SOCIOECONOMICS AND HEALTH SERVICES
`
`SECTION EDITOR: PAUL P. LEE, MD
`
`Use of Retinal Procedures in Medicare Beneficiaries
`From 1997 to 2007
`
`Pradeep Y. Ramulu, MD, MHS, PhD; Diana V. Do, MD; Kevin J. Corcoran, COE, CPC, FNAO;
`Suzanne L. Corcoran, COE; Alan L. Robin, MD
`
`Objective: To observe how the treatment of retinal con-
`ditions changed over the preceding decade.
`
`Methods: Medicare fee-for-service data claims filed be-
`tween 1997 and 2007 were analyzed.
`
`Results: Fewer than 5000 intravitreal injections of a phar-
`macological agent were performed annually between 1997
`and 2001. Thereafter, the annual number of intravitreal
`injections more than doubled every year through 2006,
`reaching a high of 812 413 in 2007. Photodynamic therapy
`procedures decreased 83% from a peak of 133 565 proce-
`dures in 2004 to 22 675 procedures in 2007, while laser
`treatment of choroidal lesions or neovascularization de-
`creased 83% from a peak of 82 089 in 1999 to a mini-
`mum of 13 821 in 2007. Vitrectomies for primary retinal
`detachment (with or without scleral buckling) increased
`72% over the study period from 11 212 in 1997 to 19 923
`in 2007, while scleral buckles performed without vitrec-
`
`tomy decreased 69% from 8691 to 2660. Substantial vol-
`ume increases were also observed for vitrectomy with reti-
`nal membrane stripping (90% increase from 29 426 in 1997
`to 56 051 in 2007) or endolaser panretinal photocoagu-
`lation (86% increase from 10 319 in 1997 to 19 154 in
`2007). Volumes of pneumatic retinopexy, laser prophy-
`laxis for retinal detachment, laser treatment for retinal
`edema, and laser treatment for retinopathy all changed less
`than 25% from 1997 and 2007.
`
`Conclusions: Marked changes in the use of several reti-
`nal procedures occurred between 1997 and 2007, par-
`ticularly in the treatment of macular degeneration and
`retinal detachment. These changes point to greater ac-
`ceptance and incorporation of vitrectomy and intravit-
`real injection as treatment modalities.
`
`Arch Ophthalmol. 2010;128(10):1335-1340
`
`R ETINAL DISEASE IS HIGHLY
`
`prevalent among older in-
`dividuals, and both age-
`related macular degenera-
`tion (AMD) and diabetic
`retinopathy account for more than half the
`irreversible blindness in older Ameri-
`cans.1-5 The prevalence of both macular de-
`generation and diabetic retinopathy in-
`creases with age, and the number of
`Americans affected by these conditions is
`expected to increase substantially as the
`number of Americans older than 65 years
`doubles from 2010 to 2040.6-8 Addition-
`ally, dietary and exercise habits are ex-
`pected to increase the prevalence of dia-
`betes mellitus within each age group.7,8
`Thus, many more individuals with reti-
`nal diseases are expected to require treat-
`ment in future years.
`The last decade has seen substantial
`changes in the treatment options available
`
`for many retinal diseases, particularly in the
`treatment of neovascular AMD (Figure 1).
`In the 1990s, thermal laser treatment for
`extrafoveal and juxtafoveal choroidal neo-
`vascularization (CNV) represented the only
`significant treatment option with a dem-
`onstrated benefit.9,10 In 2000, photody-
`namic therapy, involving laser activation of
`intravenously delivered verteporfin, was ap-
`proved for use after having been demon-
`strated to be effective for subgroups of in-
`dividuals with subfoveal CNV due to AMD
`who met specific angiographic guide-
`lines.11,12 In 2006, monthly intravitreal in-
`jections of ranibizumab, a monoclonal an-
`tibody that inhibits vascular endothelial
`growth factor (VEGF), demonstrated su-
`perior visual acuity outcomes compared
`with photodynamic therapy in eyes with
`CNV due to AMD13 and was approved by
`the Food and Drug Administration. Off-
`label use of intravitreal bevacizumab, also
`
`Author Affiliations: Wilmer
`Eye Institute (Drs Ramulu, Do,
`and Robin), and Bloomberg
`School of Public Health
`(Dr Robin), Johns Hopkins
`University, Baltimore, Maryland;
`and Corcoran Consulting
`Group, San Bernardino,
`California (Mr K. J. Corcoran
`and Ms S. L. Corcoran).
