Early Treatment Diabetic

Retinopathy Study Design

and Baseline
. Patient
Characteristics
ETDRS Report Number 7
EARLY TREATMENT DIABETIC RETINOPATHY STUDY RESEARCH GROUP*

Abstract: The Early Treatment Diabetic Retinopathy Study (ETDRS), a multi-

center collaborative clinical trial supported by the National Eye Institute, was
designed to assess whether argon laser photocoagulation or aspirin treatment
can reduce the risk of visual loss or slow the progression of diabetic retinopathy
in patients with mild-to-severe nonproliferative or early proliferative diabetic ret-
inopathy. The 3711 patients enrolled in the ETDRS were assigned randomly to
either aspirin (650 mg per day) or placebo. One eye of each patient was assigned
randomly to early argon laser photocoagulation and the other to deferral of
photocoagulation. Both eyes were to be examined at least every 4 months and
photocoagulation was to be initiated in eyes assigned to deferral as soon as
high-risk proliferative retinopathy was detected. Examination of a large number
of baseline ocular and patient characteristics indicated that there were no im-
portant differences between randomized treatment groups at baseline.
Ophthalmology 1991; 98:741-756

The Early Treatment Diabetic Retinopathy Study
(ETDRS), a multicenter collaborative trial sponsored by
the National Eye Institute, was designed to evaluate pho-
tocoagulation and aspirin treatment in patients who have
mild-to-severe nonproliferative or early proliferative di-
Originally received: July 19, 1990.
Revision accepted: January 24, 1991.
* A list of the ETDRS Research Group investigators appears in Appendix
1 of this report.
Presented in part at the American Academy of Ophthalmology Annual
Meeting, New Orleans, October 1989.
Presented in part at the American Academy of Ophthalmology Annual
Meeting, Atlanta, OctjNov 1990
Reprint requests to the Biometry and Epidemiology Program, National Eye
Institute, Bldg 31, Room 6A-24, 9000 Rockville Pike, Bethesda, MD 20892.
abetic retinopathy. The three principal clinical questions
were:
1. When in the course of diabetic retinopathy is it most
effective to initiate photocoagulation therapy?
2. Is photocoagplation effective in the treatment of
macular edema?
3. Is aspirin effective in altering the course of diabetic
retinopathy?
The first of these clinical questions arose from the results
of the Diabetic Retinopathy Study (DRS). 1 In 1976,
members of the DRS reported that scatter (panretinal)
photocoagulation was an effective treatment for prolif-
erative diabetic retinopathy. In that study, there was a
60% reduction in the development of severe visual loss
(visual acuity less than 5/200 at two consecutive 4-month
visits) for eyes with severe nonproliferative or proliferative

741
 OPHTHALMOLOGY MAY 1991 VOLUME 98 SUPPLEMENT

Table 1. Definitions of Commonly Used Terms

A. Macular edema
Thickening of retina within 1 disc diameter of the center of the macula; and/or hard exudates ~ standard photograph 312 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
Retinal thickening at or within 500 ~m of the center of the macula; and/or hard exudates at or within 500 ~m of the center of the macula, if
associated with thickening of the adjacent retina;
and/or a zone or zones of retinal thickening one disc area in size at least part of which was within one disc diameter of the center
C. Mild nonproliferative retinopathy
At least one microaneurysm, and definition not met forD, E, F, or G below
D. Moderate nonproliferative retinopathy
Hemorrhages and/or microaneurysms ~ standard photograph 2A12 ; 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, and intraretinal microvascular abnormalities all definitely present in at least two of Fields 4 through 7; or two
of the preceding three lesions present in at least two of fields 4 through 7 and hemorrhages and microaneurysms present in these four
fields, equaling or exceeding standard photo 2A in at least one of them; or intraretinal microvascular abnormalities present in each of
fields 4 through 7 and equaling or exceeding standard photograph SA 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 10A12 (about 1/4 to 1/3 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) ~ 1/4 disc area
H. Less severe retinopathy
Mild or moderate nonproliferative retinopathy
I. More severe retinopathy
Severe nonproliferative or early proliferative retinopathy
J. Severe visual loss
Visual acuity < 5/200 at two consecutive follow-up visits (scheduled at 4-month intervals)
K. Moderate visual loss
Loss of 15 or more letters between baseline and follow-up visit, equivalent to a doubling of the initial visual angle (i.e., 20/20 to 20/40 or 20/
50 to 20/100)

retinopathy assigned randomly to scatter photocoagula-
tion compared with eyes assigned to no photocoagulation.
(Various terms used in this report, e.g., severe visual loss,
severe nonproliferative retinopathy, are defined in Table
1.) The DRS Research Group demonstrated that eyes with
proliferative retinopathy and vitreous hemorrhage or those
with new vessels on the disc greater than approximately
one fourth to one third disc area were at particularly high
risk of severe visual loss without treatment. 2 The DRS
Research Group recommended treatment for all such
eyes, but cautioned that, "For eyes with less severe reti-
nopathy, DRS findings do not provide a clear choice be-
tween prompt treatment or deferral unless progression to
these more severe stages occurs. " 34
To obtain information on the appropriate timing of
scatter photocoagulation, one eye of each patient in the
ETDRS was assigned randomly to early photocoagulation
(either mild or full scatter) and the other to a strategy of
initiating photocoagulation only if high-risk proliferative
retinopathy was detected. The primary endpoint for as-
sessment of early photocoagulation was the development
of severe visual loss.
The second clinical question concerned the effect of
photocoagulation on diabetic macular edema. Several
small randomized trials have reported encouraging results
regarding photocoagulation for macular edema. 5- 7 Al-
though each of these studies reported a benefit from pho-
tocoagulation, it was suggested that treatment benefit
might be limited to certain subgroups, such as eyes with
742
focal as opposed to diffuse fluorescein leakage, or eyes
with intact as opposed to extensively damaged parafoveal
capillaries. One randomized trial reported that xenon-
arc photocoagulation was effective in treating macular
edema. The relatively large xenon bums used in that study
were not placed closer than 1 disc diameter from the center
of the macula and were sometimes combined with scatter
photocoagulation, suggesting that scatter treatment itself
might have a beneficial effect on macular edema. 6
The effects of photocoagulation on diabetic macular
edema were evaluated in the ETDRS by assigning ran-
domly those eyes selected for early photocoagulation to
either of two timing strategies for focal photocoagulation
(immediate or delayed) as well as to either mild or full
scatter. For those eyes, early photocoagulation was a
combination of focal and/or scatter photocoagulation.
The primary endpoint for assessing photocoagulation ef-
fects on macular edema was the occurrence of moderate
visual loss.
The third clinical question in the study addressed a
possible medical treatment for diabetic retinopathy.
Among a number of medical therapies proposed were as-
pirin, dipyridamole, vitamins, and calcium dobesilate, a
drug that decreased capillary permeability. The most
promising treatments seemed to be those that reduced
platelet aggregation. Patients with diabetic retinopathy
have been shown to exhibit alterations of platelet function,
including increased platelet adhesiveness, 8 hypersensitivity
to aggregating agents in vitro, 9 10 platelet-plasma inter-
 ETDRS RESEARCH GROUP PATIENT CHARACTERISTICS

Table 2. Major Features of ETDRS Early Photocoagulation

Scatter Full Mild

Burn characteristics
Size 500 Jtm (at retina) 500 Jtm (at retina)
Exposure 0.1 seconds 0.1 seconds
Intensity Moderate Moderate
Number 1200-1600 400-650
Placement 1/2 burn apart > 2 disc apart > 2 disc
2':: 1 burn
diameters from fovea out to diameters from fovea out to
equator equator
Number of episodes 2'::2 1
Lesion treated directly Patches of NVE < 2 disc areas Patches of NVE < 2 disc areas
Indications for follow-up Recurrent or new NVE or high-risk Recurrent or new NVE or high-risk
treatment proliferative retinopathy proliferative retinopathy

Focal Direct Grid

Burn characteristics
Size 50-100 Jlm <200 Jtm (at retina)
Exposure 0.05-0.1 seconds 0.05-0.1 seconds
Intensity Sufficient to whiten or darken Mild
large microaneurysms
Number Sufficient to satisfactorily treat all Sufficient to cover areas of diffuse
focal leaks leakage and non-perfusion
Placement 500-3000 Jtm from center of Spaced greater than one burn
fovea width apart 500-3000 Jtm from
center of fovea
Number of episodes 1 1
Indications for follow-up Presence of CSME and treatable Presence of CSME and treatable
treatment lesions at 2'::4 months lesions at 2'::4 months

actions, 1011 and increased production ofthe proaggregat-
ing arachidonic acid metabolites, prostaglandin E2 and
thromboxane A2 12- 14 Several authors speculated that these
alterations might be associated with the capillary closure
observed in diabetic retinopathy. 9 15- 17
If abnormal platelet activity were important in the evo-
lution of diabetic retinopathy, then aspirin treatment,
which has been shown to block the enzyme cyclooxygen-
ase and thereby inhibit prostaglandin production and
platelet aggregation, 18 19 might be effective. In addition,
three clinical studies suggest that the prevalence of diabetic
retinopathy is lower than expected in patients with dia-
betes mellitus who also are taking moderately high doses
of aspirin, usually for arthritis. 20- 22 To test the possible
effects of aspirin, patients were assigned randomly to either
650 mg of aspirin per day or to placebo. The primary
endpoint was the development of high-risk proliferative
retinopathy. Other endpoints were development of vit-
reous hemorrhage, change in retinopathy, mortality, and
the development of cardiovascular disease.
This report summarizes the design of the ETDRS and
the baseline characteristics of the patients enrolled.
ETDRS DESIGN
To be eligible for the ETDRS, patients were required
to have diabetic retinopathy in both eyes. Each eye had
to meet either of the following eligibility criteria: ( 1) no
macular edema, visual acuity of 20/40 or better, and
moderate or severe nonproliferative or early proliferative
retinopathy; or (2) macular edema, visual acuity of 20/
200 or better, and mild, moderate, or severe nonprolifer-
ative retinopathy or early proliferative retinopathy.
Patients were assigned randomly to aspirin (650 mg
per day) or placebo. One eye of each patient was assigned
randomly to early photocoagulation and the other eye to
deferral of photocoagulation. Both eyes were to be ex-
amined at least every 4 months and photocoagulation
treatment was to be initiated in the eye assigned to deferral
as soon as high-risk proliferative retinopathy was detected.
All eyes chosen. for early photocoagulation were as-
signed randomly to either of two scatter (panretinal) pho-
tocoagulation techniques (full or mild). Eyes with macular
edema were assigned randomly to either of two timing
strategies for focal photocoagulation (immediate or de-
layed), so that for these eyes, there were four strategies of
early photocoagulation.
STRATEGIES FOR PHOTOCOAGULATION
The specific techniques for photocoagulation have been
described previously and are summarized in Table 2. 23 - 27
The argon laser was chosen for photocoagulation in the
ETDRS because of(l) the availability of small spot sizes
for macular (focal) treatment, (2) DRS evidence of milder
743
 OPHTHALMOLOGY MAY 1991 VOLUME 98 SUPPLEMENT

