Early Photocoagulation for
`Diabetic Retinopathy
`
`ETDRS Report Number9
`
`EARLY TREATMENT DIABETIC RETINOPATHY STUDY RESEARCH GROUP*
`
`Abstract: The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled
`3711 patients with mild-to-severe nonproliferative or early proliferative diabetic
`retinopathy in both eyes. One eye of each patient was assigned randomly to
`early photocoagulation and the other to deferral of photocoagulation. Follow-
`up examinations were scheduled at least every 4 months and photocoagulation
`wasinitiated in eyes assigned to deferral as soon as high-risk proliferative ret-
`inopathy was detected. Eyes selected for early photocoagulation received one
`of four different combinations of scatter (panretinal) and focal treatment. This
`early treatment, compared with deferral of photocoagulation, was associated
`with a small reduction in the incidence of severe visual loss (visual acuity less
`than 5/200 at two consecutive visits), but 5-year rates were low in both the
`early treatment and deferral groups (2.6% and 3.7%, respectively). Adverse
`effects of scatter photocoagulation on visual acuity and visualfield also were
`observed. These adverse effects were most evident in the months immediately
`following treatment and wereless in eyes assigned to less extensive scatter
`photocoagulation. Provided careful follow-up can be maintained, scatter pho-
`tocoagulation is not recommended for eyes with mild or moderate nonprolifer-
`ative diabetic retinopathy. When retinopathy is more severe, scatter photoco-
`agulation should be considered and usually should not be delayed if the eye
`has reached the high-risk proliferative stage. The ETDRS results demonstrate
`that, for eyes with macular edema, focal photocoagulation is effective in reducing
`the risk of moderate visual loss but that scatter photocoagulation is not. Focal
`treatmentalso increases the chanceof visual improvement, decreasesthe fre-
`quencyof persistent macular edema, and causesonly minorvisualfield losses.
`Focal treatment should be considered for eyes with macular edemathat involves
`or threatens the center of the macula. Ophthalmology 1991; 98:766-—785
`
`The Early Treatment Diabetic Retinopathy Study
`(ETDRS), a multicenter, collaborative, clinical
`trial
`sponsored by the National Eye Institute, was motivated
`principally by three clinical questions:
`
`Originally received: July 19, 1990.
`Revision accepted: January 24, 1991.
`
`1. Whenin the course of diabetic retinopathyis it most
`effective to initiate photocoagulation therapy?
`2. Is photocoagulation effective in the treatment of
`macular edema?
`3. Is aspirin effective in altering the course of diabetic
`retinopathy?
`
`* A list of the ETDRS Research Group investigators appears at the end
`of ETDRSreport number 7 in this supplement to Ophthalmology.
`
`Presented in part at the American Academy of Ophthalmology Annual
`Meeting, Atlanta, Oct/Nov 1990.
`
`Reprint requeststo the Biometry and Epidemiology Program, National Eye
`Institute, Bldg 31, Room 6A-24, 9000 Rockville Pike, Bethesda, MD 20892.
`
`This report focuses on thefirst two questions. Specific
`approaches were developed during the design of the
`ETDRSto provide information relevant to these ques-
`tions. A brief summary ofthe design and methodsis given
`below; a more detailed explanation is available elsewhere
`in this issue.'