`
`(REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 10), OCT 2010
`1335
`
`WWW.ARCHOPHTHALMOL.COM
`
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`
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`
`

`

`First publication of
`intravitreal bevacizumab
`
`2000
`
`2001
`
`l
`
`Photodynamic
`therapy approved
`
`2002
`
`2003
`
`2004
`
`2005
`
`Pegaptanib
`approved
`
`!
`l
`
`Ranibizumab
`approved
`
`!
`
`2006
`
`2007
`
`Communication with the Johns Hopkins institutional re-
`view board determined that the study did not require institu-
`tional review board approval. Because human subjects were not
`directly involved, it was not necessary to obtain Health Insur-
`ance Portability and Accountability Act approval nor register
`the study as a clinical trial.
`
`RESULTS
`
`The volume of the posterior segment laser treatments and
`surgeries performed among Medicare beneficiaries be-
`tween 1997 and 2007 is cataloged by CPT code in the
`Table. The total number of procedures increased every
`year except from 1997 to 1998, with a total increase of
`192% over the study period. The largest year-to-year gains
`were observed in 2006 and 2007, where a greater than
`20% increase in total volume was observed.
`Procedure volumes changed most markedly for treat-
`ments directed toward neovascular AMD. Fewer than
`5000 intravitreal injections of a pharmacological agent
`were performed annually between 1997 and 2001 but then
`increased 193-fold from 4215 injections in 2001 to
`812 413 injections in 2007 (Figure 2).
`Photodynamic therapy first became available for the
`treatment of neovascular AMD in 2001, when 85 411 pro-
`cedures were performed. Volume increased 56% to a maxi-
`mum of 133 565 procedures through 2004, but then
`decreased 83% to a total of 22 675 procedures in 2007
`(eFigure 1, http://www.archophthalmol.com). Thermal la-
`ser treatment for CNV decreased 83% over the study pe-
`riod, from 56 966 procedures in 1997 to 13 821 proce-
`dures in 2007. Volume decreased 56% between 2004 and
`2007, corresponding to the period of greatest growth for
`intravitreal injections of pharmacologic agents.
`Little change was observed for treatments primarily
`used for diabetic retinopathy (eFigure 2). Laser treat-
`ments for retinal edema (CPT code 67210) ranged from
`123 909 to 186 964 over the studied decade, while laser
`treatment for proliferative retinopathy (CPT code 67228)
`fluctuated between 93 200 and 115 789.
`The use of vitrectomy in several settings increased
`over the study period. Large increases were observed
`for vitrectomy with membrane stripping (90% increase
`from 29 426 to 56 051), endolaser (126% increase from
`2002 to 4527), or endolaser panretinal photocoagula-
`tion (PRP) (86% increase from 10 319 to 19 154). Vi-
`trectomy performed with or without scleral buckling
`for repair of retinal detachment (CPT code 67108) also
`increased 78% over the study period from 11 212 to
`19 923 procedures, while scleral buckling as a stand-
`alone procedure decreased 69% from 8691 to 2660 pro-
`cedures (Figure 3). Other retinal detachment proce-
`dures, including cryotherapy, pneumatic retinopexy,
`and laser prophylaxis of retinal detachment, were rela-
`tively stable, changing less than 25% from 1997 to
`2007.
`
`COMMENT
`
`Observing changes in procedural volume is one method
`to determine if, and to what extent, new technological
`
`Figure 1. New retinal treatments introduced since 2000.
`
`a monoclonal antibody against VEGF, is also commonly
`used for the treatment of neovascular AMD.14,15
`Intravitreal injections of steroids and VEGF inhibi-
`tory agents have also been described in the treatment of
`diabetic, pseudophakic, and uveitic macular edema.16-22
`Intravitreal VEGF inhibitory agents have also been shown
`to quickly (though temporarily) resolve retinal or ante-
`rior segment neovascularization from diabetes or other
`conditions producing retinal ischemia.23,24 Additional clini-
`cal trials are being conducted with numerous intravit-
`real pharmacologic agents to determine their efficacy and
`safety in a variety of retinal vascular diseases.