No Macular Edema Macular Edema

and
More Severe Retinopathy
Early --------- --------------
Photocoagulation
Deferral of
Photocoagulation

/~
Immediate Immediate
Mild Full
Scatter Scatter
Immediate
Delayed Delayed Mild
Focal Focal Scatter
Immediate Delayed
Fig 1. Early Treatment Diabetic Retinopathy Study photocoagulation Focal
[ ~ocai __ J
treatment scheme for eyes without macular edema with moderate-to-
severe nonproliferative or early proliferative retinopathy. Eyes were as- Fig 3. Early Treatment Diabetic Retinopathy Study photocoagulation
signed randomly to early photocoagulation or deferral of photocoagu- treatment scheme for eyes with macular edema and more severe reti-
lation. Eyes assigned to early photocoagulation were further assigned nopathy. Eyes were assigned randomly to immediate photocoagulation
randomly to either mild or full scatter (panretinal) photocoagulation. or to deferral of photocoagulation. Eyes assigned to immediate photo-
coagulation were further assigned randomly to either mild or full scatter
(panretinal) photocoagulation, and to either immediate focal treatment

l
or to deferral of focal treatment for at least 4 months.
Macular Edema
and
Less Severe Retinopathy CATEGORY 1: EYES WITHOUT MACULAR EDEMA

Eyes in this category (Fig l) had moderate-to-severe

nonproliferative or early proliferative retinopathy. "Im-
mediate" photocoagulation for these eyes was either mild
or full scatter. "Delayed" focal photocoagulation was ini-
tiated during follow-up if macular edema developed that
involved or threatened the center of the macula (clinically
significant macular edema, CSME).

IT';w
Immediate Immediate Immediate
Focal Mild Focal Full
Delayed
Scatter
Delayed
catter CATEGORY 2: EYES WITH MACULAR EDEMA AND
Mild Delayed Full elayed LESS SEVERE RETINOPATHY
Scatter Focal Scatter Focal
------ '--------
Eyes in this category (Fig 2) had macular edema and
Fig 2. Early Treatment Diabetic Retinopathy Study photocoagulation mild-to-moderate nonproliferative retinopathy. Early
treatment scheme for eyes with macular edema and less severe retinopathy photocoagulation for these eyes was: (I) immediate focal
(mild-to-moderate nonproliferative retinopathy). Eyes were assigned photocoagulation, with scatter photocoagulation (mild or
randomly to early photocoagulation or to deferral of photocoagulation.
full) added if severe nonproliferative or early proliferative
Eyes assigned to early photocoagulation were further assigned randomly
to either mild or full scatter (panretinal) photocoagulation, and to either
retinopathy developed during follow-up, and (2) imme-
immediate focal or delayed focal treatment. In eyes assigned to immediate diate scatter photocoagulation (mild or full), with focal
focal treatment, the assigned scatter treatment was not applied initially, photocoagulation delayed for at least 4 months. Focal
but only if severe nonproliferative retinopathy or worse developed during photocoagulation was initiated at or after the 4-month
follow-up. visit only if CSME was present. However, focal photo-
coagulation was withheld at the 4-month visit if the mac-
ular edema had improved or the visual acuity score had
increased by five or more letters. Optionally, focal pho-
side effects with argon laser than with xenon-arc photo- tocoagulation could be withheld at the 8-month visit if
coagulation, and (3) its ready availability. there was substantial improvement, such as return to nor-
Implementation of early photocoagulation differed de- mal thickness of an initially thickened macular center or
pending on retinopathy status at baseline (Figs 1-3). Three improvement in visual acuity score by I 0 or more letters.
categories, differing in retinopathy severity and the pres- At and after the 12-month visit, initiation of focal pho-
ence or absence of macular edema, were defined. The tocoagulation was required for all eyes assigned to early
strategies for photocoagulation for each category are out- photocoagulation if they had CSME and had not yet re-
lined in the following sections. ceived focal photocoagulation.

744
 ETDRS RESEARCH GROUP PATIENT CHARACTERISTICS

Table 3. Number of Eyes in Each Baseline Category

Strategy for Photocoagulation

Early* Full Scatter Early* Mild Scatter

Immediate Delayed Immediate Delayed

Baseline Category Focal Focal Focal Focal Deferral

Eyes without macular edema

Placebo 292 297 613
Aspirin 291 293 566
Eyes with macular edema and less severe retinopathy
Placebo 184 179 178 187 722
Aspirin 178 177 187 178 707
Eyes with macular edema and more severe retinopathy
Placebo 134 135 136 133 520
Aspirin 138 135 140 139 583
Total 634 1209 641 1227 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.
Early photocoagulation for these eyes was (I) immediate
focal and scatter photocoagulation (mild or full), and (2)
immediate scatter photocoagulation (mild or full), with
focal photocoagulation delayed for at least 4 months. The
same procedure as described above for initiating focal
photocoagulation at or after 4 months was used.
Table 3 shows the number of eyes enrolled by baseline
category. Both eyes of a patient did not have to have the
same category at baseline.
ASPIRIN TREATMENT
The third question the ETDRS was designed to answer
was what effects aspirin would have on the progression
of diabetic retinopathy (Fig 4 ). Each patient was assigned
randomly to receive either 650 mg of aspirin or placebo
daily. The study was double-masked; neither clinical cen-
ter staff nor the patient knew the contents of the assigned
tablets.
The choice of aspirin dose was based on balancing the
following considerations. During the design phase of the
ETDRS in the late I970s, most of the secondary preven-
tion trials in cardiovascular disease investigating a possible
protective effect of aspirin against major vascular events
(e.g., myocardial infarction and stroke28 - 30) were using
approximately I gram per day. Other studies suggested
that a lower dose might be preferable because it was dem-
onstrated that doses of aspirin as low as 75 mg per day
or even every other day were sufficient to block the cyclo-
oxygenase enzyme while minimizing the inhibitory effect
of aspirin on biosynthesis of prostacyclin, 31 an enzyme in
vascular endothelial cells that decreases the tendency for
platelets to adhere to them and causes dissolution of
platelet aggregates. However, in the three published case
series,20- 22 the diabetic patients showing apparently low
prevalence rates of retinopathy all were taking moderately
high doses of aspirin.
For the ETDRS, a dose of 650 mg once a day was
selected because this dose both inhibited production of
platelet prostaglandin and was similar to that used in other
studies, 31 while being low enough to allow production of
endothelial prostacyclin to resume after several hours
when the aspirin had cleared from the bloodstream. Ad-
ministration of two 325 mg tablets once a day was ex-
pected to be generally well accepted by patients and to be
accompanied by minimal side effects. Progression of ret-
inopathy and the occurrence of vitreous or preretinal
hemorrhages during follow-up were the main endpoints
used to assess the effect of aspirin on retinopathy. The
occurrence of cardiovascular events or death were the
main endpoints used to assess the systemic effects of as-
pirin treatment.
METHODS
STUDY ORGANIZATION
Between Aprili980 and June I985, 22 clinical centers
(Appendix I) enrolled 37II patients, after obtaining In-
stitutional Review Board approval. Enrollment at each
clinical center ranged from 3I to 255 patients, with all
but 2 of the initial I8 centers enrolling I 50 or more pa-
tients (Table 4).
The central units included a Central Laboratory, a Co-
ordinating Center, a Drug Procurement and Distribution
Center, an ECG Reading Center, a Fundus Photograph
Reading Center, and the National Eye Institute (Appendix

