Clinical Trials in Retina

THE DIABETIC RETINOPATHY STUDY

The role of laser photocoagulation in the treatment of diabetic retinopathy remained controversial following its first description by Meyer-Schwickerath in the 1950s. In 1971, the Diabetic Retinopathy Study (DRS), which was organized under the leadership of Mathew Davis, MD, began to address these fundamental controversies definitively. The study was the first of many well-designed, prospective, and randomized clinical trials that guide the current practice of ophthalmology.

Study Objectives

The question posed by the DRS was, “Does photocoagulation surgery reduce the risk of severe visual loss in diabetic retinopathy?” The DRS set out to better establish the natural course of untreated diabetic retinopathy. It also was designed to compare the effects of treatment techniques involving extensive scatter photocoagulation and focal treatment of new vessels on the surface of the retina with either xenon arc or argon laser energy.

Treatment Groups/Trial Design

Eligible patients had diabetic retinopathy in both eyes, with proliferative diabetic retinopathy (PDR) in at least one eye, or severe, nonproliferative changes in both eyes. Severe nonproliferative changes were defined as the presence of at least three of the following:

■cotton wool spots

■intraretinal microvascular abnormalities (IRMAs)

■extensive retinal hemorrhages

■venous beading

Eligible eyes had to have a visual acuity 20/100 in each eye. Eyes with a traction retinal detachment that threatened the macula were excluded, as were eyes with a history of previous laser photocoagulation treatment. One eye of each participating patient was randomly selected to receive photocoagulation, and the fellow eye was followed independently without photocoagulation. The mode of laser treatment was also randomly assigned as either xenon arc or argon laser.

A total of 1727 patients were enrolled from 15 centers; 858 eyes were randomized to receive argon laser photocoagulation and 869 were randomized to receive xenon arc.

The primary outcome measure was development of severe visual loss, that is, visual acuity 5/200 at two or more consecutive 4-month follow-up visits.

Secondary outcome measures included regression of diabetic retinopathy and side effects related to treatment.

Summary of Results and Implications for Clinical Practice

The findings of the DRS mandate prompt scatter laser photocoagulation in eyes with high-risk PDR. High-risk characteristics are defined as the presence of three or more of the following:

■vitreous or pre-retinal hemorrhage;

■new vessel growth;

■new vessel growth on or within 1 disc diameter (DD) of the optic disc (NVD); or

■severe new vessels (NVD one-fourth to one-third of a disc area or, in the absence of NVD, an area one-half disc area of retinal neovascularization elsewhere [NVE]).

The DRS scatter laser photocoagulation treatment protocol reduced the risk of severe visual loss by greater than 50%. Ongoing follow-up of some of the original study participants confirmed that the beneficial effects of extensive scatter photocoagulation persist for at least 15 years after treatment and suggested that these beneficial effects are permanent.

In high-risk PDR, the benefits of photocoagulation were clear. In eyes with severe nonproliferative diabetic retinopathy (NPDR) or PDR without high-risk characteristics, however, the DRS findings were not clear. They did not provide a clear choice between prompt treatment and careful follow-up with deferral of treatment until high-risk characteristics developed. The risk of severe visual loss in these eyes appeared to be relatively low. Subsequent analysis of the data accumulated in the DRS found that the incidence of severe visual loss in eyes of older-onset diabetic patients randomized to deferral of photocoagulation exceeded that of younger-onset diabetics. In eyes of older-onset diabetics, the analysis suggested that laser treatment should be seriously considered, even though these eyes may not fulfill the original criteria for high-risk characteristics.

The DRS also found that treated eyes were more likely to suffer an initial loss of two to four lines of visual acuity. This loss was largely secondary to increased macular edema. As more untreated eyes suffered significant visual loss over time, this difference no longer existed after 1 year.

Treatment also resulted in peripheral visual field loss, an effect that was more often seen in eyes randomized to xenon arc treatment than in those randomized to receive argon laser scatter photocoagulation.

The Diabetic Retinopathy Study (DRS) clearly demonstrated the benefits of panretinal laser photocoagulation in proliferative diabetic retinopathy (PDR) with high-risk characteristics. The DRS did not, however, address the question of timing or extent of panretinal laser photocoagulation in diabetic retinopathy. Also, it did not clarify the role of laser photocoagulation in early PDR. While diabetic macular edema had been recognized as an important source of visual loss in diabetic retinopathy, the role of laser treatment in this setting had yet to be verified by a randomized, controlled clinical trial. The Early Treatment Diabetic Retinopathy Study (ETDRS) addressed these issues. In addition, the literature of the day was replete with papers extolling both the risks and benefits of adjunctive aspirin use in the management of diabetic retinopathy. The results of the ETDRS would finally settle the issue.

Study Objectives

The ETDRS set out to answer three questions:

■When in the course of diabetic retinopathy is it most effective to initiate panretinal photocoagulation?