`Pharmacological advances for the treatment of reti-
`nal conditions have been complemented by advances in
`surgical technique. In particular, several advances have
`been made in vitrectomy, including the development of
`sutureless, microincisional vitrectomy surgery; better vi-
`sualization systems; and a greater variety of microinci-
`sional instruments and materials.25 These advances may
`have allowed vitrectomy to obtain a greater role in the
`treatment of retinal disease.
`One method to gauge the acceptance of newly intro-
`duced procedures, and to measure to what extent they
`have displaced the previous standard of care, is to track
`how frequently these procedures are performed. This re-
`port examines the trends in use of the most common reti-
`nal laser and surgical treatments for Medicare beneficia-
`ries over the period from 1997 to 2007.
`
`METHODS
`
`As previously described,26 files generated by the Centers for
`Medicare and Medicaid Services, previously known as the Health
`Care Financing Administration, were used to acquire data points
`for this retrospective analysis. The data gathered are in the pub-
`lic domain and are never more recent than 2 years old. In 2009,
`the most recent data available were for 2007. Data for indi-
`viduals enrolled in managed care Medicare plans or Medicare
`Part C are not publicly available and are not included in this
`analysis. Similarly, data for non-Medicare beneficiaries are avail-
`able only through providers of specific health plans and are not
`included as part of this analysis.
`The volumes of paid claims for Part B services correspond-
`ing to specific Current Procedural Terminology (CPT) codes were
`tabulated into separate files for Medicare beneficiaries for each
`calendar year. Current Procedural Terminology codes ranging
`from 67015 to 67228 were analyzed as part of this study. These
`CPT codes correspond with procedures used for retinal and pos-
`terior chamber procedures.
`
`(REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 10), OCT 2010
`1336
`
`WWW.ARCHOPHTHALMOL.COM
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`Novartis Exhibit 2308.002
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`
`

`

`Table. Volume Comparison Between Years for Retina Surgery Codes
`
`CPT
`Code 1997
`67015
`1812
`
`No. of Procedures
`
`1998
`1990
`
`1999
`1900
`
`2000
`1891
`
`2001
`1863
`
`2002
`1938
`
`2003
`1784
`
`2004
`1781
`
`2005
`1807
`
`2006
`1878
`
`2007
`1755
`
`67025
`67027
`67028
`
`1622
`NA
`3305
`
`1761
`406
`3218
`
`1868
`359
`2637
`
`1817
`293
`2745
`
`2244
`1270
`2127
`1536
`2185
`1986
`2203
`119
`126
`133
`193
`251
`109
`163
`4215 14853 43093 82994 250793 530 018 812413
`
`215
`189
`180
`67030
`160
`230
`209
`202
`199
`205
`208
`180
`4197
`3651
`4460
`4539
`67031
`3817
`3554
`3754
`2996
`2927
`3847
`3849
`13024 11884 14595 12986 13208 13698 13285 13010
`67036 12410 11907 12 811
`67038
`29426 31895
`41397 41712 40063 51068 48752 52099 54683 55375 56051
`4218
`67039
`2171
`2471
`4527
`2002
`5655
`2258
`2851
`3029
`3522
`3856
`15087 13852 14742 17044 18595 19946 20145 19470 19154
`67040 10319 12081
`
`1257
`1422
`1530
`67101
`1388
`4224
`4299
`4741
`67105
`4486
`7822
`67107
`6592
`7636
`8691
`67108 11 212 11557 15066 15 711
`671 10
`2878
`2829
`2819
`3060
`931
`671 12
`907
`941
`709
`
`1546
`1550
`1822
`1346
`1242
`1720
`592
`5443
`5709
`5196
`4858
`5484
`5293
`5429
`3162
`4341
`4838
`5181
`5412
`2660
`3706
`14830 17477 18318 19213 19804 19593 19923
`3514
`2976
`3790
`3285
`3701
`3554
`3476
`914
`660
`783
`862
`976
`958
`856
`
`671 15
`67120
`
`67121
`
`127
`823
`
`445
`
`148
`818
`
`551
`
`112
`838
`
`809
`
`102
`794
`
`750
`
`106
`535
`
