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The Long-term Effects of Laser Photocoagulation Treatment in Patients with Diabetic Retinopathy The Early Treatment Diabetic Retinopathy Follow-up Study Emily Y. Chew, MD,1 Frederick L. Ferris III, MD,1 Karl G. Csaky, MD, PhD,2 Robert P. Murphy, MD,1 Elvira Agrón, MSc,1 Darby J. S. Thompson, MSc,3 George F. Reed, PhD,1 Andrew P. Schachat, MD4 Objectives: To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. Design: Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. Methods: Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). Main Outcome Measures: The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. Results: Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. Conclusions: As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high. Ophthalmology 2003;110:1683–1689 © 2003 by the American Academy of Ophthalmology. Diabetic retinopathy is a leading cause of vision impairment in the adult population in the United States.1 The treatment Originally received: August 21, 2002. Accepted: February 19, 2003. Manuscript no. 220573. 1 National Eye Institute/National Institutes of Health, Division of Epidemiology and Clinical Research, Bethesda, Maryland. 2 National Eye Institute/National Institutes of Health, Laboratory of Immunology, Bethesda, Maryland. 3 EMMES Corporation, Rockville, Maryland. © 2003 by the American Academy of Ophthalmology Published by Elsevier Inc. strategies for diabetic retinopathy developed over the last several decades are, in part, based on National Institutes of Health–supported clinical trials evaluating diabetes control, 4 Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland. Reprint requests to Emily Y. Chew, MD, Division of Biometry and Epidemiology, National Eye Institute/National Institutes of Health, Building 31, Room 6A52, 31 Center Drive, MSC-2510, Bethesda, MD 208922510. ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00579-7 1683 Ophthalmology Volume 110, Number 9, September 2003 laser photocoagulation, and vitrectomy.1–5 The efficacy of laser photocoagulation for proliferative diabetic retinopathy was demonstrated in the Diabetic Retinopathy Study (DRS).3 Treatment with photocoagulation, either laser or xenon arc, reduced the rate of severe vision loss (visual acuity of worse than 5/200 for at least 4 months’ duration) by 50%. This treatment became the standard of care for patients with proliferative diabetic retinopathy. In the subsequent clinical trial of diabetic retinopathy, the Early Treatment Diabetic Retinopathy Study (ETDRS), 3711 patients were randomly assigned to early laser photocoagulation and aspirin treatment and followed for 5 to 9 years. Patients had retinopathy that ranged from mild nonproliferative retinopathy to early proliferative retinopathy. The data from the ETDRS suggested that scatter laser photocoagulation should be considered for all eyes with severe nonproliferative diabetic retinopathy or worse and not for those with mild to moderate nonproliferative retinopathy.5 For patients with type 2 diabetes, early treatment at the severe nonproliferative stage rather than waiting for the onset of high-risk proliferative retinopathy is considered, because the rate of severe loss was reduced by more than 50% in such eyes treated with early laser photocoagulation compared with eyes assigned to deferral of laser photocoagulation.6 This beneficial effect of early treatment at the severe nonproliferative stage was not seen in patients with type 1 diabetes. Many factors need to be considered in deciding when to initiate photocoagulation for these patients, but it is apparent from both the DRS and ETDRS that virtually all patients with high-risk proliferative retinopathy should have scatter photocoagulation without delay. Focal laser photocoagulation treatment for diabetic macular edema was also evaluated in the ETDRS. The treatment of eyes with clinically significant macular edema (defined as retinal edema that affects or threatens the center of the macula) with focal laser photocoagulation reduced the risk of moderate vision loss (loss of 3 or more lines on a logarithm of the minimum angle of resolution visual acuity chart) by 50%.4 Focal treatment with laser photocoagulation has become the standard