`
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`ETDRS RESEARCH GROUP ® EARLY PHOTOCOAGULATION
`
`Table 1. Definitions of Commonly Used Terms
`
`A. Macular edema
`Thickening ofretina within 1 disc diameter of the center of the macula; and/or hard exudates = standard photograph 3" in a standard 30°
`photographic field centered on the macula(field 2), with some hard exudates within 1 disc diameter of the center of the macula
`B. Clinically significant macular edema (CSME)
`Retinal thickening at or within 500 4m of the center of the macula; and/or hard exudates at or within 500 «um of the center of the macula,if
`associated with thickening of the adjacent retina; and/or a zone or zonesofretinal thickening 1 disc area in size at least part of which was
`within 1 disc diameter of the center
`C. Mild nonproliferative retinopathy
`At least one microaneurysm; and definition not metfor D, E, F, or G below
`D. Moderate nonproliferative retinopathy
`Hemorrhages and/or microaneurysms > standard photograph 2A"; and/or soft exudates, venous beading,or intraretinal microvascular
`abnormalities definitely present; and definition not met for E, F, or G below
`E. Severe nonproliferative retinopathy
`Soft exudates, venous beading, andintraretinal microvascular abnormalities ail definitely present in at least two offields 4 through 7; or two of
`the preceding three lesions present in at least two offields 4 through 7 and hemorrhages and microaneurysmspresentin these fourfields,
`equaling or exceeding standard photo 2A in at least one of them; or intraretinal microvascular abnormalities present in each offields 4
`through 7 and equaling or exceeding standard photograph 8A in at least two of them; and definition not met for F or G below
`F. Early proliferative retinopathy(i.e., proliferative retinopathy without DRS high-risk characteristics)
`New vessels, and definition not met for G below
`G. High-risk proliferative retinopathy (proliferative retinopathy with DRS high-risk characteristics)
`New vessels on or within 1 disc diameter of the optic disc (NVD) = standard photograph 10A"' (about % to % disc area), with or without
`vitreous or preretinal hemorrhage; or vitreous and/or preretinal hemorrhage accompanied by new vessels, either NVD < standard
`photograph 10A or new vessels elsewhere (NVE) = ¥%disc area
`H. Less severe retinopathy
`Mild or moderate nonproliferative retinopathy
`. More severe retinopathy
`Severe nonproliferative or early proliferative retinopathy
`J. Severe visua! loss
`Visual acuity < 5/200 at two consecutive follow-up visits (scheduled at 4-monthintervals)
`K. Moderate visual loss
`Loss of 15 or more letters between baseline and follow-upvisit, equivalent to a doubling of the initial visual angle (i.e., 20/20 to 20/40 or 20/
`50 to 20/100)
`
`METHODS
`
`From April 1980 to July 1985, the ETDRS enrolled
`3711 patients with diabetes mellitus who metthe following
`criteria: (1) no macular edema, visual acuity of 20/40 or
`better, and moderate or severe nonproliferative diabetic
`retinopathyor early proliferative diabetic retinopathy, or
`(2) macular edema,visual acuity of 20/200 orbetter, and
`mild, moderate, or severe nonproliferative diabetic reti-
`nopathy orearly proliferative diabetic retinopathy (defi-
`nitions of retinopathy severity categories and other terms
`used in this report are given in Table |). Patients meeting
`eligibility requirements in both eyes and with favorable
`prognosis for survival and follow-up for at least 5 years
`were enrolled in the ETDRSandassigned randomly to
`aspirin 650 mg per day or matching placebo. As shown
`in a companionreport,’ aspirin had noeffect on the course
`of retinopathy, either in eyes assigned to deferral of pho-
`tocoagulation or in those assigned to early photocoagu-
`lation. Therefore, in this report, the results for patients
`assigned to aspirin and placebo have been combined.
`Toassess the effect of the timing of photocoagulation,
`one eye of each patient was assigned randomlyto early
`photocoagulation (scatter and/or focal) and the other eye
`was assigned to “deferral of photocoagulation” (Figs 1-
`3). Follow-up visits were scheduled at 4-monthintervals.
`
`The primary endpoint used to compare early photoco-
`agulation with deferral of photocoagulation was the rate
`ofdevelopmentof“‘severe visual loss,”i.e. (Table 1, item
`J), visual acuity less than 5/200 at two consecutivefollow-
`up visits. The primary endpoint for assessing the effects
`of photocoagulation on macular edema wasthe occur-
`rence of “moderate visual loss,” i.e. (Table 1, item K),
`loss of 15 or more letters (equivalent of 3 lines) between
`baseline and follow-up visit on the visual acuity charts
`used in the ETDRS.