■Is photocoagulation effective in the management of diabetic macular edema?

■Is aspirin treatment effective in altering the course of diabetic retinopathy?

Treatment Groups/Trial Design

Eligible patients were diabetics with mild, moderate, or severe nonproliferative diabetic retinopathy (NPDR) or early PDR in both eyes. As the DRS had clearly shown the benefit of scatter laser photocoagulation in eyes with high-risk PDR, such patients were excluded from the ETDRS.

The ETDRS defined macular edema as thickening of the retina and/or hard exudates within 1 disc diameter (DD) of the center of the macula. Clinically significant macular edema (CSME) was defined as the presence of one or more of the following:

■retinal thickening at or within 500 µm of the center of the macula;

■hard exudates at or within 500 µm of the center of the macula, if associated with adjacent retinal thickening; or

■a zone or zones of retinal thickening 1 disc area in size, at least part of which is within 1 DD of the center of the fovea.

Eyes were stratified into three different categories and randomized accordingly:

1.Eyes with moderate to severe NPDR or early PDR and no macular edema were assigned randomly to either early photocoagulation or deferral of photocoagulation until high-risk characteristics appeared. Those assigned to early photocoagulation were further randomized to either

■immediate full scatter panretinal photocoagulation or

■immediate mild scatter panretinal photocoagulation.

2.Eyes with macular edema and “less severe” retinopathy were assigned randomly to either early photocoagulation or deferral of photocoagulation. Those assigned to early photocoagulation were further randomized to one of the following four groups:

■immediate focal photocoagulation with deferral of mild scatter panretinal photocoagulation until severe NPDR develops;

■immediate focal photocoagulation with deferral of full scatter panretinal photocoagulation;

■immediate mild scatter panretinal photocoagulation with deferral of focal photocoagulation for (at least) 4 months, and focal treatment given only if CSME is present; or

■immediate full scatter panretinal photocoagulation with deferral of focal photocoagulation.

3.Eyes with macular edema and “more severe” retinopathy were assigned randomly to either early photocoagulation or deferral of photocoagulation. Those assigned to early photocoagulation were further randomized to one of these four groups:

■immediate mild scatter panretinal photocoagulation with immediate focal photocoagulation;

■immediate mild scatter panretinal photocoagulation with deferral of focal photocoagulation;

■immediate full scatter panretinal photocoagulation with immediate focal photocoagulation; or

■immediate full scatter panretinal photocoagulation with deferral of focal photocoagulation.

Further randomization of patients to either aspirin (650 mg daily) or placebo in a double-masked manner at enrollment resulted in approximately one half of the patients in each group receiving aspirin.

A total of 3928 study patients were enrolled at 23 clinical centers between April 1980 and August 1985.

Outcome Measures

Outcome measures to assess the benefits of early photocoagulation were severe visual loss (visual acuity 5/200 at two consecutive follow-up visits) and vitrectomy rate.

The outcome measure to assess the effect of photocoagulation on macular edema was moderate visual loss (loss of 15 or more letters).

Outcome measures to assess the role of aspirin were mortality, development of cardiovascular disease, progression to high-risk retinopathy, development of vitreous hemorrhage, and development of cataract. Secondary outcome measures included changes in the visual field, as measured by Goldmann perimetry; and changes in color vision, evaluated with the Farnsworth-Munsell 100-hue test.

Summary of Results and Implications for Clinical Practice

The ETDRS addressed the question of timing and extent of panretinal laser photocoagulation in eyes with severe NPDR or early PDR. The findings showed that scatter photocoagulation before the development of high-risk PDR did not significantly alter the end point of severe visual loss. The ETDRS data, however, do suggest that patients with type 2 diabetes and severe NPDR or early PDR are more likely to benefit from early scatter laser treatment than are patients with type 1 diabetes. Eyes approaching high-risk characteristics should be considered for scatter photocoagulation. Such treatment should not be delayed if the eye already has high-risk characteristics. Once this threshold to treat has been reached, scatter photocoagulation should be given as a “full” treatment.

Focal photocoagulation of CSME substantially decreased the risk of moderate visual loss and was recommended for all eyes with CSME and mild to moderate NPDR. Focal treatment should also be performed in eyes with CSME and severe NPDR or early PDR,

preferably before or in conjunction with scatter photocoagulation. Laser photocoagulation applied in the form of “focal” or “grid” treatment decreases the frequency of persistent macular edema, reduces the risk of moderate visual loss, increases the chance of visual improvement, lessens the loss of color vision, and is associated with only minor visual field loss.

The study also concluded that aspirin offered no benefit in preventing progression of diabetic retinopathy or cataract, or in reducing systemic morbidity and mortality in the ETDRS population of diabetic patients. However, no hazardous ocular or systemic effects of taking aspirin were noted in diabetic patients who required aspirin for cardiovascular disease or other medical conditions.