treatment for diabetic macular edema. The results of the Diabetic Retinopathy Vitrectomy Study, a randomized clinical trial of vitrectomy for eyes with dense vitreous hemorrhage and for eyes with very severe proliferative diabetic retinopathy, showed a greater chance of recovering good vision with vitrectomy.7 With the improvement in vitrectomy techniques and instrumentation, the visual results have markedly improved since these early trials. Vitrectomy has become an important part of the treatment strategy for patients with diabetic retinopathy that is not resolved by photocoagulation. A review of the effects of using all these therapeutic strategies has demonstrated that their timely implementation can reduce the risk of severe vision loss by as much as 90%.8 Only 4% of eyes and 1% of patients with proliferative diabetic retinopathy in the ETDRS had severe vision loss at 5 years. This is remarkably lower than the 50% 5-year blindness rate seen in patients before the availability of photocoagulation and also estimated from untreated eyes of the patients enrolled in the DRS and other early studies of 1684 diabetic retinopathy.3,9 –11 Although these treatment strategies have become the standard therapy, their long-term effects have not been assessed beyond 10 years. Patients enrolled in the original ETDRS at the Johns Hopkins Clinical Center were re-examined to determine the long-term rates of severe and moderate vision loss and further ocular complications requiring further surgery. This information on the long-term effects of treatment is important in providing care for all patients affected with diabetes, particularly with the increasing incidence of type 2 diabetes in the United States. The improvement in medical care of patients with diabetes has resulted in increased survival. This growing population of patients with diabetes has increased the public health importance of the treatment of diabetes and its complications. Materials and Methods The ETDRS was designed to assess photocoagulation and aspirin treatment for patients with mild nonproliferative to early proliferative diabetic retinopathy.12 Study patients were randomly assigned to 650 mg of aspirin or placebo daily. One eye of each patient was randomly assigned to early laser scatter and/or focal photocoagulation, whereas the fellow eye was given scatter laser photocoagulation only when high-risk proliferative diabetic retinopathy developed. At baseline, these patients were aged 18 to 69 years with a favorable prognosis for 5-year survival. All patients who were enrolled and followed in the original ETDRS at the Johns Hopkins Medical Institution and who were living at the closeout visit of August 1989 were identified (n ⫽ 214). Those still living were invited for an eye examination at the National Eye Institute, National Institutes of Health. The institutional review boards for research on human subjects at both the John Hopkins University and the National Eye Institute/National Institutes of Health approved the follow-up study. A total of 3711 patients had been enrolled in 22 ETDRS clinical centers and followed from 5 to 9 years. This follow-up study was conducted from 1997 to 2000 on the patients enrolled at the Johns Hopkins Clinical Center, providing 13 to 19.5 years of follow-up (median, 16.7 years) after the study randomization visit and the initiation of laser photocoagulation. The surviving patients were all invited for an examination at the clinical center at the National Eye Institute/National Institutes of Health. After obtaining signed informed consents, historical information was obtained. Patients received a comprehensive eye examination, which included best-corrected visual acuity, slitlamp biomicroscopy, and dilated ophthalmoscopy. Lens opacities were assessed clinically by slit-lamp biomicroscopy, using the Age-Related Eye Disease Study classification system.13 Stereoscopic fundus photography of seven fields and fluorescein angiography were performed. The Fundus Photograph Reading Center at the University of Wisconsin, in Madison, centrally graded and compared the fundus photographs and fluorescein angiograms obtained at this follow-up visit with those obtained at baseline and during the course of the study. Six patients were willing