745
 OPHTHALMOLOGY
Patient
Randomized
Aspirin
Placebo
650 mglday
N = 1855
N = 1856
Deferral of
Early Photo- Early Photo-
Photo-
coagulation coagulation
coagulation
N = 1856
N = 1856
N =1855
Fig 4. Randomization ofETDRS patients to aspirin or placebo treatment,
and of eyes to photocoagulation strategies.
Table 4. Number of Patients Enrolled by Clinical Center
Clinical Center No., Name, and Location
21. Johns Hopkins Hospital, Baltimore, MD
22. Joslin Diabetes Center, Boston, MA
23. University of Wisconsin, Madison, WI
24. University of Miami, Miami, FL
25. University of Minnesota, Minneapolis, MN
27. Good Samaritan Hospital, Portland, OR
28. University of Illinois, Chicago, IL
29. University of California at Los Angeles, Los Angeles, CA
30. Albany Medical College, Albany, NY
32. Zweng Memorial Retinal Research Foundation, Menlo
Park, CA
33. Pacific Presbyterian Medical Center, San Francisco, CA
34. Wills Eye Hospital, Philadelphia, PA
35. Holy Cross Hospital, Salt Lake City, UT
36. University of Puerto Rico, Rio Piedras, PR
37A. Wayne State University, Detroit, Ml
37B. Associated Retinal Consultants, East Lansing, Ml
38. University of Washington, Seattle, WA
39. Medical College of Wisconsin, Milwaukee, WI
41. Eye Research Institute of Retina Foundation, Boston,
MA*
42. Ingalls Memorial Hospital, Harvey, IL*
43. Hermann Eye Center, University of Texas, Houston, TX*
44. Louisiana State University Eye Center, New Orleans, LA*
Total
* Funded in May 1982.
1). An Executive Committee and a smaller Operation~
Committee guided the study. A Data Monitoring Com-
mittee had primary responsibility for assessing accumu-
lating study data on beneficial and/or adverse treatment
effects. A list of all committee participants is included in
Appendix 1.
ELIGIBILITY CRITERIA
Patient eligibility. To be eligible for enrollment in the
study, male or female patients between the ages of 18 and
746
MAY 1991 VOLUME 98 SUPPLEMENT
70 years with a clinical diagnosis of diabetes mellitus had
to have retinopathy meeting the ocular eligibility require-
ments in both eyes. In addition, it was necessary that each
patient be a suitable candidate medically for random as-
signment to aspirin and available for regular follow-up
examinations for 5 years or more. Specific details of eli-
gibility and exclusion criteria are available in the ETDRS
Manual of Operations. 23
Ocular eligibility. The ocular eligibility criteria were
based on retinal characteristics and visual acuity require-
ments as described in the ETDRS Design section. Specific
details of ocular exclusion criteria are available in the
ETDRS Manual of0perations. 23
Deferral of
Photo-
coagulation PATIENT VISITS
N = 1855
One or more qualifying visits and a randomization visit
were completed for each patient within a 4-month period
(Appendix 2). After an initial explanation of the ETDRS,
potentially eligible patients signed a preliminary consent
form for completion of the qualifying visit examinations.
Qualifying visit assessments included obtaining stereo-
Number scopic color fundus photographs and fluorescein angio-
grams that were evaluated for eligibility by the Fundus
214 Photograph Reading Center staff who had no knowledge
255 of other patient data. A preliminary grading was assigned
197 for each eye with regard to retinopathy severity level and
169
210 to the absence or presence of macular edema, with or
204 without involvement of the center of the macula. Patients
209 were eligible only if both eyes met the eligibility criteria;
201 however, both eyes were not required to be symmetrical
187
with respect to either retinopathy severity or macular
31 edema.
75 The Coordinating Center staff reviewed all qualifying
192 visit data to confirm eligibility and assigned randomly
220 each patient's treatment. The randomization schedules
189
192 were designed to provide balance in: ( 1) the number of
206 patients assigned to aspirin and placebo within each clin-
150 ical center, (2) the number of right and left eyes assigned
167 to early photocoagulation, and (3) the number of eyes
36
assigned to each of the four photocoagulation treatment
94 strategies within each of the three retinopathy categories.
164 At the randomization visit, the Clinical Center
149 ophthalmologist and staff reviewed the patient's ocular
3711 and systemic eligibility. If the patient remained eligible
in all respects, the second consent form was signed. The
sealed mailer from the Coordinating Center containing
the description of the photocoagulation strategy and coded
drug assignment was then opened, photocoagulation was
initiated, and the patient's coded bottle of study medi-
cation was dispensed.
The initial treatment session comprised all applications
of photocoagulation within 5 weeks of its initiation. Ste-
reoscopic color fundus photographs were taken after
treatment to document the photocoagulation applied.
Without knowledge of the assigned strategy for photo-
coagulation, the Fundus Photograph Reading Center staff
graded these photographs for adherence to the photoco-
agulation protocol. As part of monitoring adherence to
 ETDRS RESEARCH GROUP
the protocol, these assessments were forwarded to the
treating ophthalmologist and to study ophthalmologists
performing site visits.
Each follow-up visit (Appendix 2) included an assess-
ment of best-corrected visual acuity, an ophthalmoscopic
examination to determine whether follow-up photoco-
agulation treatment was indicated, 23 - 27 and a review of
possible symptoms and side effects of aspirin. Each patient
was scheduled for follow-up visits at 6 weeks and 4 months
after the randomization visit, and thereafter at 4-month
intervals until the final study visit.
PHOTOCOAGULATION
Techniques for photocoagulation, which have been de-
scribed previously, 24- 26 are summarized in Table 2. The
two types of scatter photocoagulation were "full" and
"mild" scatter. Full scatter was similar to that used in the
DRS, consisting of a total of 1200 to 1600 argon laser
burns of moderate whiteness and 500 J.L diameter spot
size, spaced a half burn width apart. Mild scatter consisted
of 400 to 650 similar burns, spaced more than one burn
width apart. Focal photocoagulation for macular edema
consisted of the application of argon laser burns to focal
lesions (such as microaneurysms that filled or leaked dur-
ing fluorescein angiography) located between 500 and
3000 J.L from the center of the macula.
At the first occurrence of high-risk proliferative reti-
nopathy during follow-up in an eye assigned to deferral
of treatment, the protocol specified that full scatter be
applied. When CSME was present in such eyes at the time
high-risk proliferative retinopathy developed, or when it
developed subsequent to scatter treatment, focal photo-
coagulation for macular edema was given if the indications
for follow-up focal photocoagulation were present (i.e.,
CSME and one or more treatable lesions), provided the
fellow eye assigned to early photocoagulation had been
assigned to delayed focal photocoagulation. The ETDRS
protocol was modified in September 1985 to allow focal
photocoagulation for macular edema in eyes assigned to
deferral of photocoagulation that had CMSE at that time
or developed it subsequently. 24- 25
During follow-up, at the first occurrence of high-risk
proliferative retinopathy in an eye assigned to early pho-
tocoagulation, the protocol specified additional scatter
photocoagulation.
MEASUREMENT OF VISUAL ACUITY
In the ETDRS, best-corrected visual acuity was mea-
sured with logarithmic visual acuity charts32 at a distance
of 4 meters, and at 1 meter as well if visual acuity was
worse than 20/100. The protocol specified that visual
acuity examiners be trained and certified, that they be
masked from treatment assignment, and that they follow
standard procedures for encouraging patients to make a
maximum effort to read as many letters as possible with
each eye. 23
PATIENT CHARACTERISTICS
NCKZO
32(1601
RHSDK
251125)
DOVHR
20(100)
CZRHS
ONHRC
12(63)====
16(80)
DKSNV
10(50)
ZSOKN
CKDNR
______
6(401
SRZKD
6(32)
5(25) HZOVC ,"'
!:~~------ NVCOK
lfHCNO
~ ~ j;%,5'
Fig 5. One of three ETDRS visual acuity charts. Four-meter testing dis-
tance with this chart yields the following Snellen equivalent lines: 20/
10, 20/12.5, 20/16, 20/20, 20/25, 20/31.5, 20/40, 20/50, 20/63, 20/80,
20/100,20/125, 20/160, and 20/200. At I meter, the following additional
Snellen equivalent lines of visual acuity could be measured: 20/250, 20/
315, 20/400, 20/500, 20/630, and 20/800. Notice that every three lines
is a doubling of the visual angle and that there are five letters on each
line.
The visual acuity charts used in the ETDRS had 14
rows of five letters each, corresponding to visual acuities
from 20/10 to 20/200 when viewed at a distance of 4
meters (Fig 5). When 20 or more letters were read correctly
at 4 meters (corresponding to visual acuity of 20/100 or
better), the visual acuity score was the number read cor-
rectly plus 30 (the total number of letters on the top six
lines of the chart, which were used at a 1-meter distance
for testing low visual acuity). When fewer than 20 letters
were read correctly at 4 meters, only the number ofletters
read correctly at 1 meter of the 30 letters on the top 6
lines was added to the 4-meter total to obtain the visual
acuity score.
A perfect visual acuity score was 100, corresponding
to visual acuity of 20/10. The visual angle doubled (e.g.,
20/20 to 20/40, 20/100 to 20/200) with each decrement
of 15letters (the equivalent of three lines on these charts).
A visual acuity score of five corresponded to visual acuity
of 5/200. If no letters could be read correctly at 1 meter,
the presence or absence of light perception was recorded.
ASSESSMENT OF VISUAL FUNCfiON OTHER
THAN VISUAL ACUITY
Visual fields were assessed along each of 12 meridians
with the I/2e and I/4e test objects of the Goldmann pe-
rimeter. For each test object, a visual field score was cal-
culated by totaling the peripheral extent of the field in
degrees on each of the 12 meridians, after subtracting any
747
 OPHTHALMOLOGY MAY 1991
scotomas encountered along them23 ; the smaller the sum,
the more constricted the field. The presence of scotomas
within 10 and between 10 and 20 of fixation also was
recorded.
Color vision was assessed with the Farnsworth-Munsell
100 Hue Test, 23 scored by the method of Farnsworth. The
square root of the score was calculated and used to assess
change between baseline and follow-up visits. An increase
of 7.5 or more in the square root of the score or the in-
ability to perform the test due to poor visual acuity was
considered a clinically important loss.
ASSESSMENT OF SEVERITY OF RETINOPATHY
AND MACULAR EDEMA
Fundus Photograph Reading Center staff, without
knowledge of treatment assignments and clinical data,
followed a standardized procedure to grade fundus pho-
tographs and fluorescein angiograms for individual lesions
of diabetic retinopathy. 33 - 36 Stereoscopic fundus photo-
graphs and fluorescein angiograms were taken at baseline
and periodically during follow-up. 23
MAJOR ENDPOINTS AND OTHER
STATISTICAL CONSIDERATIONS
The recruitment goal was 4000 patients, with approx-
imately half assigned to aspirin and half to placebo. It
was expected that there would be 150 to 200 eyes assigned
to each of the four strategies of early photocoagulation
for each group defined by baseline category and assigned
study drug.
ESTIMATES OF STUDY POWER
Estimates of study power were made for each of the
three main study questions during the design phase of the
study. The first question was whether early photocoagu-
lation would reduce the risk of severe visual loss compared
with deferral of photocoagulation. For the primary end-
point, it was estimated that 10% of eyes assigned to deferral
in patients assigned to placebo would develop severe visual
loss within 5 years (less than half the rate of severe visual
loss observed in the DRS in treated eyes with high-risk
proliferative retinopathy of all degrees of severity, not just
newly developed). With 2000 eyes assigned to deferral in
patients assigned to placebo and their 2000 fellow eyes
assigned to early photocoagulation, a 40% reduction in
the rate of severe visual loss (corresponding to a 6% rate
of occurrence) could be detected with 98% power (to be
conservative, alpha = 0.01 for two-sided test was specified
rather than the customary 0.05). The power calculation
indicates this design had sufficient power to consider the
results for aspirin separately from the results for placebo.
This was important since there might be more hemorrhage
(and thus subsequent severe visual loss) in eyes that re-
748
VOLUME 98 SUPPLEMENT
ceived early photocoagulation in patients who were as-
signed to aspirin than in patients assigned to placebo.
Half the eyes assigned to early photocoagulation were
assigned to immediate full scatter and the other half to
immediate mild scatter. A 40% reduction in the rate of
severe visual loss could be detected with more than 87%
power for eyes assigned to one of these strategies, com-
pared with the rate in eyes assigned to deferral. If the
effect of aspirin treatment were observed to be small, the
results in patients assigned to aspirin and placebo could
be pooled and these estimates of study power would be
more than 99%.
The second study question was whether different com-
binations of focal and scatter photocoagulation would re-
duce the rate of development of moderate visual loss in
eyes with macular edema, compared with deferral of pho-
tocoagulation. The development of moderate visual loss
in these eyes assigned to deferral was estimated to be 50%
in 5 years. It was expected that there would be 1500 eyes
with macular edema assigned to deferral in patients as-
signed to placebo, 750 such eyes assigned to immediate
focal treatment, and 750 assigned to delayed focal treat-
ment. With these assumptions, there would be more than
99% power to detect a 25% reduction in the rate of mod-
erate visual loss (38% rate of occurrence) in either of the
groups assigned to early photocoagulation compared with
deferral (alpha= 0.01, two-sided test).
These power calculations indicate the ETDRS design
was adequate for assessing the effects of scatter photoco-
agulation if any one of the following were true: ( 1) the
effects of scatter photocoagulation were independent of
the effects of focal photocoagulation, (2) the effects of
scatter photocoagulation were independent of the effects
of aspirin, or (3) the effects of scatter photocoagulation
were independent of baseline category. If none of these
assumptions were true, the results would have to be based
on comparisons of findings within baseline category, tak-
ing account of the strategy for photocoagulation. Similar
considerations were used to assess the effects of focal pho-
tocoagulation.
The final study question was whether aspirin treatment
would reduce the rate of progression to high-risk prolif-
erative retinopathy. It was estimated that the 5-year rate
of this event in eyes assigned to deferral in patients as-
signed to placebo would be 40%. With 2000 patients in
each drug treatment group, there would be more than
99% power (alpha= 0.01, two-sided test) to detect a 25%
reduction in the rate of developing high-risk proliferative
retinopathy in the patients assigned to aspirin (corre-
sponding to a 5-year rate of 30% ).
Power also was evaluated with a model that assumed
less than perfect compliance with study medication. In
this model, 85% of the patients assigned to aspirin either
were taking the study drug or known to be taking aspirin
from other sources, and 75% of the patients assigned to
placebo were not taking any aspirin. Based on these as-
sumptions, the power to detect a 25% reduction in the
rate of developing high-risk proliferative retinopathy
was 92%.
 ETDRS RESEARCH GROUP PATIENT CHARACTERISTICS