`652
`
`127
`942
`
`930
`
`108
`892
`
`979
`
`103
`1030
`
`1127
`
`96
`979
`
`85
`974
`
`83
`912
`
`1018
`
`1056
`
`1043
`
`Description
`Posterior sclerotomy
`Vitreous placement
`Vitreous substitute
`lntravitreal drug implant
`Pharmacological agent (injection)
`Lysis of vitreous strands
`Manual
`Laser
`PPV
`With retinal membrane stripping
`With endolaser
`With endolaser PRP
`Retinal detachment repair
`Cryotherapy/diathermy
`Laser
`Scleral buckling
`PPV
`Pneumatic retinopexy
`Previous PPV or scleral buckle
`RemovaVrelease of:
`Encircling element
`Posterior segment implant,
`extraocular
`Posterior segment implant,
`intraocular
`Prophylaxis for retinal detachment
`Cryotherapy/diathermy
`Laser
`Treatment of retinal lesion or edema
`Cryotherapy/diathermy
`Laser
`Radiation
`Treatment of choroidal lesion or
`neovascularization
`67220
`Laser
`67221
`Photodynamic therapy
`Photodynamic therapy, second eye 67225
`Treatment of retinopathy
`Cryotherapy/diathermy
`Laser
`Total
`Change from previous year, %
`
`67141
`3455
`3899
`67145 16476 16031
`
`2486
`2771
`15 714 15161
`
`2671
`2025
`2270
`2505
`1908
`2621
`2325
`16124 17531 18819 19364 19437 19433 18906
`
`428
`1033
`67208
`367
`380
`732
`562
`530
`552
`580
`846
`893
`67210 139487 143149 123909 171688 177152 186964 182224 176463 163194 147 829 139495
`412
`67218
`445
`391
`818
`684
`346
`506
`715
`732
`626
`599
`
`56966 58471
`NA
`NA
`NA
`NA
`
`82089
`NA
`NA
`
`47 142 31367 32203 31082 31285 26240 18323 13821
`82628 100012 98 169 126603 112183 43823 21337
`NA
`2783
`5107
`7495
`3124
`1338
`NA
`4876
`6962
`
`678
`493
`974
`1166
`1880
`67227
`NA
`984
`525
`1008
`1262
`669
`67228 115789 99922 106 208 101 011 103875 108464 109846 109601 105480 99051
`93200
`432 755 423371 453 456 454029 530865 599047 617073 692310 82674110021421240740
`7.1
`12.2
`19.4
`12.8
`-2.2
`0.1
`16.9
`3.0
`21.2
`23.8
`
`Abbreviations: CPT. Current Proceduta/ Terminology, NA, not applicable; PPV, pars plana vitrectomy; PRP, panretinal photocoagulation.
`
`advances are being accepted into clinical practice. Pre-
`vious studies that examined the use of retinal proce-
`<lures did not cover the period after the introduction of
`VEGF inhibitory agents and only focused on subsets of
`procedures. 27•28 In this report, we examined the volume
`of retinal procedures performed in Medicare recipients
`between 1997 to 2007. The 192% increase in the total
`volume of retinal procedures was much larger than the
`11 % increase in the population older than 65 years pre-
`dieted by census data for the closest corresponding 10-
`year period and the 11 % increase in overall Medicare
`enrollment from 1997 to 2007.6•29 Overall, procedure
`totals were driven higher by large increases in the num-
`her of intravitreal injections performed from 2003 to
`2007. Most of the observed increase in intravitreal in-
`jection of pharmacologic agents likely resulted from the
`use of intravitreal VEGF inhibitors for neovascular AMD.
`
`800000
`
`~
`
`l 600000
`
`0
`"t:
`&'.
`~ 400000
`1i
`~
`0 200000
`0
`z
`
`0
`
`1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
`Year
`
`Figure 2. lntravitreal injections of pharmacologic agents, Medicare
`recipients, 1997 to 2007.
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 128 (NO. 10), OCT 2010
`1337
`
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`
`

`

`40000
`
`al
`~ 30000
`i;;
`a.
`gi
`'5 20000
`B
`~
`0 10000
`0 z
`
`0
`
`■ Cryotherapy or laser only ■ Scleral buckling
`D Vrtrectomy
`D Pneumatic retinopathy
`D Repeated operation, any method
`
`1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
`Year
`
`Figure 3. Retinal detachment procedures, Medicare recipients, 1997 to
`2007.