`
`STRATEGIES FOR PHOTOCOAGULATION
`
`Thespecific techniques for photocoagulation have been
`described previously and are summarized in Table 2.**
`For eyes assigned to deferral, the protocol specified that
`full scatter be applied as soon as high-risk proliferative
`retinopathy was detected. If clinically significant macular
`edema (CSME)was presentat that time, focal photoco-
`agulation was initiated also, but only for those patients
`whose strategy for early photocoagulation for the fellow
`eye included delayed focal photocoagulation. After 5 years
`in this 9-year study, the accumulating data showed focal
`photocoagulation waseffective in reducing moderate vi-
`sual loss. Therefore, the protocol for all eyes assigned to
`deferral was modified to allow focal photocoagulation for
`CSME wheneverit occurred.° This report presents anal-
`
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`OPHTHALMOLOGY ¢ MAY 1991
`
`e VOLUME 98
`
`«
`
`SUPPLEMENT
`
`
`
`
`
`Macular Edema
`and
`Less Severe Retinopathy
`_—
`a_ a
`Early
`|
`Deferral of
`Photocoagulation
`| Photocoagulation
`
`
`
`—
`
`Immediate
`immediate
`|immediate
`Immediate
`Focal
`Mild
`|
`Focal
`Full
`Delayed
`Scatter
`| Delayed
`Scatter
`Mild
`Delayed
`|
`Full
`Delayed
`Scatter Focal Focal | Scatter
`
`
`
`
`
`
`
`
`
`
`
`
`|
`|
`
`Fig 2. Early Treatment Diabetic Retinopathy Study photocoagulation
`treatment schemefor eyes with macular edemaand Jess severe retinop-
`athy. Eyes were assigned randomlyto early photocoagulation orto deferral
`of photocoagulation. Eyes assigned to early photocoagulation were further
`assigned randomly to either mild or full scatter (panretinal) photoco-
`agulation and to either immediate focal or delayed focal treatment. In
`eyes assigned to immediate focal treatment, the assigned scatter treatment
`wasnotapplied initially, but only if severe nonproliferative retinopathy
`or worse developed during follow-up.
`
`
`
`
`Macular Edema
`and
`More SevereRetinopathy
`
`
`
`
`Early
`
`Eyes in this category (Fig 1) had moderate-to-severe
`|Photocoagulation
`
`nonproliferative or early proliferative retinopathy and did
`
`not have macular edema. “Immediate” strategies for
`
`photocoagulation for these eyes were either mild or full
`
`immediate
`Immediate
`
`
`
`scatter. “Delayed” focal photocoagulation wasto be ini-
`Miid
`Mild
`
`tiated during follow-up if macular edema developed that
`Scatter
`Scatter
`
`involved or threatened the center of the macula (CSME).
`
`
`
`No Macular Edema
`
`
`
`
`
`
`Deferral of
`Early
`Photocoagulation
`Photocoagulation|
`
`
`
`
`
`Immediate
`Immediate
`
`
`Mild
`Full
`Scatter
`Scatter
`
`
`
`Delayed
`Delayed
`
`Focal Focal
`
`Fig 1. Early Treatment Diabetic Retinopathy Study photocoagulation
`treatment scheme for eyes without macular edema with moderate-to-
`severe nonproliferative or early proliferative retinopathy. Eyes were as-
`signed randomly to early photocoagulation or deferral of photocoagu-
`lation. Eyes assigned to early photocoagulation were further assigned
`randomly to either mild or full scatter (panretinal) photocoagulation.
`
`yses of all eyes according to their original randomized
`assignment of treatment; observations made after the
`modification of the protocol are included.
`Initiation of early photocoagulation differed depending
`on the retinopathyat baseline (Figs 1-3). Three categories
`were defined on the basis of preliminary grading of fundus
`photographsand fluorescein angiograms;these differed in
`retinopathy severity and presence or absence of macular
`edema (Table 3). The strategies for early photocoagulation
`for each category are outlined in the following sections.
`
`CATEGORY 1: EYES WITHOUT MACULAR EDEMA
`
`CATEGORY 2: EYES WITH MACULAR EDEMA AND
`LESS SEVERE RETINOPATHY
`
`Eyes in this category (Fig 2) had macular edema and
`mild-to-moderate nonproliferative retinopathy (/ess severe
`retinopathy, Table 1). Early photocoagulation for these
`eyes was:
`(1) immediate focal photocoagulation, with
`scatter photocoagulation (mild or full) added if severe
`nonproliferative or early proliferative retinopathy devel-
`oped during follow-up; and (2) immediate scatter pho-
`tocoagulation (mild orfull), with focal photocoagulation
`delayed for at least 4 months. Eyes assigned to delayed
`focal photocoagulation received treatmentat the 4-month
`visit ifthe macular edemahad not improved andthevisual
`acuity score had not increased by five or moreletters by
`that time. Focal photocoagulation was initiated at the 8-
`monthvisit if the edema wasnotsubstantially improved,
`
`768
`
`
`
`Immediate
`Focal
`
`Delayed
`Focal
`
`—
`Immediate
`Full
`Scatter
`
`Immediate
`Focal
`
`Immediate
`Full
`Scatter
`
`Focal
`
`Delayed
`
`Fig 3. Early Treatment Diabetic Retinopathy Study photocoagulation
`treatment scheme for eyes with macular edema and more severe reti-
`nopathy. Eyes were assigned randomly to immediate photocoagulation
`or to deferral of photocoagulation. Eyes assigned to immediate photo-
`coagulation were further assigned randomly to either mild orfull scatter
`(panretinal) photocoagulation, and to either immediate focal treatment
`or to deferral of focal treatment for at least 4 months.