NONOCULAR ENDPOINTS Table 5. Baseline Characteristics of Enrolled Patients,

by Assignment of Drug Treatment
The three primary endpoints for assessing the systemic
effects of aspirin treatment were ( 1) total (i.e., all causes) Aspirin Placebo
mortality, (2) mortality due to cardiovascular disease, and (n = 1856) (n = 1855)
(3) the occurrence of fatal and nonfatal myocardial in-
farction. n Percent n Percent
Age at entry (yrs)
OTHER OCULAR ENDPOINTS <30 324 17 302 16
Other endpoints for the effects of' photocoagulation 30-49 572 31 596 32
identified during study planning were change in visual ~50 960 52 957 52
Sex (male) 1031 56 1065 57
acuity, development or resolution of macular edema, and Race (white) 1420 76 1414 76
worsening of retinopathy during follow-up. For the ocular Type I diabetes 559 30 571 31
effects of aspirin treatment, other endpoints were the oc- Duration of diabetes (yrs)
currence of vitreous or preretinal hemorrhage as well as <10 306 16 304 16
the other endpoints for evaluating photocoagulation. 10-19 1084 58 1035 56
~20 466 25 516 28
STATISTICAL METHODS Percent desirable weight
~120% 793 43 748 40
Comparisons of endpoints expressed as proportions of Systolic blood pressure
events were made with two-sample tests of equality of ~130 mmHg 1228 66 1220 66
~160 mmHg 385 21 364 20
proportions. 37 The Cutler-Ederer actuarial life table
method38 was used to estimate rates of first occurrence of Diastolic blood pressure
~85 mmHg 735 40 716 39
certain events. The Mantel-Cox method was used to ~90 mmHg 552 30 509 27
compute chi-square values for comparison of life table Serum creatinine ~ 1.5 mg/1 00 ml 114 6 139 8
curves. 39 Comparisons of continuous variables were based History of cardiovascular disease 912 49 900 49
on the two-sample z-test of equality of means. 37 Cigarettes/day ~ 6 819 44 822 44
Because multiple endpoints in the different groups were Visual acuity score (deferral eyes)
compared several times for the Data Monitoring Com- ~85 letters (20/20 or better) 938 50 901 49
mittee, the critical value of test statistics corresponding 84-70 letters (20/25 to 20/40) 721 39 734 39
to an 0.05 level of significance for a two-sided test was <70 letters (worse than 20/40) 197 11 220 12
not used. For monitoring purposes, observed z values of Severity of retinopathy35
1.96 to 2.57 or -1.96 to -2.57 were considered suggestive Level : ;:; 35 (mild NPDR) 288 16 321 17
Level 43 (moderate NPDR) 437 24 469 25
of a treatment difference. Observed z values of 2.58 or Level 47 (moderately severe
more extreme (corresponding to an 0.01level for a single NPDR) 499 27 439 24
test of significance) were considered statistically signifi- Level 53a-d (severe NPDR) 255 14 245 13
cant. Level 53e (very severe NPDR) 53 3 39 2
The majority of analyses included in the interim reports Level 61 (mild PDR) 165 9 174 9
prepared at least twice a year for review by the Data Mon- Level 65 (moderate PDR) 155 8 163 9
itoring Committee were based on all eyes in a specified Level 71 (high-risk PDR) 4 <1 5 <1
group, that is, the "pairing" of eyes was not taken into For patients enrolled before
account. A few analyses were based on all eyes pooled September 1983
over baseline categories. At infrequent intervals, the results Hemoglobin A1c ~ 10% 538 41 584 43
Serum cholesterol
for "paired" eyes and results for "unpaired" eyes were ~ 240 mg/1 00 ml 470 35 495 36
calculated separately. The results ofboth approaches sug- Low density lipoprotein
gested that not taking pairing into account led to conser- cholesterol ~ 160 mg/1 00 ml 336 26 328 25
vative tests.

RECRUITMENT AND PATIENT

ENROLLMENT
BASELINE CHARACTERISTICS AND
ADHERENCE TO INITIAL TREATMENT
Screening of eligible patients began in December 1979.
The first patient was enrolled in April 1980, the last was
enrolled in July 1985. Recruitment ended with 98% of BASELINE DESCRIPTION
the goal of 4000 patients enrolled. Data reported here are
for 3711 patients (data from 217 patients have been ex- A brief description of enrolled patients is presented in
eluded as previously reported). 40 Table 5. Ofthe 3711 patients, 56% were males. Approx-

749
 OPHTHALMOLOGY MAY 1991 VOLUME 98 SUPPLEMENT

Table 6. Baseline Characteristics of Enrolled Patients, The proportion of right eyes selected for immediate
by Assignment of Scatter Photocoagulation photocoagulation was 50%. In 75% of ETDRS patients,
both eyes belonged to the same baseline category.
Mild Full Table 6 provides baseline data by assigned scatter pho-
(n = 1868) (n = 1843)
tocoagulation. There were no important or statistically
n Percent n Percent significant (P < 0.01) differences, except for slightly greater
prevalence of increased diastolic blood pressure in patients
Age at entry (yrs) assigned to full scatter photocoagulation.
<30 300 16 326 18 Within each baseline category, there were no large dif-
30-49 611 33 S57 30 ferences in mean visual acuity scores between groups of
~so 957 51 960 52 eyes assigned to various strategies for early photocoagu-
Sex (male) 1063 57 1033 56 lation and eyes assigned deferral of photocoagulation
Race (white) 1440 77 1394 76 (Table 7).
Type I diabetes 558 30 572 31
Duration of diabetes (yrs)
<10 312 17 298 16 ADHERENCE TO PROTOCOL THROUGH INITIAL
10-19 1085 58 1034 56 TREATMENT
~20 471 25 511 28
Percent desirable weight
~120% 768 41 773 42 For a total of 15 (0.4%) patients, exceptions to the pro-
Systolic blood pressure tocol were noted on the randomization visit form. For
~130 mmHg 1215 65 1233 67 example, in 8 of 15 patients, randomization visit photo-
~160 mmHg 357 19 392 21 graphs were not taken, although results of the ophthal-
Diastolic blood pressure mologic examination at that visit indicated change had
~as mmHg 691 37 760 41* occurred since the qualifying visit photographs were taken.
~90 mmHg 478 26 583 32t Two eyes among the 3711 assigned to deferral ofpho-
Serum creatinine ~ 1.5 mg/1 00 ml 121 7 132 7 tocoagulation were treated at the initial treatment session
History of cardiovascular disease 884 47 928 50
Cigarettes/day ~ 6 842 45 799 43 (one fellow eye assigned to early photocoagulation was
Severity of retinopathy 35 treated by the 4-month follow-up visit and the other fellow
Level ~ 35 (mild NPDR) 316 17 288 16 eye was never treated). Five eyes among the 3711 assigned
Level 43 (moderate NPDR) 452 24 459 25 to early photocoagulation were not treated at the initial
Level 47 (moderately severe treatment session (two eyes described in the preceding
NPDR) 477 26 482 26 sentence, one eye that was treated by the 4-month follow-
Level 53a-d (severe NPDR) 245 13 231 13 up visit, and two eyes never treated). For 68 (1.8%) of the
Level 53e (very severe NPDR) 50 3 53 3 3711 patients, photograph sets to document the initial
Level 61 (mild PDR) 169 9 169 9 treatment session were not taken or were lost. For 66
Level 65 (moderate PDR) 153 8 155 8 (1.8%) of the 3643 patients with initial treatment session
Level 71 (high-risk PDR) 6 <1 6 <1
For patients enrolled before photograph sets, the Fundus Photograph Reading Center
September 1983 assessment differed from the indicated assignment of
Hemoglobin A1c ~ 10% 566 42 556 42 scatter and/or focal photocoagulation (i.e., one type or
Serum cholesterol the other was omitted when it should have been applied,
~ 240 mg/100 ml 495 36 470 35 or vice versa).
Low density lipoprotein For the 1472 eyes assigned to immediate mild scatter
cholesterol ~ 160 mg/100 ml 318 25 346 27 that had photographs taken at the initial treatment session,
all but 8 (1464, 99.5%) either were assessed by the Fundus
* P< 0.01. Photograph Reading Center staff as having photographs
t P < 0.001 (using a l-test for equality of proportions). showing burn separations consistent with mild scatter or
were reported by the Clinical Center staff as having an
approximate number of burns applied consistent with
imately half of the patients were between 50 and 70 years mild scatter. Of the 1460 eyes assigned to immediate full
of age; approximately 30% were classified as having type scatter, 1436 (98.4%) photographs were judged to show
I diabetes (unpublished data). The duration of diabetes burn separations consistent with full scatter or were re-
was between 10 and 19 years for more than half of the ported by the Clinical Center staff as having the approx-
enrolled patients. imate number of burns applied consistent with full scatter.
Data on the comparability of baseline characteristics
of patients assigned aspirin or placebo are shown in Table
5. There were no important or statistically significant (P SUMMARY
< 0.01) differences. Baseline visual acuity scores were ob-
tained for both eyes in all but one patient, and for this
patient the qualifying visit visual acuity scores were used The ETDRS evaluated photocoagulation and aspirin
as baseline measurements. treatment in patients who had mild-to-severe nonproli-