`
`These injections now represent a major component of
`the treatment of retinal disease.
`Our data derived from CPT codes used in billing ser(cid:173)
`vices for Medicare recipients do not identify which phar(cid:173)
`macologic agent was injected. Thus, we could not as(cid:173)
`sess the relative use ofbevacizumab and ranibizumab. It
`is also possible that some of the growth of intravitreal
`injections is attributable to other pharmacologic agents,
`particularly in the period prior to 2004 when injections
`were less than 2.5% of retinal procedures. For instance,
`intravitreal steroid injections have been described for use
`in uveitic, pseudophakic, diabetic, and central retinal vein
`occlusion- associated macular edema and in combina(cid:173)
`tion with photodynamic therapy for treatment of neo(cid:173)
`
`vascular AMD. 17•19•22,30,3, Additionally, pegaptanib was in(cid:173)
`troduced for treatment of neovascular AMD in 200432 and
`may have contributed to the growth in intraocular in(cid:173)
`jections prior to ranibizumab approval.
`Less fluctuation was observed with common laser
`treatments of diabetic retinopathy, ie, laser for macular
`edema and PRP, though small decreases in use were
`observed between 2002 and 2007. No studies have
`demonstrated superiority of VEGF inhibitory agents
`and/or intravitreal steroids over established laser-based
`therapies for the treatment of diabetic macular edema
`or proliferative diabetic retinopathy. 16
`24 As such, the
`18
`•
`•
`small decrease in PRP and laser for macular edema dur(cid:173)
`ing the latter half of the studied decade may represent
`variations due to demographic or health care use trends
`and not necessarily a shift to alternative therapies (ie,
`intravitreal injections).
`Our data provide limited insights into the treatment
`of surgical complications of PDR, including vitreous
`hemorrhage, traction retinal detachment, rhegmatog(cid:173)
`enous retinal detachment, or combined tractional/rheg(cid:173)
`ma togenous retinal detachment. While the database
`does not allow us to firmly distinguish the type nor
`underlying etiology of the retinal detachment, one
`notable trend was that vitrectomies with endolaser PRP
`(CPT code 67040) doubled from 1997 to 2007. It is pos(cid:173)
`sible that this trend may reflect a tendency to intervene
`earlier in eyes with vitreous hemorrhage, though other
`
`reasons for increasing endolaser PRP with vitrectomy
`cannot be excluded.
`Our data demonstrated that, over the study decade,
`the use of scleral buckling alone to treat retinal detach(cid:173)
`ment decreased, while the use of vitrectomy increased
`substantially. However, vitrectomy performed alone or
`in combination with scleral buckling for retinal detach(cid:173)
`ment repair is coded similarly in this database. Thus, we
`cannot differentiate whether scleral buckling is being re(cid:173)
`placed by vitrectomy alone or by procedures combining
`vitrectomy with scleral buckling. Vitrectomy (with or
`without scleral buckling surgery) for pseudophakic reti(cid:173)
`nal detachments has been suggested to produce better
`anatomic success and visual outcomes compared with
`scleral buckling alone.33 However, no difference in out(cid:173)
`comes has been suggested in the treatment of phakic reti(cid:173)
`3
`nal detachments. 34
`' It is possible that advances in vi(cid:173)
`•
`trectomy technique and instrumentation, perceptions that
`better results were achieved with vitrectomy, and/or a rise
`in fellowship-trained retinal specialists resulted in greater
`use of vitrectomy as the preferred method of repairing
`retinal detachment. In addition, given the older ages as(cid:173)
`sociated with our Medicare study population, it is likely
`that a significant proportion had pseudophakia, which
`may have influenced the decision to choose vitrectomy
`over scleral buckling as the surgical procedure.
`Vitrectomy use was also noted to increase in several
`other settings, including with non-PRP endolaser and
`with membrane stripping. The broader use of vitrec(cid:173)
`tomy across numerous conditions suggests that alter(cid:173)
`nate explanations for its increased use, ie, changing dis(cid:173)
`ease prevalence or demographic shifts, are unlikely. It is
`possible, however, that the frequency of vitrectomy for
`specific conditions such as epiretinal membranes, vit(cid:173)
`reomacular traction, or macular holes may have in(cid:173)
`creased with improved retinal imaging, such as optical
`coherence tomography, which may help better visualize
`the pathology involved and can yield better insight into
`when surgical intervention would be appropriate for a
`specific patient.
