conjunctivochalasis? 13. Gumus K, Pflugfelder SC. Increasing prevalence and severity of conjunctivochalasis with aging detected by anterior segment optical coherence tomography. Am J Ophthalmol. a. Central tear meniscus height of 225 μm 2012 Oct 1. [Epub ahead of print] b. Enhanced tear clearance 14. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma c. Pooling of tears patients. J Glaucoma. 2008;17(5):350-355. d. Tear osmolarity 300 mOsm/L 15. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011;151(5):792-798.e1. 5. According to Reardon and colleagues, approximately what percent of patients refill their 16. Tomlinson A, Khanal S, Ramaesh K, Diaper C, McFadyen A. Tear film osmolarity: latanoprost at 6 months’ time? determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci. 2006; 47(10): a. 25% 4309-4315. b. 50% 17. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress c. 75% MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium d. 100% in experimental dry eye. Exp Eye Res. 2006;83(3):526-535. 18. Kim HS, Luo L, Pflugfelder SC, Li DQ. Doxycycline inhibits TGF-beta1-induced MMP-9 via 6. Which of the following is an appropriate strategy to improve adherence to ocular Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci. hypotensive therapy? 2005;46(3):840-848. a. Suggest patients attend office visits alone to minimize distraction 19. Rossi GC, Pasinetti GM, Raimondi M, et al. Efficacy and ocular surface tolerability of during counseling preservative-free tafluprost 0.0015%: a 6-month, single-blind, observational study on b. Decrease the frequency of drop administration by prescribing naïve ocular hypertension or glaucoma patients. Expert Opin Drug Saf. 2012;11(4):519-525. fixed-combination drops 20. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topical c. Avoid providing patients with details of their glaucoma assessments pilocarpine treatment. Am J Ophthalmol. 1986;101(5):515-523. d. Recommend patients simplify ocular hypotensive administration by avoiding 21. Reardon G, Schwartz GF, Mozaffari E. Patient persistency with topical ocular hypotensive administering the doses close to other routine tasks therapy in a managed care population. Am J Ophthalmol. 2004;137(1 suppl):S3-S12. 22. Stewart WC, Chorak RP, Hunt HH, Sethuraman G. Factors associated with visual loss in 7. For each additional BAK-preserved eyedrop used, Leung and colleagues found that there patients with advanced glaucomatous changes in the optic nerve head. Am J Ophthalmol. were approximately _____ higher odds of showing abnormal results on corneal and 1993;116(2):176-181. conjunctival lissamine green staining. 23. Friedman DS, Hahn SR, Gelb L, et al. Doctor-patient communication, health-related beliefs, a. 2 times and adherence in glaucoma results from the Glaucoma Adherence and Persistency Study. b. 3 times Ophthalmology. 2008;115(8):1320-1327, 1327.e1-3. c. 4 times 24. Tsai JC, McClure CA, Ramos SE, Schlundt DG, Pichert JW. Compliance barriers in glaucoma: d. 5 times a systematic classification. J Glaucoma. 2003;12(5):393-398. 25. Miljanovi B, Trivedi KA, Dana MR, Gilbard JP, Buring JE, Schaumberg DA. Relation between 8. In patients at 8 weeks’ post-switch from latanoprost with BAK to travoprost with sofZia, dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Horsley and Kahook found all of the following, EXCEPT: Clin Nutr. 2005;82(4):887-893. a. Increased TBUT 26. Rashid S, Jin Y, Ecoiffier T, Barabino S, Schaumberg DA, Dana MR. Topical omega-3 and b. Decreased inferior corneal staining omega-6 fatty acids for treatment of dry eye. Arch Ophthalmol. 2008;126(2):219-225. c. Increased tear osmolarity 27. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian d. Decreased OSDI score gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-356. 28. Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid treatment in contact 9. A 72-year-old male with glaucoma presents with signs and symptoms of OSD. Ocular lens associated dry eye. Cont Lens Anterior Eye. 2008;31(3):141-146. examination finds an IOP of 12 mm Hg in both eyes and a newly found disc hemorrhage. 29. Nakagawa S, Usui T, Yokoo S, et al. Toxicity evaluation of antiglaucoma drugs using The patient is treated with timolol twice daily and brimonidine 3 times daily. Which of the stratified human cultivated corneal epithelial sheets. Invest Ophthalmol Vis Sci. 2012; following is the most likely cause of this patient’s presentation? 53(9):5154-5160. a. The patient has undiagnosed hypertension or diabetes that has led to the disc 30. Horsley MB, Kahook MY. Effects of prostaglandin analog therapy on the ocular surface of hemorrhage glaucoma patients. Clin Ophthalmol. 2009;3:291-295. b. Timolol and brimonidine are not adequately effective to provide the aggressive IOP 31. Janulevi ien I, Derka I, Grybauskiene L, Paulauskait R, Gromnickaite R, Kuzmien L. management necessary to prevent disc hemorrhage Effects of preservative-free tafluprost on tear film osmolarity, tolerability, and intraocular c. BAK-induced OSD has caused the patient to become poorly adherent with his ocular pressure in previously treated patients with open-angle glaucoma. Clin Ophthalmol. 2012; hypotensive, with resulting disc hemorrhage 6:103-109. d. Chronic brimonidine usage has induced disc hemorrhage 32. Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol. 1994;112(11):1446-1454. 10. In patients who were switched from BAK-preserved latanoprost to preservative-free 33. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by tafluprost, Janulevi ien and colleagues found that, at 12 weeks, patients’ eyes topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106(3): experienced significantly: 556-563. a. Decreased TBUT 34. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL; Tube versus b. Increased corneal staining Trabeculectomy Study Group. Treatment outcomes in the Tube Versus Trabeculectomy c. Decreased dry eye complaints (TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153(5):789-803.e2. d. Increased tear osmolarity
7 Original Release: March 1, 2013 Activity Evaluation/Credit Request Last Review: February 15, 2013 Expert Consultations in Diseases of the Aging Eye—Glaucoma, Ocular Surface Disease, and Beyond Expiration: March 31, 2014
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______Circle the number that best reflects your opinion on the degree to which the following learning objectives were met: 5 = Strongly Agree 4 = Agree 3 = Neutral 2 = Disagree 1 = Strongly Disagree Upon completion of this activity, I am better able to: C-.7=2/B8,>5*;<>;/*,.-2<.*<.276B9*=2.7=<@2=105*>,86*8;8,>5*;1B9.;=.7<287 C.<,;2+.=1..//.,=<8/9;.<.;?*=2?.<2705*>,86*6.-2,*=287<878,>5*;1.*5=1 C!5*7.//.,=2?.6.-2,*5;.026.7</8;9*=2.7=<@2=105*>,86*8;8,>5*;1B9.;=.7<287 and complex presentations including ocular surface disease
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