Ischemic Optic Neuropathy Decompression Trial:  Twenty-Four–Month Update FREE

NONARTERITIC anterior ischemic optic neuropathy (NAION) is the most common cause of acute optic neuropathy in the elderly.^1- 3 In a multicenter, randomized clinical trial, the Ischemic Optic Neuropathy Decompression Trial (IONDT) Research Group compared optic nerve decompression surgery (ONDS) with careful follow-up for NAION. Preliminary results for 181 patients with data at the 6-month follow-up indicated that visual acuity had improved by 3 or more lines in 42.7% of patients randomized to the careful follow-up group compared with 32.6% of patients randomized to ONDS.⁴ In addition, vision had worsened by 3 lines or more in 12.4% of patients in the careful follow-up group compared with 23.9% of patients in the ONDS group. Our preliminary report concluded that ONDS for NAION was not beneficial and was possibly harmful.⁴ Based on these findings and the recommendation of the Data and Safety Monitoring Board, recruitment to IONDT was stopped in October 1994. A description of the baseline characteristics of randomized patients has been published previously.⁵

The IONDT Research Group has continued to follow up all randomized participants (N=258) to evaluate longer-term outcomes. We report mean visual acuity outcomes for 6 through 24 months of follow-up.

A detailed description of the methods and eligibility requirements used to enroll patients, collect data, and tabulate results has been described previously.⁶ In brief, patients who had sudden loss of vision within the previous 14 days, a relative afferent pupillary defect, optic nerve head (disc) edema, and an abnormal visual field were eligible for the IONDT. Exclusion criteria included age younger than 50 years, any medical condition that results in nonischemic optic neuropathy or excessive surgical risk, any ophthalmologic condition that precludes reliable visual acuity measurement, and inability to give informed consent. Eligible patients were randomized if, within 30 days of onset of symptoms, their visual acuity was 20/64 or worse but better than no light perception. Randomization and surgery took place within 14 days of onset of symptoms if initial visual acuity was 20/64 or worse (regular entry). When baseline visual acuity was better than 20/64, patients were followed up for up to 30 days, and those whose visual acuity decreased to 20/64 or worse were eligible to be randomized and have surgery within 4 days (≤34 days from onset of symptoms) (late entry). The ONDS procedure has been described previously.⁴

Follow-up visits were scheduled at 1 week and at 1, 3, 6, 12, 18, and 24 months after randomization. The primary outcome, change of 3 or more lines of visual acuity at 6 months after randomization, was measured using Lighthouse charts (Lighthouse Low Vision Products, Long Island City, NY) by masked visual acuity technicians. For patients who were unable to read letters, technicians assessed the ability to count fingers, perceive hand motion, or perceive light. When visual acuity could be estimated using number of letters read on the Lighthouse chart (patients were "on chart"), we used standard methods of calculating a logMAR (logarithmic Minimum Angle of Resolution) score⁷; otherwise (patients were "off chart"), we assigned logMAR scores of 2.0 to count fingers, 2.3 to hand motion, and 2.6 to light perception.

Patients were assigned to careful follow-up or ONDS groups via a telephone call to the coordinating center. The random allocation schedule was computer generated and stratified by clinic.

Sample size was estimated before the study began. We assumed a 2-sided test for significance at the .05 level, with 90% power to detect a difference when 30% in the careful follow-up group and 50% in the ONDS group improved by 3 or more lines of vision at 6 months. We estimated 150 patients in each group would be necessary, allowing for 10% attrition.

All analyses followed the intention-to-treat principle. We initially compared patients with and without missing outcomes data to identify differences that might affect interpretation of the findings. Pearson χ² test was used to test differences in categorical variables, and the t test was used for continuous variables. We also compared the subset of patients who completed the 24-month visit (24-month cohort) (n=174) with the full set of all randomized patients with respect to visual acuity and other variables to examine the effect of possible differential losses to follow-up in the 2 treatment groups.