`Several limitations are inherent in our analysis. Be(cid:173)
`cause the database only evaluates paid Medicare claims,
`this analysis excludes patients younger than 65 years, as
`well as those older than 65 years receiving their health
`care outside of Medicare. The exclusion of younger pa(cid:173)
`tients may miss trends due to trauma, type 1 diabetes,
`or other common conditions rarely found in those older
`than 65 years. We also cannot necessarily generalize our
`findings to people older than 65 years receiving their
`health from insurers outside of Medicare and also Medi(cid:173)
`care Part C and Medicare health maintenance organiza(cid:173)
`tions. Retinal procedures paid for by Medicare may have
`changed partially as a result of Medicare enrollment or
`switching between Medicare Parts Band C. Trends might
`also be created by changes in reimbursement that al(cid:173)
`tered how surgeons coded for their services. We also as(cid:173)
`sume in our analysis that physicians coded procedures
`correctly, though it is possible that systematic errors are
`made in coding that would lead to biased conclusions.
`Finally, there is ambiguity inherent in the CPT coding
`system, because the underlying diagnosis for which the
`procedure is performed is not available in the Centers
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 128 (NO. 10), OCT 2010
`1338
`
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`

`

`for Medicare and Medicaid Services data set. For ex-
`ample, vitrectomy for retinal detachment performed with
`or without scleral buckling is assigned the same CPT code.
`The dramatic rise in retinal procedures poses impor-
`tant financial issues to both the ophthalmic community
`and society as a whole. The increased cost associated with
`procedure volumes alone may not be significant, be-
`cause most of the increase results from an intravitreal in-
`jection of a pharmacologic agent, a relatively low-cost pro-
`cedure. However, each injection is also associated with a
`separate medication charge (not covered in our Medi-
`care database), which is approximately $2000 for each
`vial of ranibizumab. Medication costs associated with
`monthly administration of ranibizumab over a 1-year pe-
`riod are approximately $24 000 per patient. Although the
`costs associated with ranibizumab are high, ranibi-
`zumab is the first therapy to significantly improve vision
`in more than 30% of treated patients, and it has been shown
`to have a positive impact on vision-related quality of life.36,37
`Further work will be necessary to investigate whether
`lower-cost alternatives, such as bevacizumab, are non-
`inferior to ranibizumab. Indeed, the Comparison of AMD
`Treatment Trials (CATT) Study is currently conducting
`a randomized clinical trial comparing bevacizumab and
`ranibizumab in eyes with neovascular AMD.
`Observing use patterns adds value, because it dem-
`onstrates how disease is treated and can be used to iden-
`tify possible discrepancies between the best evidence-
`based treatments for a condition (as defined by clinical
`trials and meta-analyses from the literature) and cur-
`rent practice patterns. In this report, we observe that in-
`travitreal injections of pharmacologic agents have gained
`widespread acceptance for the treatment of neovascular
`AMD and that vitrectomy is being increasingly applied
`to a wide range of retinal conditions.
`
`Submitted for Publication: November 19, 2009; final re-
`vision received January 26, 2010; accepted February 2,
`2010.
`Correspondence: Pradeep Y. Ramulu, MD, MHS, PhD,
`600 N Wolfe St, Maumenee B-110, Baltimore, MD 21287
`(pramulu1@jhmi.edu).
`Financial Disclosure: None reported.
`Funding/Support: This work was supported by Na-
`tional Institute of Health grant EY01765.
`Role of the Sponsors: The funding organization had no
`role in the design or conduct of this research.
`Online-Only Material: The eFigures are available at http:
`//www.archophthalmol.com.
`
`REFERENCES
`
`1. Sommer A, Tielsch JM, Katz J, et al. Racial differences in the cause-specific preva-
`lence of blindness in east Baltimore. N Engl J Med. 1991;325(20):1412-1417.
`2. Mun˜oz B, West SK, Rubin GS, et al. Causes of blindness and visual impairment
`in a population of older Americans: the Salisbury Eye Evaluation Study. Arch
`Ophthalmol. 2000;118(6):819-825.
