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A Comparison of Treated and Untreated Glaucoma Suspects
A Comparison of Treated and Untreated Glaucoma Suspects MICHAEL SCHULZER, MD, PhD, STEPHEN M. DRANCE, MD, GORDON R. DOUGLAS, MD
Abstract: One hundred forty-three patients with intraocular pressures (lOPs) above 22 mmHg and without visual field defects or any obvious evidence of optic nerve damage were randomly assigned to either a timolol treatment group or no treatment in a 6-year prospective clinical trial. Endpoints were defined as reproducible visual field defects on automatic perimetry, disc hemorrhages, or stereophotographically documented optic nerve head changes. Endpoints de veloped in 42 patients: 28 visual field defects, 8 changes in disc appearance, and 6 disc hemorrhages. Of the 42 patients, 20 were treated and 22 were not. Survival analysis showed no statistically significant differences in failure time to any endpoints between the two groups. In the untreated group, the time to failure of disc change was related to the mean lOP during the study and also to the changes in the lOP from baseline. A significant correlation was found between initial cup-to-disc ratio and survival time to visual field defects in the untreated group. Ophthalmology 1991; 98:301-307
The causal relationship between elevated intraocular pressure (lOP) and glaucoma-like changes at the optic nerve head has been established. 1 Anderson, 2 in his Jack son memorial lecture, examined the relationship between lOP and open-angle glaucoma and also the idea that other risk factors must be present. The evidence for success with medical pressure reduction in cases of damaged glaucoma eyes is still controversial, 3- 11 although the evidence that surgical pressure reduction favorably influences progres sion has been established. 12 • 13 Even if it were clearly es tablished that medical pressure reduction improved the prognosis for progression ofdamage in the glaucoma eye, the question as to whether medical pressure reduction in glaucoma suspects is beneficial would depend on, among other things, the number of people among the suspects who were at risk either from the height of the pressure
alone or from the presence of other factors that would make them susceptible to damage. The management of patients with ocular hypertension has been even more controversial and the published re ports on this subject are almost equally divided between those who find early medical treatment to be effective4 •5 and those who find no clear benefit from treatment. 6- 11 Two recent studies have shown that pressure reduction in glaucoma suspects with topical timolol favorably in fluences the subsequent development of glaucomatous damage. 14•15 The current study was undertaken 10 years ago with the same end in mind, namely to establish whether pressure reduction with timolol favorably altered the incidence of glaucomatous damage in glaucoma sus pects.
SUBJECTS AND METHODS Originally received: May 14, 1990. Revision accepted: November 7, 1990. From the Department of Ophthalmology and Medicine, University of British Columbia, Vancouver. Supported in part by a grant from Merck Sharp & Dohme Laboratories and Medical Research Council of Canada grant #1578. Presented in part at the Glaucoma Society of the International Congress of Ophthalmology, Bali, March 1990. Reprint requests to Stephen M. Drance, MD, Department of Ophthalmology, University of British Columbia, 2550 Willow St. Vancouver, British Columbia V5Z 3N9, Canada.
Our goal was to enroll 300 patients with elevated lOP and a greater risk of developing glaucomatous damage. Only 143 such patients were enrolled, two ofwhom failed to meet the criteria and four of whom failed to complete baseline evaluations (Table 1). For entry into the study, patients had to be between 45 and 70 years ofage. Thirty one percent of patients had a family history ofglaucoma. The untreated lOPs, measured with the Goldmann ap planation tonometer, had to be 22 mmHg or higher on at least three separate days. Twenty percent of patients 301
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Table 1. Outcome of Individuals in Trial
Recruited patients Did not meet criteria Completed 6 years Endpoints Dropouts Adverse drug reaction Died Intraocular pressure Branch vein occlusion Unreliable fields
Total
Treated
Untreated
143 2 63 42 22 2 3 5
70 2 28 21 12 2 2 2
73
1 3
35 21 10 1 3 1 2
had entry pressures of 30 mmHg or greater. All patients had to have previous normal manual visual fields on the Goldmann perimeter using the modified Armaly tech nique on at least two separate successive occasions. Pa tients had to have no obvious signs of acquired disc change characteristic of glaucoma. All cup-to-disc ratios were ac cepted, providing they were symmetric and there were no features of localized acquired disc change. Twenty-nine percent of patients had a cup-to-disc ratio of0.5 or greater. Patients were excluded from the study ifthey had evidence of ocular infections, intraocular surgery, or trauma within 3 months before the study. Also excluded were patients who wore contact lenses; had active keratitis within 3 months of starting the study; had increased intraocular pressure due to trauma or abnormalities preventing reli able tonometry; had disease states that could produce vi sual field loss such as multiple sclerosis, diabetic retinop athy, retinitis pigmentosa, or ischemic optic neuropathy; had bronchial asthma or chronic obstructive lung disease; patients who were of child-bearing age; and patients who had a resting pulse rate of 50 beats per minute or less or evidence