750
 ETDRS RESEARCH GROUP PATIENT CHARACTERISTICS

Table 7. Percentage Distribution of Baseline Visual Acuity Score

Part 1: Eyes without macular edema

Immediate Mild Immediate Full
Delayed Focal Delayed Focal
(%) (%) Deferral

Visual acuity score

;::-:85 (20/20 or better) 71 72 71
84-70 (20/25 to 20/40) 29 28 29
Total (number) 100 (590) 100 (583) 100 (1179)
Mean score (SE) 87.0 (0.2) 87.1 (0.2) 87.0 (0.2)

Part 2: Eyes with macular edema and less severe retinopathy

Immediate Focal Immediate Focal Immediate Mild Immediate Full
Delayed Mild Delayed Full Delayed Focal Delayed Focal Deferral
(%) (%) (%) {%) (%)

Visual acuity score

;::-:85 (20/20 or better) 42 44 46 42 41
84-70 (20/25 to 20/40) 41 44 39 40 44
<70 (worse than 20/40) 17 12 15 18 15
Total (number) 100 (365) 100 (362) 100 (365) 100 (356) 100 (1429)
Mean score (SE) 79.2 (0.7) 80.4 (0.6) 80.1 (0.6) 79.5 (0.7) 79.8 (0.3)

Part 3: Eyes with macular edema and more severe retinopathy

Immediate Focal Immediate Focal Immediate Mild Immediate Full
Delayed Mild Delayed Full Delayed Focal Delayed Focal Deferral
(%) (%) (%) (%) (%)

Visual acuity score

;::-:85 (20/20 or better) 35 31 36 36 37
84-70 (20/25 to 20/40) 46 48 46 47 45
<70 (worse than 20/40) 19 21 18 17 18
Total (number) 100 (276) 100 (272) 100 (272) 100 (270) 100 (1103)
Mean score (SE) 77.3 (0.9) 77.6 (0.8) 78.3 (0.7) 78.8 (0.7) 78.4 (0.4)

SE = standard error.

ferative or early proliferative diabetic retinopathy. Ex-
amination of the distribution of a large number of baseline
ocular and systemic characteristics indicated the random-
ized treatment groups were comparable. Adherence to the
assigned strategy for photocoagulation at the initial treat-
ment session was reviewed and found to be over 98% for
application of the assigned scatter and/or focal photoco-
agulation.
APPENDIX 1. LISTING OF ETDRS
RESEARCH GROUP
Albany Medical College, Albany, NY: Principal Investigator:
Aaron Kassoff, MD; Participating Internist: A. David Goodman,
MD; Clinic Coordinator: JoAnne Buehler; Assistant Clinic Co-
ordinator: Denise Garza; Photographer: Michel Mehu; Nurse:
Joan Locatelli, RN; Past Participating Personnel: Participating
Internists: Edward Rosenberg, MD, Steven Leveston, MD; As-
sistant Clinic Coordinators: Patricia Jo Johnson, Karen Dylong;
Photographers: Deborah Mazzoccone, David Cohen; Nurse:
Cherilyn Rubin, RN, PCN; Visual Function Examiners: Diane
Beyer, Jeanne Goldsmith, LPN; Eye Research Institute of Retina
Foundation/Retina Associates, Boston, MA: Principal Investi-
gator: Sheldon M. Buzney, MD; Co-Principal Investigators:
J. Wallace McMeel, MD, John J. Weiter, MD, PhD; Participating
Internist: Gerald J. Doyle, MD; Clinic Coordinator: R. Elna
Rapp, RN; Photographers: Andy Rosenblum, Tom O'Day; Vi-
sual Function Examiners: Rodney L. Immerman, OD, Gerald
R. Friedman, OD, Anthony J. Morandi; Good Samaritan Hos-
pital and Medical Center, Portland, OR: Principal Investigator:
Michael L. Klein, MD; Co-Principal Investigator: Richard
Dreyer, MD; Project Ophthalmologists: Richard Chenoweth,
MD, Irvin Handelman, MD; Participating Internists: Richard
Hohl, MD, Robert Biesbroeck, MD; Clinic Coordinator: Carolyn
Beardsley; Photographers: Milt Johnson, Patrick Rice, Howard
Daniel; Nurse: Linda Diehl, RN; Visual Function Examiners:
Julie Arends, Barbara Royce; Past Participating Personnel: Pro-
ject Ophthalmologist: Jack Sipperley, MD; Photographers: Carl
Kittelson, Candace Collins; Visual Function Examiners: Dana
Critchlow, Debbie Gibbons, Karin Hefting, Elaine Lorimer,