Subsequent analyses examining treatment effect included all randomized patients with baseline visual acuity data (all randomized cohort) (n=255). We used the mixed procedure in SAS version 6.12 (SAS Institute, Cary, NC) for longitudinal linear regression analysis to take into account the lack of independence in repeated measures of treatment effect during 24 months of follow-up. By using 4 categorical time variables and their interactions with the treatment group variables, we compared treatment groups at each time point, using all patients with data at that time point, examining change in visual acuity from baseline (dependent variable) by treatment group and follow-up time (independent variables). Adjustment variables were included in the model if they had a statistically significant association with change in visual acuity or meaningfully changed the observed association between the outcome and treatment group or time variables. Although not statistically significantly associated with change in visual acuity, treatment group × time interaction variables were retained as a term in the model to obtain an estimate of adjusted mean change in vision over time by treatment group. Separate analyses were performed for patients whose baseline vision was "on chart" and "off chart," because we observed differences in the amount of change in visual acuity for these 2 groups of patients. The analysis for "on chart" patients was adjusted for baseline visual acuity, age (<65 years or ≥65 years), and diabetes; the analysis for "off chart" was adjusted for baseline visual acuity. Analyses were performed for both the 24-month and the all randomized cohorts, but only the results from the all randomized cohort are reported herein.

The numbers of patients randomized in the IONDT and for whom data are available at baseline, 6 months, and 24 months are indicated in Figure 1. There were no significant differences between treatment groups in the percentage of patients missing visual acuity measurements at any of the visits (Table 1) and no significant differences between treatment groups in the percentage of patients missing visual acuity measurements at the 24-month visit by age, sex, late entry, diabetes, hypertension, previous NAION, or baseline acuity on/off chart (data not shown).

We found few significant differences when we compared mean change in vision at 3, 6, 12, and 18 months for patients with visual acuity data at 24 months with those missing 24-month visual acuity data. In patients with visual acuity "on chart" at baseline, those without visual acuity data at 24 months had significantly poorer vision at baseline (difference of 0.14 units logMAR; P=.01) compared with those with 24-month vision data. Although visual acuity improved in both groups, the group missing 24-month vision data appeared to improve more at earlier time points. There were no significant differences in vision in patients who were "off chart" at baseline and missing visual acuity data at 24 months compared with those with vision data, except at 12 months, where the 24-month cohort improved more (P=.04) (data not shown).

Demographic, visual acuity, and medical characteristics for the all randomized and the 24-month cohorts by treatment group are shown in Table 2. We could not compare these cohorts statistically, since the 24-month cohort is a subset of the all randomized cohort. There appears to be little difference in baseline visual acuity between the 24-month and the all randomized cohorts. A significantly higher percentage of patients in the surgery group were in the late entry category, but this was not seen in the 24-month cohort. In both cohorts, there were significantly more patients with diabetes in the careful follow-up group.

Losses to follow-up by 24 months were not differentially distributed across treatment groups nor were they associated with important differences in baseline or follow-up vision between treatment groups. In patients with "off chart" vision, those who were lost to follow-up at 24 months had significantly poorer baseline visual acuity than patients not lost to follow-up. There were no significant differences between patients with and without 24-month vision data on any of the baseline characteristics examined (data not shown). Therefore, as noted earlier, our analyses pertaining to visual acuity and other outcomes are based on the all randomized cohort.

For the primary outcome, the preliminary results of no benefit for ONDS reported for IONDT at 6 months of follow-up were confirmed for all follow-up times through 24 months (Table 3). Using logMAR scores treated as continuous variables, Figure 2 shows change in visual acuity as "mean chart lines improved" in the 2 treatment groups at the 3-, 6-, 12-, 18-, and 24-month visits for patients whose baseline visual acuity was "on chart" and "off chart," respectively. All patients for whom data were available were included at each time point.