`
`as demonstrated by either a return of aninitially thickened
`macular center to normal thickness or improvement in
`visual acuity score by 10 or moreletters. At and after the
`12-monthvisit, initiation of focal photocoagulation was
`required for all eyes assigned to early photocoagulation if
`they had CSMEandhad notyet received focal photo-
`coagulation.
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`

`ETDRS RESEARCH GROUP ¢ EARLY PHOTOCOAGULATION
`
`Table 2. Major Features of ETDRS Early Photocoagulation Treatment
`
`Full
`Scatter
`Mild
`
`Burn characteristics
`
`500 yum (atretina)
`0.1 seconds
`Moderate
`400-650
`=1 burn apart > 2 disc diameters from
`fovea out to equator
`
`1 P
`
`500 ym (at retina)
`0.1 seconds
`Moderate
`1200-1600
`Ye burn apart > 2 disc diameters
`from fovea out to equator
`22
`Number of episodes
`Patches of NVE < 2 disc areas
`atches of NVE < 2 disc areas
`Lesion treated directly
`Recurrent or new NVE or high-risk
`Indications for follow-up
`Recurrent or new NVEor high-risk
`
`
`proliferative retinopathytreatment proliferative retinopathy
`
`Size
`Exposure
`Intensity
`Number
`Placement
`
`Direct
`Focal
`Grid
`
`Burn characteristics
`
`Size
`Exposure
`Intensity
`
`Number
`
`Placement
`
`50-100 um
`0.05-0.1 seconds
`Sufficient to whiten or darken large
`microaneurysms
`Sufficient to satisfactorily treat all
`focal leaks
`500-3000 um from center of fovea
`
`<200 wm (atretina)
`0.05-0.1 seconds
`Mild
`
`Sufficient to cover areas of diffuse
`leakage and non-perfusion
`Spaced greater than one burn width apart
`500-3000 ym from center of fovea
`
`1 P
`
`1
`Number of episodes
`resence of CSME andtreatable lesions
`Presence of CSME and treatable
`Indications for follow-up
`lesions at = 4 months
`treatment
`at = 4 months
`
`NVE = new vessels elsewhere; CSME = clinically significant macular edema.
`
`Table 3. Numbers of Eyes in Each Baseline Retinopathy Category
`
`Photocoagulation Treatment Strategy
`
`Early* Full Scatter
`
`Early* Mild Scatter
`
`Immediate
`
`Baseline Retinopathy Category
`Focal
`
`Delayed
`Focal
`
`Immediate
`Focal
`
`Delayed
`Focal
`
`Deferral
`
`1179
`590
`583
`Eyes without macular edema
`1429
`365
`365
`356
`362
`Eyes with macular edema and Jess severe retinopathy
`1103
`272
`276
`270
`272
`Eyes with macular edema and more severe retinopathy
`634
`Total
`
`
`
`641 12271209 3711
`
`* See Figures 1 to 3.
`
`CATEGORY 3: EYES WITH MACULAR EDEMA AND
`MORE SEVERE RETINOPATHY
`
`Eyes in this category (Fig 3) had macular edema and
`severe nonproliferative or early proliferative retinopathy
`(moresevere retinopathy, Table 1). Early photocoagulation
`for these eyes was (1) immediate focal and scatter pho-
`tocoagulation (mild or full); or (2) immediate scatter pho-
`tocoagulation (mild or full), with focal photocoagulation
`delayed for at least 4 months. The same procedure de-
`
`scribed in Category 2 for initiating focal photocoagulation
`at or after 4 months wasused.