751
 OPHTHALMOLOGY MAY 1991
Mallory Otis, Claudia Shultz; Hermann Eye Center, University
of Texas, Houston, TX: Principal Investigator: Charles A. Garcia,
MD; Co-Principal Investigator: Michael A. Bloome, MD; Rich-
ard S. Ruiz, MD; Participating Internist: Thomas Y. Chandler,
MD; Brian Tulloch, MD; Clinic Coordinator: Nancy J. Ruiz;
Assistant Clinic Coordinator: Lillian Puccio; Photographer: Joey
Horton; Nurse: Lois Halley; Visual Function Examiner: Jim
Matheny, John Miller, MD; Project Ophthalmologist: Hsuan
Ho Chu, MD; Past Participating Personnel: Participating Inter-
nist: Harold Dobson, MD; Photographer: Rich Sabo, Celia
Hutchison, Mark Croswell, Holly Harwood; Visual Function
Examiner: Tom Arnold, OD, Gary Barker, OD, Tammra John-
son, OD, Sue Moss, OD; Holy Cross Hospital, Salt Lake City,
UT: Principal Investigator: F. Tempel Riekhof, MD; Co-Prin-
cipal Investigators: William A. Bohart, MD, Roy A. Goodart,
MD; Participating Internist: Dana H. Clarke, MD; Clinic Co-
ordinator: M. LaRae Challis; Photographers: Bonnie Carlstrom,
Richard Osguthorpe; Nurse: Donna Tomky; Secretary/Color
Vision Technician: Joyce Urry; Ingalls Memorial Hospital,
Harvey, IL: Principal Investigator: David H. Orth, MD; Co-
Principal Investigators: Timothy P. Flood, MD, Kirk H. Packo,
MD; Participating Internists: Jayant Malhotra, MD, Akbar
Rahmani, MD, Edward J. Winter, MD, Harish Bhatia, MD;
Clinic Coordinator: Debra Anderson; Assistant Clinic Coordi-
nator: Linda Arredondo, RN; Photographers: Douglas Bryant,
Donald Doherty, Jay Fitzgerald; Nurses: Linda Arredondo, RN,
Sharon Graff, RN, Toni Larsen, RN, Debbie Hobbs, RN; Past
Participating Personnel: Participating Internist: Charles S. Vii,
MD; Johns Hopkins Hospital (Wilmer Institute), Baltimore,
MD: Principal Investigator: Robert P. Murphy, MD; Project
Ophthalmologists: Stuart L. Fine, MD, Michael J. Elman, MD,
Steven H. Sherman, MD, Frederick L. Ferris, III, MD; Partic-
ipating Internist: James Mersey, MD, Thaddeus E. Prout, MD;
Clinic Coordinator: Sherrie Schenning; Assistant Clinic Coor-
dinator: Deborah Broomfield; Photographers: Judith Belt, Terri
Cain; Nurse Practitioner: Catherine Sackett, CANP; Past Par-
ticipating Personnel: Participating Investigators: Arnall Patz,
MD, Thomas A. Rice, MD; Project Ophthalmologist: David
Newsome, MD; Clinic Coordinators: Bessie Demos, Lee Palmer;
Assistant Clinic Coordinator: Maryanth Constantine, Marta
Hernandez; Photographers: Richard Belt, Karen Klima, Joseph
Russo; Joslin Diabetes Center (Beetham Eye Institute), Boston,
MA: Principal Investigator: Lloyd M. Aiello, MD; Co-Principal
Investigator: Lawrence I. Rand, MD; Project Ophthalmologist:
Sabera T. Shah, MD; Participating Internist: Ramachandiran
Cooppan, MD; Clinic Coordinator: Pamela Beaumont, RN;
Photographers: Robert Cavicchi, Denis Fleming; Visual Function
Examiners: Jerry Cavallerano, OD, PhD, Robert Poole, OD,
Philip Silver, OD, Elizabeth Weimann, COT; Study Secretaries:
Ann Kopple, Rita Botti; Study Administrator: Constance Lan-
gone; Past Participating Personnel: Project Ophthalmologists:
Jose Briones, Jr., MD, Mohammed Z. Wafai, MD; Participating
Internist: Abdul C. Asmal, MD, PhD; Clinic Coordinator: Jo-
sephine M. Falco, Lynn Francis; Assistant Clinic Coordinator:
Debra Koritz; Photographers: Andrew Bell, Hector Mendez;
Nurses: Claire McQuilkin, RN, Karen Green, RN, Nanci Kras-
ker, RN, Beth Perrin, RN; Louisiana State University Eye Cen-
ter, New Orleans, LA: Principal Investigator: Rudolph M.
Franklin, MD; Project Ophthalmologists: Laurence Arend, MD,
Donald Bergsma, MD, Lance Turkish, MD; Participating In-
ternist: Henry Rothschild, MD, PhD; Clinic Coordinator: Susan
Franklin, RN; Photographer: Dale Pennell; Nurse: Dale Wil-
liams, RN; Visual Function Examiner: James Lynn Hamilton;
Past Participating Personnel: Project Ophthalmologists: Paul
Beer, MD, Denis Carroll, MD, David Misch, MD, Jerry Suelflow,
752
VOLUME 98 SUPPLEMENT
MD, Edgar Thomas, MD; Clinic Coordinator: Evangeline
Evanich; Assistant Clinic Coordinator: Jan Schaefer O'Boyl;
Photographers: Tom Mueller, Deborah Elkins, Anne Sastre; Vi-
sual Function Examiner: Dan McCarthy; Medical College of
Wisconsin, Milwaukee, WI: Principal Investigator: Thomas C.
Burton, MD; Co-Principal Investigator: Gary W. Abrams, MD;
Participating Internist: Hak-Joong Kim, MD; Clinic Coordi-
nator: Mary Cianciolo; Photographers: Walt Wipplinger; Mary
Nauertz Richie, James Walters; Visual Function Examiner: Dale
Jurkiewicz; Past Participating Personnel: Principal Investigators:
George A. Williams, MD, Trexler M. Topping, MD, Frederick
H. Reeser, MD; Co-Principal Investigators: Thomas M. Aaberg,
MD, Gregory S. Brinton, MD, James K. Kingham, MD, Travis
A. Meredith, MD; Clinic Coordinators: Karen Nowakowski,
Beverly Milo, Louise Eisman; Assistant Clinic Coordinators: Jane
Culver, Diane Sterman, Sue Kubisiak, Ruth Picchiottino, Jane
Balistreri, Nancy Bryant, Kathy Haas, Pamela Robinette; Pho-
tographers: Mark Maio, Gerald Staut; Michigan State University
(Associated Retinal Consultants) East Lansing, MI: Principal
Investigator: Raymond R. Margherio, MD; Co-Principal Inves-
tigator: Patrick L. Murphy, MD; Project Ophthalmologists:
Morton S. Cox, MD, Michael Trese, MD; Participating Internist:
Steven Winokur, MD; Clinic Coordinator: Virginia S. Regan,
RN; Assistant Clinic Coordinator: Beth Mitchell, RN; Photog-
raphers: Craig Bridges, Jeffrey Sobel; Past Participating Person-
nel: Principal Investigator: Delbert P. Nachazel, MD (deceased);
Participating Internist: John Bryan, MD (deceased); Assistant
Clinic Coordinators: Eunice Green, RN, Patricia Manatrey, RN,
Doreen Medalis, RN; Pacific Presbyterian Medical Center, San
Francisco, CA: Principal Investigator: Everett Ai, MD; Co-Prin-
cipal Investigator: Robert Sorenson, MD, Gary Arsham, MD;
Clinic Coordinator: Maureen McGrath; Secretary: Peggy Coak-
ley; Photographer: Michael P. Kelly; Visual Function Examiner:
Mary Wu; Laboratory Assistants: Pat Feeney, Bruce Borgman;
Past Participating Personnel: Principal Investigator: John Cav-
ender, MD; Clinic Coordinators: Margie Berger, Cherie Daut-
Wong, Susan Fraenkel, Roberta Goldfarb; Photographers: Mar-
tin Chrobak, Mike Coppinger, Joan Gonzales, Mary Federico;
Laboratory Assistant: Josie Ramos; UCLA Center for Health
Sciences (Jules Stein Eye Institute), Los Angeles, CA: Principal
Investigator: Stanley M. Kopelow, MD; Co-Principal Investi-
gator: Alan L. Shabo, MD; Project Ophthalmologist: Jose C.
Briones, Jr., MD; Participating Internist: Richard D. Hornichter,
MD; Clinic Coordinator: Dolores Kilburn; Photographers:
Dennis Thayer, Joan Greenspan; Nurse: Florentina Sadakane,
RN; Visual Function Examiners: Robert Petrus, Robert Stalling;
Past Participating Personnel: Photographers: Richard Evans,
Audrey Freidman Jorgenson; Nurse: Heather Abby, RN; Uni-
versity of Illinois, Chicago, IL: Principal Investigator: Norman
P. Blair, MD; Co-Principal Investigators: Morton F. Goldberg,
MD, C. Ronald Lindberg, MD, Neil L. Ross, MD, Lynn E.
Hauser, MD; Clinic Coordinators: Dorothe T. Ernest, MA, CSW,
ACSW, Karen Rouse, RN; Visual Function Examiner: Andrew
C. Cross, AAS, COT; Photographers: Norbert Jednock, Thomas
Young, Alan Campbell; Past Participating Personnel: Principal
Investigators: Jose Cunha-Vaz, MD, PhD, J. Terry Ernest, MD,
PhD, James C. Liang, MD; Co-Principal Investigators: Steven
B. Cohen, MD, Harvey Z. Klein, MD, Charles Vygantas, MD;
Participating Internist: Gerald Williams, MD; Clinic Coordi-
nators: Sharon Russell, Karen Lauger; Assistant Clinic Coor-
dinator: Moira P. Keating; Nurse: Marva Trainer, RN; Univer-
sity of Miami, (Bascom Palmer Eye Institute), Miami, FL: Prin-
cipal Investigator: Harry W. Flynn, MD; Co-Principal
Investigator: George Blankenship, MD; Participating Internist:
Jeremiah Ben Zvi; Clinic Coordinator: Giselle Obregon; Assistant
 ETDRS RESEARCH GROUP
Clinic Coordinator: Roger Peacock; Photographer: Erlinda
Duria; Laboratory Assistant: Elvia Ramirez; Past Participating
Personnel: Clinic Coordinator: Rita Chiong; University of Min-
nesota, Minneapolis, MN: Principal Investigator: William H.
Knobloch, MD; Co-Principal Investigators: Robert C. Ramsay,
MD, Herbert L. Cantrill, MD; Participating Internist: Frederick
C. Goetz, MD; Clinic Coordinator: Sally Cook; Assistant Clinic
Coordinators: Donna Irlbeck, Peggy Musech, Heidi Dommer;
Photographer: Keith Anderson; Nurse: Kathy Knauth, RN; Vi-
sual Function Examiners: Anne Genia, George McDonough,
Jackie Mogan, Peggy Myers, Stephen Mma, David Philiph, Lisa
Ponwith; Past Participating Personnel: Participating Internist:
Byron Hoogwerf, MD; Photographers: Gary Vagstad, Lee Gill;
Visual Function Examiners: Vicki Henderson, Martha Mona-
han, Gail Anderson, Sara Buttke, Beth Knowles, Sidney Ryder,
Leslie Hargis, Bernice Giles; University of Puerto Rico, Rio
Piedras, PR: Principal Investigator: Jose Berrocal, MD; Project
Ophthalmologists: Raul Perez, MD, Guillermo Velazquez, MD;
Participating Internist: Myriam Allende, MD; Clinic Coordi-
nator: Maria S. Martinez; Assistant Clinic Coordinator: Vilma
Blasini; Photographer: Hector Mendez; Nurse: Haydee Delgado;
Past Participating Personnel: Co-Principal Investigator: A. Ra-
mos Umpierre, MD; Photographer: Teofilo Molina; University
of Washington, Seattle, W A: Principal Investigator: James L.
Kinyoun, MD; Co-Principal Investigator: Robert E. Kalina, MD;
Project Ophthalmologist: Craig G. Wells, MD; Participating In-
ternist: Jay Heinecke, MD; Clinic Coordinator: Betty S. Law-
rence; Assistant Clinic Coordinator: Patricia K. Ernst; Photog-
raphers: Brad C. Clifton, Ronald C. Jones; Laboratory Assistant:
Warren P. Brown; Past Participating Personnel: Principal In-
vestigator: Edward B. McLean, MD; Project Ophthalmologist:
Steven V. Guzak, MD; Participating Internist: Jerry Palmer,
MD; Clinic Coordinator: Jan Shaw, RN; Photographers: James
Foltz, Patricia Siedlak; University of Wisconsin, Madison, WI:
Principal Investigator: Frank L. Myers, MD; Co-Principal In-
vestigator: George H. Bresnick, MD; Project Ophthalmologists:
Suresh R. Chandra, MD, Matthew D. Davis, MD, Ronald Klein,
MD, Thomas S. Stevens, MD, lngolf H. Wallow, MD; Partici-
pating Internists: Russell Dixon, MD, Edward Ehrlich, MD;
Clinic Coordinator: Lyn Stewart; Assistant Clinic Coordinators:
Betty Lewis; Linda Lockwood; Photographers: Robert Harrison;
Gene Knutson, Michael Neider; Nurses: Isabelle Lobeck, RN,
Sandra Rodriquez, RN, Joanne Soderholm, RN; Visual Function
Examiners: Helen Lyngaas, Diane Quackenboss, RN, Guy So-
mers, RN; Past Participating Personnel: Participating Internist:
Robin Ewart, MD; Assistant Clinic Coordinator: Debra Hopke;
Photographers: Yvonne Magli, Dan Mattson; Nurses: Deborah
Cadwell, RN, Joan Haven, RN, Tanna Walsh, RN; Visual
Function Examiners: Sally Baumgartner, CO, Marshall Flax,
Karen H. Ritchie; Wayne State University (Kresge Eye Insti-
tute), Detroit, MI: Principal Investigator: Robert N. Frank, MD;
Participating Internists: Stephenie Lucas, MD, Fred Whitehouse,
MD; Clinic Coordinators: Robert Z. Johnson; Assistant Clinic
Coordinators: Maria Cristina Magsarili; Photographers: Marsha
Wright, Joseph Savoy; Past Participating Personnel: Project
Ophthalmologists: Harold Weiss, MD, Ann E. Ballen, MD, Mi-
chael Teske, MD; Participating Internist: Maria Warth, MD;
Clinic Coordinators: Lois Zapf, RN, Wanda M.V. Kent, RN,
Maureen Mancini; Photographer: Kenneth Christopherson;
Wills Eye Hospital, Philadelphia, PA: Principal Investigator:
William E. Benson, MD; Co-Principal Investigator: WilliamS.
Tasman, MD; Project Ophthalmologists: Gary C. Brown, MD;
J. Archibald McNamara, MD; Participating Internist: Alan Ad-
ler, MD; Clinic Coordinator: K. Stephani Hile; Assistant Clinic
Coordinator: Lynne Bradley; Photographer: Richard Lambert;
PATIENT CHARACTERISTICS
ECG Technician: Evelyn Loving; Past Participating Personnel:
Participating Internists: John Martin, MD, Guy McElwain, MD,
Theodore Duncan, MD; Clinic Coordinators: Karen Onishchuk
(deceased), Judy Krumholtz, Zoe Garner; Photographers: Jamie
Nicholl, Dennis Orlock; Zweng Memorial Retinal Research
Foundation, Menlo Park, CA: Principal Investigator: Hunter L.
Little, MD; Co-Principal Investigator: Robert L. Jack MD; Par-
ticipating Internist: Lawrence Basso, MD; Clinic Coordinator:
Joanne Showman; Photographer: Patti Mattio; Past Participating
Personnel: Clinic Coordinators: Janet Regan, Mary Casten;
Photographers: Judy Schwartz, Leslie, Morey; Laboratory
Technician: Nancy Barton, Ann Hetzel; Central Laboratory,
Centers for Disease Control, Atlanta, GA: Principal Investigator:
Dayton T. Miller, PhD; Co-Principal Investigators: Elaine Gun-
ter; Eric J. Sampson, PhD; Clinic Coordinator: Pat Yeager; Past
Participating Personnel: Principal Investigator: David D. Bayse,
PhD; Co-Principal Investigators: Vincent L. Maggio, James E.
Myrick, PhD, Clinic Coordinator: Dorothy Still; Coordinating
Center, Maryland Medical Research Institute, Baltimore, MD:
Principal Investigator: Genell L. Knatterud, PhD; Co-Principal
Investigator: Marian R. Fisher, PhD; Epidemiologist: Mary Jane
Prior, PhD; Statisticians: Franca Barton, MS, Joseph Kufera,
MA; Programming Personnel: Rosemary Giro, Cheryl Kelly,
Frances LoPresti, MS; Senior Coordinator: Jane Howard; Clinic
Coordinators: Barbara Lippy, W. Lee Monroe, Scott Needle;
Other Support Staff: Doris Battle, Joseph Bell, Kris Butler,
Brenda Carter, James Conigland, Mary Dorn, Veronica Hart-
man, Eiler Hedges, Jacqueline Nash, Wanda Riggie; Past Par-
ticipating Personnel: Co-Principal Investigator: Christian R.
Klimt, MD, DrPH; Statistician: Barbara Hawkins, MS; Pro-
gramming Personnel: George Bowden, Reginald Clem, Rennert
Kane, Susan Pollizzi, A.M.Y. Randall, Susana Rudshtein; Senior
Coordinator: Joyce Hoskins; Clinic Coordinators: Judy Dotson,
Devon Hanson, Elizabeth Heinz, Betty Schleigh; Other Support
Staff: Margie Carroll, Delores Dukes, Brendia Edmond, Richard
Gross, Ellen Kirby, Robert Meier, Diane Schwartz, Charles
Stokes; Drug Distribution Center (U.S. Public Health Service)
Perry Point, MD: Director: Thomas W. Miller, MS; Chief,
Quality Control: Captain Richard A. Moss, BS; Quality Control
Inspector: Thomas R. Shaffer; Chief, Pharmacy Service: Com-
mander James K. Hooper, MS; Label Production: Margaret E.
Pentz; Secretary: Terrie L. Stike; Past Participating Personnel:
Chief, Pharmacy Service: Captain James R. Grigdesby, BS; ECG
Coding Center, University of Minnesota, Minneapolis, MN: Di-
rector: Richard S. Crow, MD; Coding Supervisor: Margaret
Bodellan; Research Assistant: Richard R. Baker, MD; Past Par-
ticipating Personnel: Director: Ronald Prineas, MBBS, PhD;
Coding Supervisor: Denise Hesselroth; Fundus Photograph
Reading Center, University of Wisconsin, Madison, WI: Principal
Investigator/Director: Matthew D. Davis, MD; Associate Di-
rector: Larry D. Hubbard, MAT; Assistant Director: Yvonne L.
Magli; Coordinatm:: Suzanne Thomas; Senior Grader: Paul Segal,
MD; Graders: Sarah Ansay, Jane Armstrong, Darlene Badal,
Marilyn Bownds, Rosemary Brothers, Patricia Chinn-Sloan,
Lyric Dold, Barbara Esser, Patricia Geithman, Magnus Harding,
Dolores Hurlburt, James Reimers, Anita Temple; Statistician:
Susan Messing, MS; Systems Analyst: Anik Ganguly, MBA;
Programmer: Karl Jensen, MBA; Support Staff: Nina Sparr,
Mary-Ann Twist, Vicki Wipperfurth; Past Participating Person-
nel: Assistant Director: Alasstair MacCormick, PhD; Graders:
Gloria Boone, Kris Higginbotham, Cheryl Hiner, Elizabeth
Knisely, Stacy Meuer, Moary Peckham; Programmer: Dennis
Cudia, PhD; National Eye Institute, National Institutes of
Health, Bethesda, MD: Study Co-Chairman: Frederick L. Ferris,
III, MD; Study Project Officer: Richard L. Mowery, PhD; Co-
753
 OPHTHALMOLOGY MAY 1991 VOLUME 98 SUPPLEMENT