For the quantitative visual acuity outcome for "on chart" patients, we found that patients younger than 65 years improved significantly more than older patients (P=.02). Visual acuity was significantly improved over the baseline value at all follow-up visits, although less improvement was noted at month 24 (Figure 2, top), and the greatest improvement was seen at 3 months for both treatment groups. No significant differences were observed between groups, and patients with poorer visual acuity at baseline had greater mean improvement than did those with better baseline vision (P<.001). For "off chart" patients, statistically significant improvement from baseline visual acuity was observed for both study groups at all follow-up visits, but no decline over time was seen after the 3-month improvement (Figure 2, bottom). No differences between treatment groups were detected.

When results from similar analyses using the 24-month cohort were compared with analyses using the all randomized cohort, the 24-month cohort showed somewhat less improvement over time. This result is consistent with the fact that those missing data at 24 months had significantly worse baseline vision and patients with poorest baseline vision improved most.

The IONDT remains the only multicenter, randomized study of a large number of patients with NAION. Although other studies have provided important information on the natural history of NAION,^1- 2,8- 10 the IONDT is still the best source of comprehensive, prospective data on this disease process based on its experimental design.

There were no significant differences between the careful follow-up and ONDS groups in mean changes in visual acuity at the 24-month follow-up. These results support the IONDT Research Group's conclusion at the 6-month follow-up that ONDS is not of value in treating NAION.⁴ For patients "on chart" at baseline, both treatment groups improved significantly over the mean enrollment baseline visual acuity by the 3-month assessment, followed by a gradual decline over time (Figure 2, top). Despite this decline, at 24 months mean visual acuity in both treatment groups was still significantly better than that at baseline. A similar decline in visual acuity over time was not seen in either treatment group for patients "off chart" at baseline (Figure 2, bottom).

Although the average change in vision for the 2 groups is toward improvement over baseline at every subsequent time point, it is highest at 3 months. This average change should not be interpreted to mean that vision in patients with NAION declines generally during the follow-up period. A possible explanation for a decrease in average improvement is that some individuals experience a large decrease in vision, whereas others experience no change or improvement. Indeed, the median improvement for the 2 groups is about the same for each time point after baseline, supporting this interpretation. For patients with a loss of vision over time, it has been hypothesized that chronic ischemia could cause a delayed axonal death due to a variety of different mechanisms.^11- 13 Gradual development of macular degeneration or cataracts, leading to reduced vision, is another explanation for visual decline in this older population. The IONDT intends to follow up enrolled patients for 3 additional years to establish the 5-year natural history of NAION in an attempt to answer this and other important questions.

Therapy to treat acute NAION successfully, reduce the gradual decline in the visual improvement noted in some of these patients, and protect the fellow eye from NAION is not yet available. Neuroprotective agents, reduction of vascular risk factors, aspirin or other antiplatelet medication, dopaminergic medication, and other agents are potential avenues for investigation.^14- 18 Regardless of any new treatment strategy that is considered, the 6- and 24-month follow-up results of the IONDT underscore the importance of testing any new therapy with a randomized clinical trial before widespread use.

Accepted for publication January 4, 2000.

The Ischemic Optic Neuropathy Decompression Trial was supported by grants from the National Eye Institute (EY09608, EY09545, EY09556, EY09555, EY09554, EY09576, EY09565, EY09551, EY09599, EY09584, EY09578, EY09572, EY09575, EY09567, EY09598, EY09550, EY09553, EY09566, EY09569, EY09579, EY09571, EY09568, EY09557, EY09552, EY09570, EY09582, and EY09626).