`3. Congdon N, O’Colmain B, Klaver CC, et al; Eye Diseases Prevalence Research
`Group. Causes and prevalence of visual impairment among adults in the United
`States. Arch Ophthalmol. 2004;122(4):477-485.
`4. Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related
`maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci.
`1995;36(1):182-191.
`
`5. Cotter SA, Varma R, Ying-Lai M, Azen SP, Klein R; Los Angeles Latino Eye Study
`Group. Causes of low vision and blindness in adult Latinos: the Los Angeles La-
`tino Eye Study. Ophthalmology. 2006;113(9):1574-1582.
`6. 2008 National Population Projections. US Census Bureau Web site. http://www
`.census.gov/population/www/projections/2008projections.html. Accessed No-
`vember 3, 2009.
`7. Friedman DS, O’Colmain BJ, Mun˜oz B, et al; Eye Diseases Prevalence Research
`Group. Prevalence of age-related macular degeneration in the United States. Arch
`Ophthalmol. 2004;122(4):564-572.
`8. Kempen JH, O’Colmain BJ, Leske MC, et al; Eye Diseases Prevalence Research
`Group. The prevalence of diabetic retinopathy among adults in the United States.
`Arch Ophthalmol. 2004;122(4):552-563.
`9. Macular Photocoagulation Study Group. Argon laser photocoagulation for se-
`nile macular degeneration: results of a randomized clinical trial. Arch Ophthalmol.
`1982;100(6):912-918.
`10. Macular Photocoagulation Study Group. Argon laser photocoagulation for neo-
`vascular maculopathy: three-year results from randomized clinical trials. Arch
`Ophthalmol. 1986;104(5):694-701.
`11. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macu-
`lar degeneration with verteporfin: one-year results of 2 randomized clinical trials—
`TAP report. Treatment of Age-related Macular Degeneration With Photodynamic
`Therapy (TAP) Study Group. Arch Ophthalmol. 1999;117(10):1329-1345.
`12. Bressler NM; Treatment of Age-Related Macular Degeneration with Photody-
`namic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroi-
`dal neovascularization in age-related macular degeneration with verteporfin: two-
`year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol. 2001;
`119(2):198-207.
`13. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab
`for neovascular age-related macular degeneration. N Engl J Med. 2006;355
`(14):1419-1431.
`14. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intra-
`vitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.
`Ophthalmology. 2006;113(3):363-372.
`15. Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN.
`Intravitreal bevacizumab for the management of choroidal neovascularization in
`age-related macular degeneration. Am J Ophthalmol. 2006;142(1):1-9.
`16. Beck RW, Edwards AR, Aiello LP, et al; Diabetic Retinopathy Clinical Research
`Network (DRCR.net). Three-year follow-up of a randomized trial comparing focal/
`grid photocoagulation and intravitreal triamcinolone for diabetic macular edema.
`Arch Ophthalmol. 2009;127(3):245-251.
`17. Shimura M, Nakazawa T, Yasuda K, et al. Comparative therapy evaluation of in-
`travitreal bevacizumab and triamcinolone acetonide on persistent diffuse dia-
`betic macular edema. Am J Ophthalmol. 2008;145(5):854-861.
`18. Cho WB, Oh SB, Moon JW, Kim HC. Panretinal photocoagulation combined with
`intravitreal bevacizumab in high-risk proliferative diabetic retinopathy. Retina.
`2009;29(4):516-522.
`19. Boscia F, Furino C, Dammacco R, Ferreri P, Sborgia L, Sborgia C. Intravitreal
`triamcinolone acetonide in refractory pseudophakic cystoid macular edema: func-
`tional and anatomic results. Eur J Ophthalmol. 2005;15(1):89-95.
`20. Arevalo JF, Maia M, Garcia-Amaris RA, et al; Pan-American Collaborative Retina
`Study Group. Intravitreal bevacizumab for refractory pseudophakic cystoid macu-
`lar edema: the Pan-American Collaborative Retina Study Group results.
`Ophthalmology. 2009;116(8):1481-1487.
`21. Cervantes-Castan˜eda RA, Giuliari GP, Gallagher MJ, et al. Intravitreal bevaci-
`zumab in refractory uveitic macular edema: one-year follow-up. Eur J Ophthalmol.
