Early Treatment Diabetic Retinopathy Study (ETDRS)

• To evaluate the effectiveness of both argon laser photocoagulation and aspirin therapy in delaying or preventing progression of early diabetic retinopathy to more severe stages of visual loss and blindness.
• To help determine the best time to initiate photocoagulation treatment in diabetic retinopathy.
• To monitor closely the effects of diabetes mellitus and of photocoagulation on visual function.
• To produce natural history data that can be used to identify risk factors and test etiologic hypotheses in diabetic retinopathy.

ETDRS was a multicenter, randomized clinical trial designed to evaluate argon laser photocoagulation and aspirin treatment in the management of patients with nonproliferative or early proliferative diabetic retinopathy. A total of 3,711 patients were recruited to be followed for a minimum of 4 years to provide long-term information on the risks and benefits of the treatments under study.

The eligibility criteria for the ETDRS were designed to include a broad range of macular edema severity, from a few small hard exudates within a disc diameter of the fovea with normal visual acuity to extensive cystoid spaces with a visual acuity of 20/200. All study patients had one eye randomly assigned to immediate photocoagulation and the other eye to deferral of photocoagulation until high-risk proliferative retinopathy developed. During followup, additional photocoagulation was allowed for any degree of macular edema within the eligibility range, but additional photocoagulation was required only for edema involving or threatening the center of the macula. The term "clinically significant macular edema" was coined to designate this level of severity.

The trial use of aspirin therapy was based on clinical observation and on aspirin's possible mechanisms of action. Previous observations of diabetic patients who were taking large doses of aspirin for rheumatoid arthritis showed that the prevalence of retinopathy in this group was lower than the prevalence that would be expected in the diabetic population at large. Evidence suggested that diabetic patients have altered platelet aggregation and disaggregation, which may contribute to the capillary closure seen in retinopathy. This abnormality is reversed by aspirin in vitro. However, because of aspirin's other possible mechanisms of action and its well-known side effects, such as allergic, idiosyncratic, and intolerance reactions, the use of this therapy in the ETDRS was carefully controlled and monitored.

Men and women between the ages of 18 and 70 years with moderate or severe nonproliferative diabetic retinopathy or mild proliferative retinopathy in both eyes, with no previous photocoagulation treatment, and with visual acuity of 20/40 or better (20/200 or better if macular edema is present) were eligible for this study.

No longer recruiting. Comments: Recruitment began in December 1979 and was completed in July 1985. The 3,711 patients accepted for the study were followed through 1989.

Completed, with results published. Comments: Completed.

The results of the ETDRS can be briefly summarized. Aspirin use did not affect the progression of retinopathy to the high-risk proliferative stage in eyes assigned to deferral of photocoagulation. However, aspirin did not increase the risk of vitreous hemorrhage, did not affect vision, and was associated with a decreased risk of cardiovascular disease. The study therefore concluded that for patients with mild to severe nonproliferative or early proliferative diabetic retinopathy, it is likely that aspirin has no clinically important beneficial effect on the progression of retinopathy. However, the study also showed no clinically important harmful effects for diabetic patients with retinopathy and therefore no ocular contraindications to aspirin use when required for cardiovascular disease or other medical indications.

With regard to focal treatment for macular edema, the ETDRS demonstrated that photocoagulation definitely reduced the risk of moderate vision loss, especially for those eyes with macular edema that involved or threatened the center of the macular. There was an increase of moderate visual gain in those eyes that received focal treatment as well as a decrease in the amount of retinal thickening.

Finally, with regard to early scatter treatment, the study demonstrated a statistically significant reduction in severe visual loss for those eyes with early treatment, especially for those patients with non-insulin-dependent diabetes mellitus (NIDDM). However, the reduction was small and the risk was low in the deferral group.

Scatter treatment should be deferred for eyes with mild to moderate nonproliferative diabetic retinopathy. As the retinopathy progresses to the severe nonproliferative or early proliferative stage, scatter treatment should be considered, especially for patients with NIDDM. Scatter photocoagulation should be performed for virtually all eyes with high-risk proliferative retinopathy. Eyes with clinically significant macular edema should be considered for focal photocoagulation. Finally, early vitrectomy should be considered for advanced active proliferative diabetic retinopathy, and most importantly, all patients with diabetic retinopathy should receive careful followup.

Before current treatments, the prognosis for patients with proliferative diabetic retinopathy was blindness within 5 years for more than 50 percent of patients. Rates of blindness in ETDRS patients following the development of proliferative retinopathy are remarkably lower. Legal blindness is reduced to less than 5 percent in 5 years for patients with proliferative retinopathy. Severe vision loss is reduced to 1 percent.