The participants in the Ischemic Optic Neuropathy Decompression Trial (IONDT) Research Group as of March 1999 were:

Clinical Centers

Allegheny General Hospital, Pittsburgh, Pa: John Kennerdell, MD (principal investigator); Anna Bruchis, MD (coordinator). St Louis University Eye Institute, St Louis University Health Sciences Center, St Louis, Mo: Sophia Chung, MD (principal investigator); Dawn Govreau (coordinator); John Holds, MD; John Selhorst, MD. Carolinas Medical Center, Charlotte, NC: Mark Malton, MD (principal investigator); Amy Rogers (coordinator); Timothy Saunders, MD. Cleveland Clinic Foundation, Cleveland, Ohio: Gregory Kosmorsky, DO (principal investigator); Karen King, COT (coordinator); Tami Fecko; Deborah Ross, CRA. Doheny Eye Institute, Los Angeles, Calif: Steven Feldon, MD (principal investigator); Lori Levin, MPH (coordinator); Kerry Zimmerman, MS (coordinator, 1992-1995); Kathy Friedberg, COMT; Nahid Sadaati, CO. Emory University, Atlanta, Ga: Nancy J. Newman, MD (principal investigator); Donna Loupe, BA (coordinator); Ted Wojno, MD. Henry Ford Hospital, Detroit, Mich: Barry Skarf, MD (principal investigator); Mark Croswell; Wendy Gilroy Clements; George Ponka, COMT. University of Texas, Houston: Rosa Tang, MD (principal investigator); Melissa Hamlin (coordinator); Jewel Curtis; Kirk Mack; Portia Tello. Jules Stein Eye Institute, Los Angeles, Calif: Anthony Arnold, MD (principal investigator); Janet Buckley (coordinator); Robert Goldberg, MD; Lynn Gordon, MD; Howard Krauss, MD; Robert Stalling. W. K. Kellogg Eye Center, University of Michigan, Ann Arbor: Wayne Cornblath, MD (principal investigator); Barbara Michael (coordinator). Mason Institute of Ophthalmology, University of Missouri, Columbia: Lenworth N. Johnson, MD (principal investigator); Gaye Baker (coordinator); Coy Cobb, CRA, COT; Sharon Turner, COT. Mayo Clinic, Rochester, Minn: Brian Younge, MD (principal investigator); Jacqueline Leavitt, MD (co-principal investigator); Rebecca Nielsen, LPN (coordinator); Barbara Eickhoff, COT; James Garrity, MD; Jacqueline Ladsten; Kathleen Lebarron; Thomas Link, BA; Jay Rostvold; Karen Weber. Medical College of Virginia, Richmond: Warren Felton III, MD (principal investigator); Tammy Anderson (coordinator); George Sanborn, MD. Michigan State University, East Lansing: David Kaufman, DO (principal investigator); Eric Eggenberger, DO (co-principal investigator); Suzanne Bickert, RN (coordinator); Robert Granadier, MD; Sandra Holliday; Thomas Moore, MD. State University of New York, Syracuse: Deborah Friedman, MD (principal investigator); Patricia Jones (coordinator); Thomas Bersani, MD. University of California, San Francisco: Jonathan Horton, MD (principal investigator); Maeve Chang, BA (coordinator); Lou Anne Aber, COA; Stuart Seiff, MD. University of Florida, Gainesville: John Guy, MD (principal investigator); Z. Suzanne Zam, BS (coordinator); Revonda Burke (coordinator). University of Illinois, Chicago: James Goodwin (principal investigator); Allen Putterman. University of Kentucky, Lexington: Robert Baker, MD (principal investigator); Judy Beck (coordinator); Michael Hanson; Toni Scoggins, COA. University of Maryland, Baltimore: Shalom Kelman, MD (principal investigator); Charlotte Frank (coordinator); Rani Kalsi. University of South Carolina, Columbia: Kakarla Chalam, MD (principal investigator); Shirley Hackett (coordinator). University of Utah, Salt Lake City: Kathleen Digre, MD (principal investigator); Jolyn Erickson (coordinator); Terrell Blackburn (coordinator, 1992-1993, deceased); Richard Anderson, MD; Paul Langer, MD (1993-1995); Paula Morris; Sandra Osborn (1995); Bhupendra Patel, MD; Sandra Staker; Judith Warner, MD. University of Virginia, Charlottesville: Steven Newman, MD (principal investigator); Christine Evans, COMT (coordinator); Carolyn Harrell, COA; Helen Overstreet, RN; James Scott, RBP; Lillian Tyler, COA. West Virginia University, Morgantown: John Linberg, MD (principal investigator); Brian Ellis, MD (principal investigator, 1995-present); Charlene Campbell, COT (coordinator); Gordon McGregor (1993-1994). William Beaumont Hospital, Royal Oak, Mich: Edward Cohn, MD (principal investigator); Kristi Cummings (coordinator); Patricia Manatrey (coordinator, 1992-1995); Sara Casey (1992-1995); Robert Granadier, MD; Virginia Regan; David Roehr; Patricia Streasick.