`These strategies for early photocoagulation were based
`on the following considerations:(1) for eyes with macular
`edema and /ess severe retinopathy, macular edema was
`considered the more immediate threat to vision, and the
`primary focus ofearly photocoagulation wason the treat-
`ment of the macular edema. Delaying scatter photoco-
`agulation in eyes with macular edemaand/ess severe ret-
`inopathy assigned to immediate focal photocoagulation
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`OPHTHALMOLOGY e¢ MAY 1991
`
`e VOLUME 98 e SUPPLEMENT
`
`Table 4. Patient Enrotiment and Close-out
`
`Patients
`
`Survival through
`Close-out
`
`provided a group ofeyes in whichtheeffects of focal pho-
`tocoagulation without concurrent scatter photocoagula-
`tion could be assessed. Because this was early treatment,
`scatter photocoagulation was delayed only until the de-
`velopmentof severe nonproliferative or early proliferative
`retinopathy rather than until the development of high-
`risk proliferative retinopathy. Similarly, by delaying focal
`Complete
`photocoagulation for at least 4 months in eyes assigned
`
`Enrollment Follow-up*|Number Close-out
`
`to immediate scatter photocoagulation, the effects of im-
`Year
`(yrs)
`Enrolled
`No.
`Examinations
`Deaths
`mediate scatter photocoagulation without concurrentfo-
`cal photocoagulation could be assessed. (2) For eyes with
`macular edema and more severe retinopathy, an increased
`rate of progression to high-risk proliferative retinopathy
`was expected compared with the rate for eyes that had
`less severe retinopathy. For these eyes, strategies for early
`photocoagulation could not focus primarily on the treat-
`ment of macular edema. Scatter photocoagulation,if it
`was to be considered “early,” could not be delayed, and
`thus immediate scatter photocoagulation (mild or full)
`wasspecified for all eyes with macular edema and more
`severe retinopathy assigned to early photocoagulation.
`Best corrected visual acuity was measured and ocular
`examinations were performed according to a standardized
`protocol at baseline and at 6 weeks and 4 monthsafter
`randomization. This procedure was repeated every 4
`monthsthereafter. The visual acuity score was defined as
`the total numberofletters that could be read correctly
`from the logarithmic visual acuity charts used in the
`ETDRS.A score of 100 correspondsto a visual acuity of
`20/10, and the visual angle doubles with each decrement
`of 15 letters.’ When oneor morevisual acuity scores were
`missing, scores from the preceding and following visits
`were averaged to replace the missing score(s).
`Visual field scores were calculated by totaling the pe-
`ripheral extent of the visual fields in degrees, obtained
`using the I/4e and I/2e test objects with the Goldmann
`perimeter, on each of 12 meridians after subtracting any
`scotomas encountered along them. Color vision was as-
`sessed with the Farnsworth-Munsell 100-Hue Test, scored
`by the method of Farnsworth. The square rootofthe score
`was calculated and used to assess change between baseline
`and follow-upvisits. Stereoscopic fundus photographs and
`fluorescein angiogramstakenat baseline and periodically
`during follow-up were graded centrally at the ETDRS
`Fundus Photograph Reading Center.
`
`1980
`1981
`1982
`1983
`1984
`1985
`Total
`
`8
`7
`6
`5
`4
`3
`—
`
`366
`780
`761
`874
`669
`261
`3711
`
`251
`579
`621
`719
`590
`245
`3005
`
`234 (93%)
`538 (93%)
`567 (91%)
`672 (93%)
`562 (95%)
`234 (96%)
`2807 (93%)
`
`115
`201
`140
`155
`79
`16
`706
`
`* Close-outvisits occurred between August1, 1988 and June 30, 1989.
`
`Other endpoints evaluated were the occurrence ofeither
`severe visual loss or vitrectomy, visual acuity worse than
`20/100 (equivalent to “legal blindness’’), and change be-
`tween baseline and follow-up visits in visual field, color
`vision, or retinopathy.
`A two-sample z-test ofequality ofproportions*® was used
`when comparing proportions of eyes with a given end-
`point. The Cutler-Edererlife table method’ was used to
`estimaterates offirst occurrence of certain events. In the
`absence ofthe specified event, observations were censored
`at the patient’s last visit or at death. The Mantel-Cox
`statistic!? was used to provide probabilities for tests of
`significance for the comparison oflife table results for the
`entire period of follow-up. Because multiple endpoints
`were compared at frequent intervals during the course of
`the study, a 0.01 probability level, rather than 0.05, was
`considered statistically significant for the primary end-
`points. For other comparisons, P-values between 0.01 and
`0.001 provided some evidence of differences between
`treatments, and P-values less than 0.001 provided stronger
`evidence of such differences.