to be examined but were unable to travel to the National Eye Institute for examination. These patients were examined by collaborating ophthalmologists, most of whom were coinvestigators in the original ETDRS study. They examined these patients in their institutions and private offices using the standardized protocol for examination and fundus photography and completing the data collection forms used at the National Eye Institute. Chew et al 䡠 Effects of Laser Photocoagulation in Diabetic Retinopathy Table 1. Baseline Characteristics Johns Hopkins N (%) Total Age ⬍20 20–29 30–39 40–49 50–59 60–69 Gender Male Female Race White Black Hispanic Pacific Islander American Indian Diabetes type Type 1 Mixed Type 2 Duration of diabetes ⬍10 10–19 ⱖ20 Insulin use No Occasionally Daily Smoking Never Stopped ⱖ2 yrs Stopped ⬍2 yrs Currently smokes Systolic blood pressure (mmHg) ⱕ120 121–149 150⫹ Diastolic blood pressure (mmHg) ⱕ76 77–89 90⫹ Antihypertensive medications Yes No History of coronary artery disease Yes No Suspect History of myocardial infarction Yes No Suspect History of congestive heart failure Yes No Suspect History of stroke Yes No Suspect 214 (100) Table 1. (continued) All Other Early Treatment of Diabetic Retinopathy Study Clinics P N (%) Value 3497 (100) 3 (1.4) 49 (1.4) 38 (17.7) 536 (15.3) 26 (12.1) 536 (15.3) 35 (16.3) 571 (16.3) 64 (29.9) 1005 (28.7) 48 (22.4) 800 (22.8) 0.817 120 (56.0) 1976 (56.5) 94 (43.9) 1521 (43.4) 0.902 174 (81.3) 2660 (76.0) 40 463 (13.2) 0 337 (9.6) 0 24 (6) 0 13 (3) ⬍0.0001 55 (25.7) 1075 (30.7) 81 (37.8) 1348 (38.5) 78 (36.4) 1074 (30.7) 0.146 33 (15.4) 577 (16.4) 138 (64.4) 1981 (56.6) 43 (20.0) 939 (26.8) 0.055 47 (21.9) 546 (15.6) 1 (4) 4 (1) 166 (77.5) 2947 (84.2) 0.013 104 (48.5) 1536 (43.9) 35 (16.3) 834 (23.8) 17 (7.9) 152 (4.3) 58 (27.1) 974 (27.8) 0.009 54 (25.2) 887 (25.4) 104 (48.6) 1497 (42.8) 56 (26.2) 1112 (31.8) 0.165 46 (21.5) 876 (26.1) 90 (42.1) 1637 (46.8) 78 (36.5) 983 (28.1) 0.032 41 (19.1) 618 (17.6) 173 (80.8) 2878 (82.3) 0.582 18 (8.4) 173 (4.9) 192 (89.7) 3232 (92.4) 4 (1.8) 91 (2.6) 0.071 16 (7.4) 146 (4.1) 195 (91.1) 3305 (94.5) 3 (1.4) 45 (1.2) 0.071 11 (5.1) 63 (1.8) 200 (93.4) 3405 (97.3) 3 (1.4) 28 (8) 0.004 4 (1.8) 42 (1.2) 208 (97.1) 3473 (98.3) 2 (9) 17 (4) 0.294 All Other Early Treatment of Diabetic Retinopathy Johns Study Hopkins Clinics P N (%) N (%) Value History of transient ischemic attack Yes No Suspect Proteinuria Negative, trace 1⫹, 2⫹, 3⫹, 4⫹ Cholesterol ⬍200 200–240 ⬎240 Mean Median Range Serum creatinine (mg/dl) ⬍1.0 1.0–1.3 ⬎1.3 Mean Median Range Hemoglobin A1c (%) ⬍10 10⫹ Mean Median Range Ocular characteristics Total Visual acuity at baseline 20/20 or better ⬍20/20 to ⱖ20/40 ⬍20/40 to ⱖ20/200 ⬍20/200 Severity of retinopathy at baseline Mild to moderate NPDR Severe NPDR PDR Severity of retinopathy at last visit Mild to moderate NPDR Severe NPDR PDR Macular edema at baseline Yes No Intraocular pressure at baseline (mmHg) ⬍14 14–20 ⬎20 Photocoagulation given during the original study Scatter Yes No Focal Yes No 2 (9) 11 (3) 209 (97.6) 3446 (98.5) 3 (1.4) 39 (1.1) 0.210 157 (73.3) 2498 (71.5) 57 (26.6) 992 (28.4) 0.573 47 (25.9) 860 (34.0) 54 (29.8) 783 (30.9) 80 (44.1) 885 (35.0) 239⫾4 228⫾1 235 220 138–426 106–852 0.025 0.014 80 (38.0) 1236 (37.2) 109 (51.9) 1724 (52.0) 21 (10.0) 354 (10.6) 1.05⫾0.02 1.07⫾0.01 1.00 1.00 0.5–2.1 0.1–5.6 0.942 102 (56.3) 1449 (58.1) 79 (43.6) 1043 (41.8) 9.85⫾0.15 9.67⫾0.04 9.73 9.62 3.30 3.03 0.637 0.232 0.290 214 (100) 3497 (100) 122 (57.0) 1936 (55.3) 73 (34.1) 1238 (35.4) 19 (8.8) 311 (8.8) 0 (0) 11 (3) 0.834 83 (38.7) 1432 (40.9) 92 (42.9) 1438 (41.1) 39 (18.2) 627 (17.9) 0.814 80 (38.4) 1218 (36.3) 27 (12.9) 475 (14.1) 101 (48.5) 1660 (49.5) 0.788 144 (67.2) 2388 (68.2) 70 (32.7) 1109 (31.7) 0.761 35 (16.4) 695 (19.9) ⬍0.0001 149 (69.6) 2588 (74.2) 30 (14.0) 207 (5.9) 101 (47.1) 1366 (39.0) 113 (52.8) 2131 (60.9) 0.018 110 (51.4) 1518 (43.4) 104 (48.5) 1979 (56.5) 0.022 NPDR ⫽ nonproliferative diabetic retinopathy; PDR ⫽ proliferative diabetic retinopathy. 