Investigators: Emily Y. Chew, MD, Daniel G. Seigel, SeD; Past
Participating Personnel: Co-Investigators: Sylvan Green, MD,
Carol Currier, MD, Gary Cassel, MD.
STUDY COMMIITEES
Operations Committee: Lloyd M. Aiello, MD (Chairman),
Frederick L. Ferris, MD, Marian R. Fisher, PhD, Genell L.
Knatterud, PhD, Richard L. Mowery, PhD, Lawrence I. Rand,
MD; Executive Committee: Permanent Members: Lloyd M.
Aiello, MD (Chairman), George H. Bresnick, MD, Matthew D.
Davis, MD, Robin B. L. Ewart, MD, Frederick L. Ferris, MD,
Aaron Kassoff, MD, Genell L. Knatterud, PhD, Dayton T.
Miller, PhD, Richard L. Mowery, PhD, FrankL. Myers, MD,
Thaddeus E. Prout, MD, Lawrence I. Rand, MD, Daniel G.
Seigel, SeD; Elected Principal Investigator Members: Harry W.
Flynn, MD (October 1987 to December 1989), Rudolph M.
Franklin, MD (October 1987 to December 1989), Charles A.
Garcia, MD (October 1984 to March 1987), James L. Kinyoun,
MD (August 1982 to October 1984), Michael L. Klein, MD
(August 1982 to October 1984), Raymond R. Margherio, MD
(April1980 to August 1982), Robert P. Murphy, MD (September
1983 to November 1985), Frederick H. Reeser, MD (June 1981
to June 1983), F. Tempel Riekhof, MD (October 1984 to March
1987), Robert Watzke, MD (June 1978 to June 1980); Elected
Clinic Coordinator Members: Carolyn Beardsley (March 1986
to March 1988); JoAnne Buehler (October 1984 to March 1987),
LaRae Challis (March 1987 to December 1989), Sally Cook
(October 1980 to September 1983), Josephine Falco (June 1979
to August 1982); Dolores Kilburn (September 1983 to March
1986), Maureen McGrath (March 1988 to December 1989),
Virginia Snyder Regan (August 1982 to October 1984), Lyn
Stewart (June 1979 to October 1980); Data Monitoring Com-
mittee: Voting Members: Peter Armitage, PhD (Chairman), John
A. Colwell, MD, Brian P, Conway, MD, Matthew D. Davis,
MD, Genell L. Knatterud, PhD, Robert Machemer, MD, Dayton
T. Miller, PhD, Thaddeus E. Prout, MD, Lawrence I. Rand,
MD, Colin White, PhD; Nonvoting Members: Lloyd M. Aiello,
MD, Frederick L. Ferris, MD, Richard L. Mowery, PhD, Daniel
G. Seigel, SeD; Editorial Committee: Robert N. Frank, MD
(Chairman), Lloyd M. Aiello, MD, John E. Connett, PhD, Fred
Ederer, MS, J. Terry Ernest, MD, Daniel Finkelstein, MD, Genell
L. Knatterud, PhD, Richard L. Mowery, PhD, Thaddeus E.
Prout, MD; Clinic Performance Monitoring Committee: Law-
rence I. Rand, MD (Chairman), George H. Bresnick, MD, LaRae
Challis, Jane Howard, Yvonne Magli, Mary Jane Prior, PhD,
Maureen McGrath, Dayton T. Miller, PhD, Richard L. Mowery,
PhD, Aaron Kassoff, MD (Consultant); Past Members: Carolyn
Beardsley, Andrew Bell, JoAnne Buehler, Suresh R. Chandra,
MD, Sally Cook, Josephine Falco, Marian R. Fisher, PhD, Bar-
bara Hawkins, Joyce Hoskins, Dolores Kilburn, Virginia Snyder
Regan, Lyn Stewart; Central Laboratory Performance Monitor-
ing Committee: Ralph Ellefson, PhD (Chairman), Fred Auletta,
MD, Victor Fang, PhD, Lawrence I. Rand, MD, Daniel G. Seigel,
PhD; Coordinating Center Performance Monitoring Committee:
Voting Members: Lawrence I. Rand, MD (Chairman), Patricia
Cleary, Jonn E. Connett, PhD, Robert Hardy, PhD, Jay Levi-
sohn, PhD, Richard L. Mowery, PhD, Joel Verter, PhD; Non
voting Members: Lloyd M. Aiello, MD, Matthew D. Davis, MD,
Frederick L. Ferris, MD; Fundus Photograph Reading Center
Performance Monitoring Committee: Voting Members: Lawrence
I. Rand, MD, Lloyd M. Aiello, MD, Patricia Cleary, John E.
Connett, PhD; Nonvoting Member: Genell L. Knatterud, PhD;
Analysis Planning Committee: Frederick L. Ferris, MD (Chair-
man), Lloyd M. Aiello, MD, George H. Bresnick, MD, Matthew
D. Davis, MD, Marian R. Fisher, PhD, Aaron Kassoff, MD,
Genell L. Knatterud, PhD, FrankL. Myers, MD, Dayton T.
Miller, PhD, Richard L. Mowery, PhD, Thaddeus E. Prout, MD,
Lawrence I. Rand, MD, Daniel G. Seigel, PhD; Eligibility and
End Point Committee: Matthew D. Davis, MD (Chairman),
Lloyd M. Aiello, MD, William Benson, MD, George H. Bresnick,
MD, Suresh R. Chandra, MD, Frederick L. Ferris, MD, Michael
L. Klein, MD, Genell L. Knatterud, PhD; Medical Review
Committee: Thaddeus E. Prout, MD (Chairman), Ramachan-
diran Cooppan, MD, Robin B. L. Ewart, MD, Robert N. Frank,
MD; Mortality and Morbidity Classification Sub-Committee of
the Medical Review Committee: Robin B. L. Ewart, MD (Chair-
man), Ramachandiran Cooppan, MD, Marian R. Fisher, PhD,
Lawrence Friedman, MD, Dinesh Kumar, MD; Photocoagu-
lation Treatment Committee: FrankL. Myers, MD (Chairman);
Lloyd M. Aiello, MD, Genell L. Knatterud, PhD, William
Knobloch, MD, Raymond R. Margherio, MD, F. Tempel Riek-
hof, MD; Visual Function Committee: George H. Bresnick, MD
(Chairman), Lloyd M. Aiello, MD, Carolyn Beardsley, JoAnne
Buehler, Frederick L. Ferris, MD, Robert N. Frank, MD, Robert
Harrison, Aaron Kassoff, MD, Genell L. Knatterud, PhD, Robert
Ramsay, MD; Visual Function Monitors: Robert Harrison, Car-
olyn Beardsley, JoAnne Buehler