`The Cox proportional hazards model with adjustment
`for retinopathy severity and presence or absence of mac-
`ular edemawas used to assess therelative risk (along with
`the 99% confidence interval)'® of some primary endpoints
`
`Fig 4. Life table cumulative event rates offirst application of focal photocoagulation treatment for macular edema in eyes assigned to immediate
`mild scatter/delayedfocal (orange), immediatefull scatter/delayedfocal (red), or deferral ofphotocoagulation (black). Top left, A, eyes without macular
`edema. Second rowleft, B, eyes with macular edema and less severe retinopathy. Third row left, C, eyes with macular edema and more severe
`retinopathy. Fig 5. Bottom left, life table cumulative event rates offirst application of scatter treatment in eyes with macular edemaand Jess severe
`retinopathy assigned to immediate focal/delayed mild scatter (green), immediate focal/delayed full scatter (blue), or deferral ofphotocoagulation
`(black). Fig 6. Life table cumulative event rates of high-risk proliferative retinopathy. Top right, A, cyes without macular edemaassigned to immediate
`mild scatter/delayedfocal (orange), immediatefull scatter/delayedfocal (red), or deferral ofphotocoagulation (black). Second row right, B, eyes with
`macular edemaand /ess severe retinopathy assigned to immediatefocal/delayed mild scatter (green), immediate mild scatter/delayedfocal (orange),
`immediatefocal/delayedfull scatter (blue), immediatefull scatter/delayedfocal (red), or deferral ofphotocoagulation(black). Third row right, C, eyes
`with macular edema and moresevere retinopathy, assigned to immediatefocal/immediate mild scatter (green), immediate mild scatter/delayedfocal
`(orange), immediate focal/immediate full scatter (blue), immediate full scatter/delayed focal (red), or deferral ofphotocoagulation (black). Fig 7.
`Bottom right, life table cumulative eventrates of high-risk proliferative retinopathy bylevel on retinopathy severity scale'* at baseline in eyes assigned
`to deferral of photocoagulation.
`
`SEes
`
`770
`
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`Page6é
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`771
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`

`OPHTHALMOLOGY ¢ MAY 1991
`
`¢ VOLUME 98
`
`¢ SUPPLEMENT
`
`for the entire period of follow-up for eyes assigned to early
`photocoagulation compared with eyes assignedto deferral.
`Termsfor two- and three-wayinteractions were included
`and if ascertained to be nonsignificant (P > 0.01) were
`omitted from the model. A relative risk significantly less
`than 1.0 indicates a reducedrisk of the endpointfor eyes
`assigned to early photocoagulation compared with eyes
`assigned to deferral. A relative risk significantly greater
`than 1.0 indicates an increased risk of the endpoint for
`eyes assigned to early photocoagulation compared with
`eyes assigned to deferral. In these analyses, a 99% confi-
`denceinterval of the relative risk that included 1.0 indi-
`cated that the observed data were consistent with no dif-
`ference between the strategies for photocoagulation.
`
`
`RESULTS
`
`COMPLETENESS OF FOLLOW-UP
`
`Results presented in this report include all data pro-
`cessed at the ETDRSCoordinating Center as ofNovember
`8, 1990, when all collected ETDRS data up to and in-
`cluding all close-out visits (scheduled between August 1,
`1988 and June 30, 1989) were available for analysis. Table
`4 showsthe distribution of the 3711 patients by each year
`of enrollment, including the number of deaths and the
`length of follow-up.
`At close-out, 706 patients were dead, 2971 patients were
`knownto be alive, and vital status of 34 patients (1%) was
`unknown. Of the 2971 patients knownto be alive, only
`164 patients did not have an eye examinationat the close-
`outvisit, and only 11 of the patients did not have atleast
`a nonprotocolestimate ofvisual acuity (e.g., a homevisit,
`a non-ETDRSophthalmologist assessment, or other as-
`sessment).
`Duringthefirst 3 years of follow-up, 90 to 95% of ex-
`pected follow-up visits were completed. This rate de-
`creased to 80 to 90% for follow-up longer than 3 years.
