Evaluation of new techniques of macular surgery

Guest Editorial Evaluation of New Techniques of Macular Surgery In this issue of Ophthalmology, Paques and coworkers have conducted a carefully designed randomized clinical trial evaluating the efficacy of autologous platelet concentrate in achieving anatomic success in patients with stage 3 or 4 macular holes. The primary outcome for this study was reapposition of the edge of the macular hole 1 month postsurgery, an anatomic endpoint. The authors found a statistically significant benefit using platelet concentrate in achieving their goal of anatomic success (P ⫽ 0.009). However, no statistically significant differences in the secondary endpoint of visual acuity were found between the two groups. Can the Paques study be regarded as a success? The answer is “Yes” from the point of view of the investigators in achieving statistical significance with regard to the primary endpoint, namely anatomic success. But the answer is “No” with regard to the point of view of the patient, because the improvement in visual acuity resulting from this procedure was not statistically different from that for the control group. In our opinion, improvement in visual acuity, not anatomic success, is the key 1 endpoint from the perspective of the patient. This is why the designers of the Silicone Study chose improvement in visual acuity, and not anatomic success, as the primary endpoint in designing their study. Of interest is that there was a marginally significant trend for improved vision using platelet concentrate at 3 months (P ⫽ 0.06). Further, there even appeared to be a (nonsignificant) trend for improved vision using platelet concentrate at 6 months (P ⫽ 0.25). Given these trends, an external review group (e.g., a Data and Safety Monitoring Committee) upon review of interim study results might have recommended randomizing more subjects to ascertain whether these trends in visual acuity were “real.” Assuming that these trends persisted, our calculations revealed that with 80% power, only 4 more patients per treatment group had the potential of yielding significant results at 3 months; 14 more patients per treatment group had the potential of yielding significant results at 6 months. (Of course, appropriate adjustments in significance testing would need to be implemented to accommodate the second “look” at the data.) We are now aware that for stage 3 and 4 macular holes, hole closure rates well above 70% can be obtained, particularly if the holes are not longstanding large holes.2 Techniques to increase the rates of hole closure and improve vision have included removal of epiretinal membranes, less traumatic surgery, avoidance of phototoxicity, and visualization and treatment of retinal tears. In addition, there has been interest in the use of adjuvant factors that will “seal” the holes, either through stimulating the adhesion of the neurosensory retina to the retinal pigment epithelium or through some other mechanism. Factors that have been studied include transforming growth factor-beta (TGF-beta), autologous serum, and autologous plasma in combination with bovine thrombin and other factors. For serum and TGF-beta, evaluative studies have suggested minimal or no benefit.3 With regard to platelet concentrate, the randomized trial conducted by Paques and associates has led to interesting results but also points to important lessons for all ophthalmologists who wish to measure the overall success of their surgical interventions. It is important to decide on relevant outcomes and endpoints in studies of all diseases, including macular diseases. In the treatment of age-related macular degeneration, there has also been confusion regarding outcomes of newly developed treatments. The technical ability to remove submacular neovascularization has only recently become possible as our vitrectomy instrumentation and experience have improved, yet many investigators have come to the sober conclusion that such surgical excision, although technically feasible, often leaves patients with poor vision, at least when the etiology of the neovascularization is age-related macular degeneration.4 Similarly, there was great enthusiasm for the treatment of drusen with scatter laser photocoagulation to the macula. Although the drusen do indeed regress, recent studies have shown that there may be complications of the treatment, and it is unclear if there is any beneficial effect of this procedure on visual function.5 Because there has been a recent surge in new techniques designed to treat macular diseases, it is important to design and objectively analyze studies in ways that are meaningful. How do we meaningfully measure the function of the macula? Anatomic success (successful eradication of a subretinal neovascular membrane without recurrence, closure of a macular hole, resolution of macular edema) is important but must be regarded as a secondary endpoint.6 With regard to visual acuity, the Snellen visual acuity chart, although not ideal, does measure the ability to view fairly high-contrast test objects. As a clinical marker of vision, it has been greatly improved on in the form of the Bailey Lovie or Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The standardized “ETDRS”

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Ophthalmology Volume 106, Number 5, May 1999 visual acuity chart is scored using a logarithmic scale, with refraction performed each time. Other tests of macular function include contrast sensitivity, color vision, and tests of reading speed. In cases where there is media opacity, the Potential Acuity Meter can be used. Unfortunately, this method is not fully standardized. Other outcomes that should be evaluated in macular disease include the evaluation of vision-specific health-related quality of life using the NEI-Visual Function Questionnaire. In addition, it is important to not only evaluate our success rates at a given point in time but also longitudinally. Long-term studies are needed if there is reason to believe that initially successfully surgeries may subsequently lead to ocular problems. In the multicentered Vitrectomy for Macular Hole Study,2 hole closure was achieved in 69% of operated eyes versus 4% of observed eyes (P ⬍ 0.001). Although a patient might initially obtain vision improvement from the surgery, a subsequent cataract might develop. There is evidence that cataract surgery and the passage of time may improve the visual function of patients who undergo macular hole surgery with successful 7 hole closure. However, after cataract extraction, the hole may reopen or a retinal detachment may occur. Finally, it is important to report negative as well as positive results in the literature. Paques and associates have done us all a service by conducting a well-performed study. Evaluation of anatomic success may be critical in initial studies of a new technique and in evaluating improvements during the evolution of new treatments. However, it is disappointing that there was not a statistically demonstrable improvement in vision in their patients treated with platelet concentrate. Nonetheless, their paper should stimulate much discussion on mechanisms of macular hole closure and on the best ways to conduct clinical trials in macular disease. References 1. Abrams GW, Azen SP, McCuen BW II, et al. Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Arch Ophthalmol 1997;115:335– 44. 2. Freeman WR, Azen SP, Kim JW, et al. Vitrectomy for the treatment of full-thickness stage 3 or 4 macular holes: Results of a multicentered randomized clinical trial. The Vitrectomy for Treatment of Macular Hole Study Group. Arch Ophthalmol 1997;115:11–21. 3. Thompson JT, Smiddy WE, Williams GA, et al. Comparison of recombinant transforming growth factor-beta-2 and placebo as an adjunctive agent for macular hole surgery. Ophthalmology 1998;105:700 – 6. 4. Bressler NM. Submacular surgery. Are randomized trials necessary? Arch Ophthalmol 1995;113:1557– 60. 5. Choroidal neovascularization in the Choroidal Neovascularization Prevention Trial. The Choroidal Neovascularization Prevention Trial Research Group. Ophthalmology 1998;105:1364 –72. 6. Polk TD, Smiddy WE, Flynn HW Jr. Bilateral visual function after macular hole surgery. Ophthalmology 1996;103: 422– 6. 7. Leonard RE II, Smiddy WE, Flynn HW Jr, Feuer W. Long-term visual outcomes in patients with successful macular hole surgery. Ophthalmology 1997;104:1648 –52.

WILLIAM R. FREEMAN, MD La Jolla, California STANLEY P. AZEN, PHD Los Angeles, California

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