of cardiac failure. Patients on systemic /3-blockers or clonidine or who were judged to be unreliable or poor compliers and those with unreliable visual fields or a visual acuity of 20/70 or less because of cataract also were ex cluded. Patients with severe systemic illnesses and those whose pupils did not dilate sufficiently for photography of the posterior pole also were excluded. After obtaining informed consent, all patients were randomly assigned to a timolol treatment group or to no treatment at all. The timolol treatment patients started with 0.25% timolol for 1 month, followed by 0.5% timolol for 1 month. The con centration that produced the greater pressure reduction was chosen for the patient. Those patients who started on 0.25% timolol and whose pressures appeared to gradually rise were placed on 0.5% timolol during the study. A full history of ocular symptoms, presence of other diseases, family history of glaucoma and other diseases, as well as a history of all topical and systemic drug ad ministration was obtained. The baseline ocular exami nation included visual acuity, slit-lamp examination, ophthalmoscopy, color-stereo photography, and three ex aminations on automatic perimeters, performed at least 2 days apart. Results of the three visual field tests had to 302
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be normal for inclusion in the study. Blood pressure, rest ing pulse rate, and a 2-hour postprandial blood sugar were measured and an electrocardiogram was recorded. At the start of the study, the Perimetron (Coherent Radiation, Palo Alto, CA) was the only available computerized pe rimeter. Kinetic isotopers to a I 2E, II 4E, and V 4E stim ulus were plotted on the perimeter. A special program for threshold static testing at 135 locations in the inner 30° was employed and any fields with points with a 0.5-decibel loss or a 5o nasal step were labeled as not normal and excluded. Approximately 6 months after the start of the study, the Peritest automatic perimeter (Rodenstock, Munich, Germany) became available. Subsequently, this instrument was used both for the initial screening of new patients and for all follow-up perimetry measurements. One patient, who showed normal results on baseline on the Perimetron, showed an abnormal reproducible point 6 decibels depressed on the first Peritest follow-up ex amination and was excluded from the study. Each patient was clinically re-evaluated once a month for 4 months; re-evaluation included tests for visual acuity, perimetry, tonometry, disc examination, blood pressure, and pulse recording. A glaucomatous visual field defect on the Peritest was reported in the presence of any two adjacent points with a depression of 6 decibels or more, any single isolated point with a depression of 10 decibels in the central 30°, any point immediately above or below the nasal horizontal with a depression of 0.6 decibels or more, any point within 5o of fixation with a depression of 0.4 decibels or more, and adjacent peripheral points depressed 10 decibels or more, providing this was not part of a generalized depression. After each follow-up exami nation, the visual fields were masked for evaluation. If the field was labeled abnormal by the predetermined cri teria, the test was repeated. For the abnormality to be confirmed, the second field had to show that the same point or points were "abnormal." In that case, the patient was re-examined on an Octopus 201 (Interzeag, North boro, MA) with programs 31, 32, 42, or later with Hum phrey programs 30-1, 30-2, and 68. Ifthe previously con firmed abnormal points on the two Peritest examinations also were abnormal on the Octopus or Humphrey perim eter, the visual field was called abnormal and the study was terminated for that patient or eye. If the field defect was not confirmed either on re-examination or third ex amination, the patient returned for the next four follow up visits. All discs were photographed annually and eval uated in masked fashion. The horizontal and vertical cup to-disc ratios were first recorded from the photograph, and then a comparison with the initial baseline photog raphy was made to identify any changes in the disc ap pearance. The masked photographic evidence of change of the disc constituted another endpoint and the patient discontinued the study. The occurrence of a disc hem orrhage also constituted an endpoint. The data were subjected to product-limit (Kaplan Meier) time-to-failure survival analysis, using log-rank tests to compare the survival experience ofthe two groups with respect to each failure event (disc change, disc hem orrhage, disc change or hemorrhage, field change, any of
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the above). Comparisons between the treated and un treated groups and between censored and failed individ uals were performed with respect to continuous covariates and continuous demographic variables using t tests and with chi-square tests on categorical variables. In addition, survival to each endpoint also was analyzed in the two groups using Cox's proportional hazards method adjusting for the following covariates: baseline lOP, mean postbaseline lOP over the follow-up period, mean lOP change (baseline- mean follow-up pressure), logarithm ofvariance ofpostbaseline lOP measurements, and baseline cup-to-disc ratio. When both eyes ofa patient were included in the study, the first eye to fail was ana lyzed, with its own covariate values. When neither eye failed, a random eye was selected for analysis. The time from first eye failure to second eye failure also was ana lyzed and compared in the two groups.