`The proportionsof patients missing visits were similar in
`all treatment groups.
`Of 130,980 expected visual acuity scores, all but 1.5%
`were available. Ninety percent of the 129,054 available
`visual acuity scores were from measurements made ac-
`cording to the protocol; another 9% were estimated by
`averaging the two measured visual acuities bracketing
`those unavailable due to missed visits; and 1% were es-
`timated using nonprotocol measurements from eye ex-
`aminations or using answers to questions—for example,
`about the patient’s ability to read, watch television, or
`walk through doorways. During the follow-up period, 50%
`of the patients had measurements ofvisual acuity obtained
`according to the protocol for every expected visit; 30%
`missed only one or two measurements.
`
`FREQUENCY AND TIMING OF DELAYED
`PHOTOCOAGULATION
`
`Several groups of eyes were notassigned to receive focal
`photocoagulation as part of their initial treatment, i.e.,
`
`772
`
`eyes without macular edemaatbaseline, eyes with macular
`edemaassigned to immediate scatter photocoagulation
`and delayed focal photocoagulation (Figs 1-3), and all
`eyes assigned to deferral of photocoagulation. Figure 4
`presents cumulative rates of the first application of focal
`photocoagulation for macular edemato these eyes.
`Eyes without macular edemaat baseline that were as-
`signed to early photocoagulation received focal photo-
`coagulation when CSMEdeveloped during follow-up. Af-
`ter 5 years, approximately one third of such eyes hadre-
`ceived focal photocoagulation, and there was
`little
`difference between eyes assigned to mild scatterinitially
`and those assigned to full scatter (Fig 4A). Among eyes
`in this category assigned to deferral of photocoagulation,
`22% had received focal photocoagulation within 5 years;
`in 91% of these eyes, focal photocoagulation wasinitiated
`after the change in the protocol in 1985 allowing focal
`photocoagulation for CSME.
`Morethan onethird of the eyes with macular edema
`that wereassigned to immediate scatter and delayed focal
`photocoagulation had focal photocoagulation initiated at
`the 4-monthvisit. By the ]-year visit, approximately two
`thirds of these eyes had received focal photocoagulation
`(Figs 4B, C). Among eyes with macular edema assigned
`to deferral of photocoagulation, approximately twothirds
`had received focal photocoagulation within 5 years; in
`87% of these eyes, focal photocoagulation wasinitiated
`after the change in protocol that allowed focal photoco-
`agulation for CSME.
`Analyses restricted to follow-up before the 1985 change
`of protocol showed the following 48-monthrates of the
`first application of focal photocoagulation in eyes assigned
`to deferral: 3.5% for eyes without macular edema; 5.5%
`for eyes with macular edema and Jess severe retinopathy,
`and 16.7% for eyes with macular edema and more severe
`retinopathy.
`Two groupsofeyes did not receive scatter photocoag-
`ulationinitially. Eyes with macular edema and/ess severe
`retinopathy assigned to immediate focal photocoagulation
`had scatter photocoagulation (either mild orfull) delayed
`until severe nonproliferative or early proliferative reti-
`nopathy developed. Eyes assigned to deferral of photo-
`coagulation had scatter photocoagulation initiated only
`when high-risk proliferative retinopathy developed.
`Figure 5 showsthe cumulativeratesoffirst application
`ofscatter photocoagulation by assigned treatment for eyes
`with macular edemaand/ess severe retinopathy that did
`not receive scatter photocoagulation initially. After 1, 3,
`and 5 years, approximately 10%, 30%, and 40%, respec-
`tively, of the eyes assigned to early photocoagulation
`(“immediate focal/delayed mild scatter” or “immediate
`focal/delayed full scatter”) had received their assigned
`scatter photocoagulation because of progression to severe
`nonproliferative or early proliferative retinopathy (57%)
`or high-risk proliferative retinopathy (43%). These rates
`were approximately double the rates for comparable eyes
`assigned to deferral of photocoagulation, which had to
`progress to the high-risk proliferative stage before becom-
`ing eligible for scatter photocoagulation.