APPENDIX 2. OVERVIEW OF SCHEDULE AND DESCRIPTION OF PATIENT VISITS

Time From Patient's Date of

Time Examination, Test, or Procedure Enrollment

Prior to enrollment
(qualifying visits)
Enrollment
(randomization visit)
Enrollment
(initial treatment[s])
After enrollment
(follow-up visits)
Ophthalmic examination, visual acuity, fundus photography,
fluorescein angiography, medical history, physical
examination, electrocardiogram, local and central
laboratory tests, visual field,* color vision*
Ophthalmic examination, visual acuity, eligibility review,
central laboratory
Photocoagulation, aspirin or placebo treatment, fundus
photography
Ophthalmic examination, visual acuity, medical review,
drug report
Maximum of 4 months prior to date of
enrollment.
Same as date of enrollment.
From date of enrollment to 5 weeks
later.
At 6 weeks, at 4 months, and every 4
months thereafter until final visit.

754
 ETDRS RESEARCH GROUP PATIENT CHARACTERISTICS

APPENDIX 2. (CONTINUE D)
Time From Patient's Date of
Time Examination, Test, or Procedure Enrollment

After enrollment Fundus photography At 4 months, 1 year, and annually

(follow-up visits) thereafter and at the first
occurrence of high-risk proliferative
retinopathy.
Fluoresc~in angiography At 1 year, 3 years, and 5 years and at
initiation of focal treatment during
follow-up.
Physical examination Initially annually and after August
1983, at the first, third, and fifth
annual visits.
Electrocardiogram At 5 years.
Central laboratory tests Initially urine salicylate specimens at
every visit. After September 1982,
urine salicylate specimens at 4
months and every annual visit.
Initially blood specimens at 4
months and every annual visit.
After August 1983, blood
specimens at first, third, and fifth
annual visits.
Visual fieldt Initially at 4 months and 4 years and,
after August 1983, at 4 years and
80 months.
Color visiont Initially at 8 months and 3 years and,
after September 1983, at 4 years
and 80 months.

* For the 2708 patients evaluated before September 1983, assessments for visual fields and color vision were also performed.
t For patients for whom qualifying visit visual field and color vision assessments were performed.

9. Sagel J, Colwell JA, Crook L, Laimins M. Increased platelet aggregation

REFERENCES
1. The Diabetic Retinopathy Study Research Group. Preliminary report
on effects of photocoagulation therapy. Am J Ophthalmol 1976; 81:
383-96.
2. The Diabetic Retinopathy Study Research Group. Four risk factors
for severe visual loss in diabetic retinopathy. The third report from the
Diabetic Retinopathy Study. Arch Ophthalmol1979; 97:654-5.
3. The Diabetic Retinopathy Study Research Group. Photocoagulation
treatment of proliferative diabetic retinopathy. Clinical application of
Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8.
Ophthalmology 1981; 88:583-600.
4. The Diabetic Retinopathy Study Research Group. Photocoagulation
treatment of proliferative diabetic retinopathy: the second report of
diabetic retinopathy study findings. Ophthalmology 1978; 85:82-106.
5. Patz A, Schatz H, Berkow JW, et al. Macular edema-an overlooked
complication of diabetic retinopathy. Trans Am Acad Ophthalmol Oto-
laryngol1973; 77:0P34-42.
6. Cheng H, Kohner EM, Keen H, et al. Photocoagulation in treatment
of diabetic maculopathy. Interim report of a multicentre controlled
study. Lancet 1975; 2:1110-3.
7. Blankenship GW. Diabetic macular edema and argon laser photo-
coagulation: a prospective randomized study. Ophthalmology 1979;
86:69-78.
8. Heath H, Brigden WD, Canever JV, et al. Platelet adhesiveness and
aggregation in relation to diabetic retinopathy. Diabetologia 1971 ; 7:
308-15.
in early diabetes mellitus. Ann Intern Med 1975; 83:733-8.
10. Colwell JA, Sagel J, Crook L, et al. Correlation of platelet aggregation,
plasma factor activity, and megathrombocytes in diabetic subjects
with and without vascular disease. Metabolism 1977; 26:279-85.
11. Kwaan HC, Colwell JA, Cruz S, et al. Increased platelet aggregation
in diabetes mellitus. J Lab Clin Med 1972; 80:236-46.
12. Halushka PV, Lurie D, Colwell JA. Increased synthesis of prostaglandin-
E-Iike material by platelets frorn patients with diabetes mellitus. N Engl
J Med 1977; 297:1306-10.
13. Ziboh VA, Maruta H, Lord J, et al. Increased biosynthesis of throm-
boxane A2 by diabetic platelets. Eur J Clin Invest 1979; 9:223-8.
14. Halushka PV, Rogers RC, Loadholt CB, Colwell JA. Increased platelet
thrornboxane synthesis in diabetes rnellitus. J Lab Clin Med 1981;
97:87-96.
15. Dobbie JG, Kwaan HC, Colwell JA, Suwanwela N. The role of platelets
in pathogenesis of diabetic retinopathy. Trans Am Acad Ophthalmol
Otolaryngol1973; 77:0P43-47.
16. Alrner LO, Pandolfi M, Nilsson IM. Diabetic retinopathy and the fibri-
nolytic system. Diabetes 1975; 24:529-34.
17. Regnault F. Role des plaquettes dans Ia pathogenie de Ia retinopathie
diabetique. Sern Hop 1972; 48:893-902.
18. Willis AL. An enzymatic mechanism for the antithrombotic and antihe-
mostatic actions of aspirin. Science 1974; 183:325-7.
19. Colwell JA, Chambers A, Lairnins M. Inhibition of labile aggregation-
stimulating substance (LASS) and platelet aggregation in diabetes
mellitus. Diabetes 1975; 24:684-7.
20. Mooney AJ. Diabetic retinopathy- a challenge. Br J Ophthalrnol1963;
47:513-20.

755
 OPHTHALMOLOGY MAY 1991
21. Powell EDU, Field RA. Diabetic retinopathy and rheumatoid arthritis.
Lancet 1964; 2:17-8.
22. Carroll WW, Geeraets WJ. Diabetic retinopathy and salicylates. Ann
Ophthalmol1972; 4:1019-46.
23. Early Treatment Diabetic Retinopathy Study Research Group (ETDRS).
Manual of Operations. Baltimore: ETDRS Coordinating Center, Uni-
versity of Maryland. Available from: National Technical Information
Service, 5285 Port Royal Road, Springfield, VA 22161; Accession No.
PB85 223006/AS.
24. Early Treatment Diabetic Retinopathy Study Research Group. Pho-
tocoagulation for diabetic macular edema. Early Treatment Diabetic
Retinopathy Study Report Number 1. Arch Ophthalmol 1985; 103:
1796-806.
25. Early Treatment Diabetic Retinopathy Study Research Group. Treat-
ment techniques and clinical guidelines for photocoagulation of dia-
betic macular edema. Early Treatment Diabetic Retinopathy Study
Report Number 2. Ophthalmology 1987; 94:761-74.
26. The Early Treatment Diabetic Retinopathy Study Research Group:
Techniques for scatter and local photocoagulation treatment of diabetic
retinopathy: Early Treatment Diabetic Retinopathy Study Report No.
3. lnt Ophthalmol Clin 1987; 27:254-64.
27. The Early Treatment Diabetic Retinopathy Study Research Group.
Photocoagulation for diabetic macular edema: Early Treatment Diabetic
Retinopathy Study Report No. 4. lnt Ophthalmol Clin 1987; 27:265-
72.
28. The Coronary Drug Project Research Group. Aspirin in coronary heart
disease. J Chronic Dis 1976; 29:625-42.
29. Aspirin Myocardial Infarction Study Research Group. A randomized
controlled trial of aspirin in persons recovered from myocardial in-
farction. JAMA 1980; 243:661-9.
756
VOLUME 98 SUPPLEMENT
30. The Persantine-Aspirin Reinfarction Study Research Group. Persantine
and aspirin in coronary heart disease. Circulation 1980; 62:449-61.
31. Moncada S, Vane JR. Arachidonic acid metabolites and the interactions
between platelets and blood-vessel walls. N Engl J Med 1979; 300:
1142-7.
32. Ferris FL Ill, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts
for clinical research. Am J Ophthalmol 1982; 94:91-6.
33. Early Treatment Diabetic Retinopathy Study Research Group. Grading
diabetic retinopathy from stereoscopic color fundus photographs-
an extension of the modified Airlie House classification: ETDRS report
number 10. Ophthalmology 1991; 98:786-806.
34. Early Treatment Diabetic Retinopathy Study Research Group. Clas-
sification of diabetic retinopathy from fluorescein angiograms: ETDRS
report number 11. Ophthalmology 1991; 98:807-22.
35. Early Treatment Diabetic Retinopathy Study Research Group. Fundus
photographic risk factors for progression of diabetic retinopathy:
ETDRS report number 12. Ophthalmology 1991; 98:823-33.
36. Early Treatment Diabetic Retinopathy Study Research Group. Fluo-
rescein angiographic risk factors for progression of diabetic retinop-
athy: ETDRS report number 13. Ophthalmology 1991; 98:834-40.
37. Johnson NL, Leone FC. Statistics and Experimental Design in Engi-
neering and the Physical Sciences. New York: Wiley, 1964; 179-254.
38. Cutler SJ, Ederer F. Maximum utilization of the life table in analyzing
survival. J Chronic Dis 1958; 8:699-712.
39. Cox DR. Regression models and life-tables. J Roy Stat Soc [Ser B]
1972; 34:187-220.
40. Aiello LM, Ferris FL Ill. Photocoagulation for diabetic macular edema.
[Letter]. Arch Ophthalmol1987; 105:1163.