1685 Ophthalmology Volume 110, Number 9, September 2003 Table 2. Factors Associated with Increased Mortality Variable Hazard Ratio 95% Hazard Confidence Ratio Limits P Value Age (yrs) Hemoglobin A1c (%) Proteinuria (mg/dl) 1.067 1.153 2.268 1.050 1.044 1.515 1.085 1.274 3.394 ⬍0.0001 0.0049 ⬍0.0001 The names and demographic data of all patients who did not respond to the invitation for a follow-up examination were submitted to the National Death Index. Matches from the National Death Index provided confirmation of the deceased patients. The causes of death were obtained from the death certificates. Statistical Methods Comparisons of categorical baseline characteristics between the Johns Hopkins Clinic patients and the ETDRS patients enrolled in the remaining clinical centers were conducted by chi-square test analysis or by permutation testing of the chi-square test statistic if the cell sizes were too small to warrant application of the large sample method. Continuous baseline variables were compared by the t test. Cox proportional hazards regression was applied to assess and adjust for the effects of the following risk factors on mortality in the follow-up group: glycosylated hemoglobin (HBA1c), age, duration of diabetes, proteinuria, blood pressure, visual acuity score, and diabetic retinopathy severity. Because these are secondary analyses, the P value considered to be statistically significant is P⬍0.01. of the ETDRS population, one sees that the patients were similar in age and gender. There were more blacks but fewer Hispanic patients in the Johns Hopkins clinic population than in the general ETDRS population. Patients enrolled in the general ETDRS population were more likely to be cigarette smokers than in the Johns Hopkins clinic population. There were more patients in the Johns Hopkins clinic that had history of congestive heart disease compared with the ETDRS population. Other medical and baseline characteristics were similar in both the Johns Hopkins clinic population and the remaining ETDRS population. The levels of severity of retinopathy at baseline were also similar in the two populations, whereas patients from the Johns Hopkins Clinical Center had somewhat higher intraocular pressures at baseline. Visual Acuity At the ETDRS baseline examination, the visual acuities of the better eye of the 71 patients who participated in this long-term follow-up study were 20/20 or better in 57%, 20/40 or better in 91%, and less than 20/40 to 20/100 in 9%. At the ETDRS Follow-up Study examination, best-corrected visual acuities in the patients’ better eye were as follows: 20/20 or better in 42%, 20/40 or better in 84%, between 20/40 and 20/100 in 15%, and 20/200 in 1 patient (1%). The decreased visual acuity in this patient was secondary to geographic atrophy associated with age-related macular degeneration. There were no cases of severe vision loss (visual acuity of worse than 5/200). The rate of moderate vision loss (loss of 15 letters or more at follow-up compared with baseline visual acuity) was 20%. Ocular Surgeries Results Mortality Of the 214 patients who were alive at the end of the original ETDRS study in 1989, 130 (61%) were deceased by the time of the follow-up examination. The causes of death were determined by assessment of the death certificates obtained from the National Death Index report. These consist of cardiovascular disease in 48%, nonspecific diabetic complications in 28%, renal disease in 4%, neurologic causes in 7%, malignancies in 4%, and other causes in 5%. The adjusted analyses (Cox proportional hazards model) of baseline risk factors associated with death for this clinic population included increasing age, proteinuria, and elevated HBA1c (Table 1). In univariate analyses, with or without age adjustment, both poor visual acuity and more severe retinopathy were significantly associated with increased mortality. However, in the final Cox model, these two factors were no longer statistically significant, but the sample size of this study is fairly small. Of the 84 who were still living, 1 patient was hospitalized for Alzheimer’s disease, 1 was confined to a nursing home, 1 had incomplete data from the patient’s ophthalmologist, and 10 could not be contacted. Excluding these 13 patients, 71 (85%) were examined. The duration of follow-up from the beginning of the enrollment in the original ETDRS until the follow-examination was 13 to 15 years for 16 patients (23%), 16 to 17 years for 25 patients (35%), and more than 17 years