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit2121
`Page 7
`
`

`

`ETDRS RESEARCH GROUP e EARLY PHOTOCOAGULATION
`
`Table 5. Development of High-risk Proliferative Retinopathy*$$
`
`Photocoagulation Treatment Strategy
`
`Earlyt Full Scatter
`
`Earlyt Mild Scatter
`
`Immediate
`Delayed
`Immediate
`Delayed
`Baseline Retinopathy Category
`Focal
`Focal
`Focal
`Focal
`Deferral
`
`
`No macular edema
`5-yr rate (%)
`Relative riskt
`99% Cl
`No. of eyes
`Macular edema and /ess severe retinopathy
`5-yr rate (%)
`Relative risk
`99% Cl
`No. of eyes
`Macular edema and more severe retinopathy
`46.7
`40.3
`26.3
`28.8
`5-yr rate (%)
`0.67
`0.59
`0.34
`0.36
`Relative risk
`0.53-0.87
`0.46-0.77
`0.25-0.47
`0.26-0.49
`99% Ci
`
`
`
`
`
`272 270 276 272No. of eyes 1103
`
`38.5
`
`1179
`
`26.7
`
`1429
`
`61.3
`
`18.8
`0.41
`0.31-0.55
`583
`
`8.5
`0.27
`0.16-0.44
`356
`
`21.4
`0.81
`0.59-1.11
`365
`
`26.9
`0.64
`0.51-0.81
`590
`
`16.6
`0.56
`0.39-0.80
`365
`
`13.7
`0.52
`0.36-0.75
`362
`
`Cl = confidenceinterval.
`* Life table event rates of first occurrence of high-risk proliferative retinopathy using Cutler-Ederer actuarial estimates.
`t See Figures 1 to 3.
`+ Relative risk of high-risk proliferative retinopathy for each early treatment strategy versus deferral was estimated for the entire period of follow-up
`for each baseline retinopathy category. A Cox model with time to high-risk proliferative retinopathy as the dependent variable was used. The 99% Cl
`for the estimate of the relative risk was calculated.
`
`DEVELOPMENT OF HIGH-RISK PROLIFERATIVE
`RETINOPATHY
`
`Life table rates for the developmentof high-risk pro-
`liferative retinopathy are shown in Figure 6 and Table 5
`accordingto baseline retinopathy. Compared with deferral
`of photocoagulation, early photocoagulation reduced the
`rate of progression to the high-risk stage in each baseline
`category (Mantel-Cox; P < 0.001 for each strategy ofearly
`photocoagulation compared with deferral, except for im-
`mediate focal and delayed mild scatter photocoagulation
`in eyes with macular edema and /ess severe retinopathy,
`P = 0.09). Within all categories, the 5-year rate of devel-
`oping high-risk retinopathy was lowest in eyes assigned
`to immediate full scatter, highest in eyes assigned to de-
`ferral, and intermediate in eyes assigned to immediate
`mild scatter.
`Amongeyes with macular edema and more severe ret-
`inopathy (Fig 6C), the timing of focal photocoagulation
`(immediate versus delayed) had no apparenteffect on the
`rate of developmentof high-risk retinopathy. However,
`among eyes with macular edemaand/ess severe retinop-
`athy (Fig 6B), the rates of developmentof high-risk reti-
`nopathyfor eyes assigned to immediate focal and delayed
`scatter photocoagulation were intermediate between those
`for immediate scatter and delayed focal and those for de-
`ferral of photocoagulation.
`Life table rates showing the developmentofhigh-risk
`proliferative retinopathy for all eyes assigned to deferral
`(classified by baseline retinopathy, as derived from detailed
`
`gradings ofcolor fundus photographs'') are given in Figure
`7 and Table 6. The risk of progression to the high-risk
`stage increased substantially with increasing severity; 5-
`yearlife table rates rose from 15% in eyes with the least
`severe retinopathy in ETDRS(level < 35) to more than
`70% in eyes with very severe nonproliferative (level 53e)
`or moderate proliferative retinopathy (level = 65).
`
`ENDPOINTS
`
`Severe visual loss. The cumulative rates of the devel-
`opmentofsevere visual loss for eyes assigned to deferral]
`of photocoagulation and for all eyes assigned to early
`photocoagulation are shown in Figure 8 (Mantel-Cox; P
`= 0.035 for the entire period of follow-up). The relative
`risk of severe visual loss for the entire period of follow-
`up in eyes assigned to early photocoagulation compared
`with eyes assigned to deferral of photocoagulation was
`0.77 (99% confidence interval, 0.56 to 1.06, calculated
`using