Resource Centers

Chairman's Office, University of Maryland School of Medicine, Baltimore: Shalom Kelman, MD (study chairman); Michael Elman, MD (vice chairman, 1992-1994); Charlotte Frank, MS (administrator). Coordinating Center, University of Maryland School of Medicine, Baltimore: Kay Dickersin, PhD (director); Frank Hooper, ScD (deputy director 1992-1998); Roberta Scherer, PhD (project coordinator); Barbara Crawley, MS (1992-1998); Michael Elman, MD (1992-1994); Cheryl Hiner (1992-1998); Lucy Howard; Patricia Langenberg, PhD; Olga Lurye (1992-1998); Janet Masiero, MBA (1995-1997); Robert McCarter, ScD; Sara Riedel (1994-1995); Michelle Sotos (1994-1995); Laureen Spioch (1992-1998); Joann Starr (1992-1994) Judy Urban (1993-1994); Mark Waring; P. David Wilson, PhD; Jie Zhu (1998); Qi Zhu, MS (1998). Coordinating Center, Brown University School of Medicine, Providence, RI. Kay Dickersin, PhD (1998-present); Laureen Spioch (1998-present); Jie Zhu (1998-present), Qi Zhu, MS (1998-present). National Eye Institute, Bethesda, Md: Donald Everett, MA.

Committees

Data Analysis Committee: Barbara Crawley, MS; Kay Dickersin, PhD; Frank Hooper, ScD (1992-1998); Patricia Langenberg, PhD; Robert McCarter, ScD; Roberta Scherer, PhD; P. David Wilson, PhD. Data and Safety Monitoring Committee: Marian Fisher, PhD (chair); Phil Aitken, MD; Roy Beck, MD; Andrea LaCroix, PhD; Simmons Lessell, MD; Reverend Kenneth MacLean; Kay Dickersin, PhD (ex officio); Michael Elman, MD (ex officio, 1992-1994); Donald Everett, MA (ex officio); Shalom Kelman, MD (ex officio). Executive Committee: Shalom Kelman, MD (chair); Kay Dickersin, PhD; Michael Elman, MD (1992-1994); Donald Everett, MA; Frank Hooper, ScD (1992-1998). Quality Assurance Committee: Frank Hooper, ScD (chair, 1992-1998); Shalom Kelman, MD; Roberta Scherer, PhD. Steering Committee: Shalom Kelman, MD (chair); Kay Dickersin, PhD; Michael Elman, MD (1992-1994); Donald Everett, MA; Steven Feldon, MD; Frank Hooper, ScD (1992-1998); David Kaufman, DO; Nancy J. Newman, MD; Z. Suzanne Zam, BS. Surgical Quality Assurance Committee: Robert Baker, MD; Steven Feldon, MD (chair); Robert Granadier, MD; Frank Hooper, ScD (1992-1998); Shalom Kelman, MD; Gregory Kosmorsky, DO; Stuart R. Seiff, MD. Writing Committee: David Kaufman, DO; Kay Dickersin, PhD; Shalom Kelman, MD; Patricia Langenberg, PhD; Nancy Newman, MD; and P. David Wilson, PhD.

Reprints: Kay Dickersin, PhD, Brown University School of Medicine, Department of Community Health, 169 Angell St, Box G-S, Providence, RI 02912.