RESULTS The study was started in 1980 and the last patient com pleted 6 years offollow-up in December 1989. Of the 143 patients recruited into the study, 73 were assigned to the untreated control group and 70 to the treated group (Ta ble 1). Two patients failed to meet our entrance criteria, both from the treatment group (one had drusen of the optic nerve, and one had previous angle-closure glaucoma). Table 2. Covariate Values for Followed Patients* Controls (n = 70)
Treated (n = 67)
p
F 37 39 0.48 M 28 33 Family history of glaucoma Yes 21 21 0.85 No 49 46 Age (yrs) 59.28 ± 9.16 61.27 ± 11.61 0.27 Mean baseline lOP 26.1 ± 3.18 26.31 ± 3.49 0.69 (mmHg) Mean follow-up (post26.28 ± 4.34 21.77 ± 3.22 <0.001 baseline) lOP (mmHg) Mean lOP change from -0.19 ± 3.31 4.54 ± 3.89 <0.001 baseline (baseline lOP minus mean follow-up lOP) (mmHg) Mean baseline cup-to-disc 0.34 ± 0.17 0.35 ± 0.16 0.70 ratio Baseline systolic blood 138.74 ± 34.6 131.57 ± 37.10 0.24 pressure (mmHg) Baseline diastolic blood 81.06 ± 17.28 80.37 ± 20.48 0.83 pressure (mmHg) Baseline pulse rate per 71.54 ± 19.16 70.84 ± 18.39 0.83 minute lOP = intraocular pressure. * For continuous variables, means and standard deviations are given.
Table 3. Endpoints Field defects (28) Disc changes (8) Disc hemorrhages (6) Total
15 treated 13 controls 2 treated 6 controls 3 treated 3 controls
42
Four patients failed to complete the baseline examination, three in the control group and one in the treatment group, so that 137 patients were followed: 70 controls and 67 treated patients. The baseline characteristics of the treated and untreated groups are described in Table 2 and showed no statistically significant differences. Thirty-six patients were lost or discontinued during follow-up for reasons shown in Table 1. There were no significant differences between the dropouts and those who completed the study, except for the cup-to-disc ratio, which was larger among the dropouts: the mean cup-to-disc ratio of the dropouts was 0.36 ± 0.17, whereas the mean cup-to-disc ratio of the completed group was 0.29 ± 0.14 (P < 0.03). End points developed in 42 of the remaining 105 patients who were followed, and the remaining 63 patients completed the 6-year study. Among the dropouts, all deaths and reported sicknesses were unrelated to the use of topical ,6-blockers. The adverse reactions were due to topical ti molol. Of the five high lOPs that resulted in a discontin uation of the study, three occurred in patients in the un treated control group and two in patients in the treated group. In four patients, pressures rose to levels higher than 35 mmHg (27 to 40 mmHg, 39 to 50 mmHg, 27 to 45 mmHg, and 22 to 41 mmHg) and in the fifth patient (31 to 33 mmHg), a clinical decision that the pressures were too high was made. This was a patient on treatment in whom pilocarpine was added. At the present time, glau coma has not developed in any of these patients, but they were treated more intensively. Of the 42 endpoints, 28 were due to the development of abnormal visual fields using the predetermined criteria (Table 3). Eight were found photographically to have a change in the disc ap pearance and six were found to have a disc hemorrhage. Of the 42 patients, 20 were in the treatment group and 22 were in the untreated group. Among the 28 visual field defects, 15 were treated and 13 were not, whereas of the 8 patients with changes in the discs, 2 were treated and 6 were not. Among the six patients with disc hemorrhages, three were treated and three were not. The mean lOP during the study ofthe treatment group was 21.77 ± 3.22 mmHg, whereas the mean lOP of the control group was 26.28 ± 4.34 mmHg. These mean val ues were significantly lower in the treated group (P < 0.001). The mean pressures are illustrated in Figure 1, and the mean pressure differences and corresponding 95% confidence intervals at each observation time are given in Table 4. Survival analysis (Fig 2) showed that the treated group had a mean survival time of 2061 days before end point, whereas the untreated group had a mean survival 303