for 30 patients (42%), with median follow-up of 16.7 years. Table 2 shows a comparison of the baseline characteristics of the patients enrolled in the Johns Hopkins Clinic with the study population enrolled in the remaining ETDRS clinics nationwide. Comparing the patients enrolled at Johns Hopkins with the rest 1686 Photocoagulation and Vitrectomy. As stipulated by the study protocol, all patients enrolled in the ETDRS received laser photocoagulation in one eye immediately after being randomly assigned to their groups. At the closeout ETDRS visit of the 71 patients in 1989, 47% and 40% of the eyes assigned to deferral of laser photocoagulation had received focal and scatter photocoagulation, respectively. By the time of the long-term follow-up examination, all of the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse had eventually required and received scatter photocoagulation treatment. Ten of the 14 patients who had mild to moderate nonproliferative retinopathy at the closeout visit of the original study had not progressed beyond moderate nonproliferative retinopathy at the long-term follow-up visit and had not received scatter photocoagulation. The other 4 patients in this group had received scatter photocoagulation at some time between the end of the ETDRS and the time of the long-term follow-up visit. Other interventions noted at the time of the long-term follow-up visit were as follows: focal photocoagulation had been performed in 43% of patients bilaterally and 22% unilaterally, and vitrectomies had been performed in 12 (17%) patients and glaucoma surgery in 1 patient. Lens Opacities Of the patients examined at the follow-up study, cataract surgery had occurred in 22 (31%) patients; 12 were bilateral and 10 were unilateral. Of the phakic patients, 25% had posterior subcapsular cataract greater than 1 mm in diameter, 35% had cortical opacities occupying at least 12% of the lens area, and 30% had nuclear lens opacities greater than Age-Related Eye Disease Study standard photograph number 4.13 Seventy-four percent had one or more of these lenticular opacities. Chew et al 䡠 Effects of Laser Photocoagulation in Diabetic Retinopathy Figure 1. The 5-year rates of severe vision loss of Early Treatment of Diabetic Retinopathy Study patients with proliferative diabetic retinopathy were 1% in patients and 4% in eyes. This is remarkably lower than the 50% 5-year rate seen in the untreated eyes of patients enrolled in the Diabetic Retinopathy Study. Figure 2. The mortality of the Early Treatment of Diabetic Retinopathy Study patients is compared with that of a general population, adjusted for age. Discussion Visual Acuity Results More than half of the patients originally enrolled in the ETDRS clinic at Johns Hopkins were deceased at the time of the long-term follow-up examination, and those patients with the worst visual acuity at the ETDRS closeout visit were the least likely to survive. Most of the patients who survived maintained fairly good visual acuity at the time of the long-term follow-up examination; 42% of patients in this study retained visual acuity of 20/20 or better, and 84% retained visual acuity of 20/40 or better in at least one eye. These data suggest that those patients who receive photocoagulation and who survive long-term are more likely to have maintained good visual acuity during the early phases of treatment. They are also likely to maintain fairly good visual acuity with long-term follow-up. Although they continue to have diabetes, for most, the retinopathy seems to eventually become quiescent. This is due, at least in part, to the beneficial effects of laser photocoagulation and vitrectomy seen at 5 years.8 The short-term evaluation of these therapeutic strategies has demonstrated highly beneficial effects in reducing the risk of severe vision loss by more than 90% in 5 years. Only 4% of eyes and 1% of patients with proliferative diabetic retinopathy in the ETDRS had severe vision loss at 5 years. This is remarkably lower than the greater than 50% 5-year blindness rate seen in patients before the availability of photocoagulation and also estimated from untreated eyes of the patients enrolled in the DRS (Fig 1).3 The 10-year visual acuity results of the 51 patients originally enrolled in