`2009;19(4):622-629.
`22. Hogewind BF, Zijlstra C, Klevering BJ, Hoyng CB. Intravitreal triamcinolone for
`the treatment of refractory macular edema in idiopathic intermediate or poste-
`rior uveitis. Eur J Ophthalmol. 2008;18(3):429-434.
`23. Jardeleza MS, Miller JW. Review of anti-VEGF therapy in proliferative diabetic
`retinopathy. Semin Ophthalmol. 2009;24(2):87-92.
`24. Moraczewski AL, Lee RK, Palmberg PF, Rosenfeld PJ, Feuer WJ. Outcomes of
`treatment of neovascular glaucoma with intravitreal bevacizumab. Br J Ophthalmol.
`2009;93(5):589-593.
`25. D’Amico DJ. Clinical practice: primary retinal detachment. N Engl J Med. 2008;
`359(22):2346-2354.
`26. Ramulu PY, Corcoran KJ, Corcoran SL, Robin AL. Utilization of various glau-
`coma surgeries and procedures in Medicare beneficiaries from 1995 to 2004.
`Ophthalmology. 2007;114(12):2265-2270.
`27. de la Ru´a ER, Pastor JC, Ferna´ndez I, et al. Non-complicated retinal detachment
`management: variations in 4 years: retina 1 project: report 1. Br J Ophthalmol.
`2008;92(4):523-525.
`28. Shea AM, Curtis LH, Hammill BG, et al. Resource use and costs associated with
`diabetic macular edema in elderly persons. Arch Ophthalmol. 2008;126(12):
`1748-1754.
`
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`29. Centers for Medicare and Medicaid Services Web site. www.cms.gov. Accessed
`December 23, 2009.
`30. Gewaily D, Greenberg PB. lntravitreal steroids versus observation for macular
`edema secondary to central retinal vein occlusion. Cochrane Database Syst Rev.
`2009;(1):CD007324.
`31. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verte(cid:173)
`porfin and intravitreal triamcinolone acetonide for choroidal neovascularization.
`Ophthalmology. 2003;110(8):1517-1525.
`32. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibi(cid:173)
`tion Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovas(cid:173)
`cular age-related macular degeneration. N Engl J Med. 2004;351 (27):2805-2816.
`33. Arya AV, Emerson JW, Engelbert M, Hagedorn CL, Adelman RA. Surgical man(cid:173)
`agement of pseudophakic retinal detachments: a meta-analysis. Ophthalmology.
`2006;113(10):1724-1733.
`34. Heimann H, Bartz-Schmidt KU, Bomfeld N, Weiss C, Hilgers RD, Foerster MH; Sderal
`Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detach-
`
`ment Study Group. Scleral buckling versus primaryvitrectomy in rhegmatogenous
`retinal detachment: a prospective randomized multicenter clinical study.
`Ophthalmciogy. 2007;114(12):2142-2154.
`35. Heimann H, Hellmich M, Bomfeld N, Bartz-Schmidt KU, Hilgers RD, Foerster
`MH. Scleral buckling versus primary vitrectomy in rhegmatogenous retinal de(cid:173)
`tachment (SPR Study): design issues and implications. SPR Study report No. 1.
`Grae/es Arch Clin E.xp Ophthalmol. 2001 ;239(8):567-574.
`36. Bressler NM, Chang TS, Fine JT, Dolan CM, Ward J; Anti-VEGF Antibody for the
`Treatment of Predominantly Classic Choroidal Neovascularization in Age(cid:173)
`Related Macular Degeneration (ANCHOR) Research Group. Improved vision(cid:173)
`related function after ranibizumab vs photodynamic therapy: a randomized clini(cid:173)
`cal trial. Arch Ophthalmol. 2009;127(1 ):13-21.
`37. Chang TS, Bressler NM, Fine JT, Dolan CM, Ward J, KlesertTR; MARINA Study
`Group. Improved vision-related function after ranibizumab treatment of neovas(cid:173)
`cular age-related macular degeneration: results of a randomized clinical trial. Arch
`Ophthalmol. 2007;125(11):1460-1469.
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`Archives Web Quiz \ Vinner
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`PGY2 Resident, Section of Ophthalmology and Visual Science, Depart(cid:173)
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