DRS at the Bascom Palmer Eye Institute were reported in 1991. Of these patients, 24 had visual acuity of 20/40 or better (47%), and 7 were worse than 20/200 (14%).14 The comparison of the visual acuity results in this ETDRS Follow-up Study with these visual acuities and the acuities of the untreated eyes before the availability of photocoagulation reflect an improvement in the treatment of the diabetes, as well as the development and refinement of techniques such as laser photocoagulation and vitrectomy. It is also important to note that most of the ETDRS patients required further scatter laser photocoagulation during follow-up after the closeout visit, underscoring the need for vigilant follow-up during the lifetime of patients with diabetic retinopathy. Mortality Results Patients with the worst visual acuity at the end of the original ETDRS had particularly high mortality rates. Although the visual acuity results reported here might reflect the beneficial effect of laser and other medical treatments, there is also a selection bias such that those patients with better visual acuity were more likely to survive and to be available for the long-term follow-up examination. At the time of the ETDRS closeout visit in 1989, 8.4% of the Hopkins patients were legally blind, and 4.7% had severe visual loss in at least one eye. No patient with legal blindness at closeout survived to be examined in the follow-up study. More than 75% of patients who survived during the follow-up for the examination at the National Eye Institute had closeout visual acuity of 20/20. The high rate of mortality of the ETDRS Follow-up Study is reflected in the comparison with that of a general population, adjusted for age (Fig 2). The deaths occurred over the course of the follow-up, as shown in the survival curve (Fig 3). In the evaluation of the mortality among adults with or without diabetes in the National Health and Nutrition Examination Survey, the 22-year mortality for those with diabetes was 33.7% for persons aged 25 to 54 years of age at baseline and 82.9% for those aged 55 to 75 years compared with 10.2% and 64.4% for those people without diabetes, respectively.15 The rates of mortality were markedly higher for persons with diabetes compared with the rates of those without diabetes. The risk of death was doubled in the National Health and Nutrition Examination Survey for those patients who had definite proteinuria at 1687 Ophthalmology Volume 110, Number 9, September 2003 Figure 3. The deaths that occurred over the course of the study follow-up are shown in this survival curve. The death rates are adjusted for baseline visual acuity. baseline compared with those without proteinuria at baseline. The risk factors associated with mortality in the ETDRS follow-up population included baseline characteristics of age, proteinuria, and elevated HBA1c. The hazard ratio for an increase of age from 45 to 75 years was 7.0. The hazard ratio for an increase of HBA1c from 7% to 12% was 2.0 and from 9% to 12% was 1.5. The possible association of baseline risk factors of visual acuity and severity of retinopathy with mortality was investigated using the entire ETDRS data set for the duration of the original study (data not shown). Both decreased baseline visual acuity and increased severity of the baseline level of retinopathy were found to be associated with increased mortality in the univariate analyses. However, when these factors were entered into a multivariate analysis, they were no longer statistically significant. Other factors such as proteinuria, presence of cardiovascular disease at baseline, and elevated serum cholesterol levels were found to be associated with increased mortality in the multivariate analyses. In these analyses, it is important to note that the ocular risk factors might not be considered traditional risk factors of mortality but might be so-called risk markers, concomitant diabetic complications that might be markers of systemic disease. For example, decreased baseline visual acuity and increased severity of retinopathy might be indicative of generalized vascular disease that might lead to increased mortality. They might explain in part the relatively good visual acuity in the survivors examined in the follow-up study. In the analyses of a population-based study, the Wisconsin Epidemiologic Study of Diabetic Retinopathy showed that at 6 years of follow-up, the ocular risk factors associated with increasing mortality were poorer visual acuity and more severe retinopathy in both types 1 and 2 diabetes.16 Again, it is possible that poorer visual acuity and more severe retinopathy at baseline might be markers for poor systemic vascular status of the patient. Other ocular risk factors associated with decreased survival in the Wisconsin Epidemiologic Study of Diabetic Retinopathy included 1688 glaucoma in the younger population and cataract in the older population. A limitation to the current ETDRS Follow-up Study is the relatively small number of patients who were examined. However, the comparison of the baseline characteristics of the Johns Hopkins clinic with the entire ETDRS population showed that this particular clinic is representative of the entire cohort. A larger study might improve the precision of the results, but given the dramatic findings, it seems reasonable to assume that the direction and the size of the estimates would not change in a clinically important way. In addition, these findings seem to be in concert with the clinical impression of the retinal specialists regarding the prognosis of quiescent diabetic retinopathy. In summary, the long-term visual acuity results, after treatment strategies that include laser photocoagulation and vitrectomy in those survivors in the ETDRS Follow-up Study, are remarkable, with 82% of patients retaining driving vision in at least one eye. These results emphasize the need for vigilant follow-up throughout the lifetime of patients with diabetic retinopathy, because further scatter treatment was required in most patients followed. Although laser photocoagulation is a highly effective treatment for diabetic retinopathy, diabetic retinopathy remains a major cause of visual impairment in adults in the United States. Further improvement of screening methods and treatment delivery for patients with diabetes is needed. Both patients and physicians need to be aware of the beneficial effects of tight glycemic, serum lipid, and blood pressure control on diabetic retinopathy, as well as the long-term benefits of photocoagulation and vitrectomy that are currently available for those patients who have clinically important retinopathy. References 1. Klein R, Klein BEK, Moss SE. Visual impairment in diabetes. Ophthalmology 1984;91:1–9. 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329: 977– 86. 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. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796 – 806. 5. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 1991;98(5 suppl):767– 85. 6. Ferris F III. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc 1996;94:505– 37. 7. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study Report 2. Arch Ophthalmol 1985;103:1644 –52. Chew et al 䡠 Effects of Laser Photocoagulation in Diabetic Retinopathy 8. Ferris FL III. How effective are treatments for diabetic retinopathy? JAMA 1993;269:1290 –1. 9. Beetham WP. Visual prognosis of proliferating diabetic retinopathy. Br J Ophthalmol 1963;47:611–9. 10. Caird FI, Burditt AF, Draper GJ. Diabetic retinopathy: a further study of prognosis for vision. Diabetes 1968;17:121–3. 11. Deckert T, Simonsen SE, Poulsen JE. Prognosis of proliferative retinopathy in juvenile diabetes. Diabetes 1967;10:728 –33. 12. Early Treatment Diabetic Retinopathy Study Research Group. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 1991;98(5 suppl):741–56. 13. The Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS) system for classifying cataracts from photographs: AREDS Report No. 4. Am J Ophthalmol 2001;131:167–75. 14. Blakenship GW. Fifteen-year argon laser and xenon photocoagulation results of Bascom Palmer Eye Institute’s patients participating in the Diabetic Retinopathy Study. Ophthalmology 1991;98:125– 8. 15. Gu K, Cowie CC, Harris MI. Mortality in adults with or without diabetes in a national cohort of the U.S. population, 1971–1993. Diabetes Care 1998;21:1138 – 45. 16. Klein R, Moss SE, Klein BE, DeMets DL. Relation of ocular and systemic factors to survival in diabetes. Arch Intern Med 1989;149:266 –72. 1689