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time of 1942 days. These differences were not statistically significant. With our sample size and the number of pos itive events, a difference of 1 year survival would have been detected over 80% of the time and a difference in survival of 3 years would have been detected 100% of the time. The survival analysis was repeated on an "intent-to treat" basis, including the six patients who were random ized but not followed. A similar analysis also was per formed with the five patients who had been withdrawn from the study due to excessive lOP elevation analyzed as endpoints rather than as censored observations. In all cases, there was no statistically significant difference be tween the two survival curves. There also was no statistically significant difference in the survival curves of the two groups of the failure times between the first eye reaching endpoint and the second eye reaching endpoint when endpoint was reached in both. Analysis using Cox's model confirmed that even after ad justment for the covariates of lOP and cup-to-disc ratio, no significant difference could be detected in the survival pattern of the two groups with respect to any of the end points studied. However, highly significant interactions Table 4. Mean and 95% Confidence Intervals for the Intraocular Pressure Differences (mmHg) for the Followed Patients (Untreated Minus Treated) during the Study Time
Mean Difference
Baseline 6 months 12 months 18 months 24 months 30 months 36 months 42 months 48 months 54 months 60 months 66 months 72 months
-0.23 4.49 5.47 5.02 3.86 4.77 4.23 4.08 2.56 2.65 5.20 3.68 4.19
> ~ "'5 E
0.6
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() 0.4.1__2L00----6_.0_0____ 1O.L.0_0---1-14L00----18-L0-0---2....200
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Fig 1. Mean intraocular pressures at each observation time in the followed patients, treated and untreated controls.
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Confidence Interval (-1.35, (3.06, (4.10, (3.63, (2.08, (3.06, (2.37, (1.81' (0.40, (0.36, (2.52, (1.36, (2.03,
0.89) 5.92) 6.85) 6.42) 5.63) 6.47) 6.08) 6.35) 4.73) 4.94) 7.89) 6.01) 6.36)
Fig 2. Product-limit survival curves in the followed patients, treated and untreated controls. Endpoints are defined as developments offield defects, disc changes, or disc hemorrhages. Dropouts and cases followed to the end of the study without developing an endpoint are analyzed as censored observations.
were found between the survival experiences in the two groups and various covariates. In patients in the timolol-treated group, survival time to any of the endpoint criteria was found not to be sta tistically correlated with any of the covariates (i.e., the baseline cup-to-disc ratio, the baseline lOP level, the mean follow-up lOP level during treatment, or the mean lOP change). In the untreated group, however, survival correlated significantly with several of the co variates. In. particu~ar, for failure due to the development of change m the d1sc, defined as photographically demonstrable diminution of the neuroretinal rim, the untreated group showed a highly significant (P = 0.0004) correlation between survival time and the overall mean lOP level during the follow-up pe riod with shorter survival times corresponding to higher me;n lOP levels. The time until failure due to change in the disc in the untreated group also was correlated (P = 0.0042) with the mean change in lOP from baseline, so that a mean fall in lOP from baseline corresponded to a longer survival time and a mean rise corresponded to a shorter survival time. Table 2 indicates that the untreated group showed no significant systematic change in pressure from baseline over the follow-up period but had a wide range of pressure variations, with a standard deviation of mean pressure change (3.31 mmHg) similar to that of the treated group (3.89 mmHg). No significant correlation between survival and any of the covariates was found in either group when the devel opment of disc hemorrhage was considered as an end point. When the endpoint of visual field failure was con sidered, the survival time in the untreated group showed a highly significant (P = 0.0047) correlation with the initial cup-to-disc ratio, a larger ratio corresponding to a shorter survival time. Survival time to field change was not related to the overall mean lOP follow-up level. There was a cor relation in the untreated group (P = 0.026) between the mean change in lOP from baseline and survival time to visual field change; a mean fall in lOP from baseline sur
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prisingly corresponded to a shorter survival time, and a mean rise from baseline corresponded to a longer survival time. Fluctuations in lOP within patients over the follow-up period showed no statistical correlation with survival to any endpoint in either of the two groups.
CLINICAL FOLLOW-UP We have followed clinically 39 of the 42 patients who reached any of the study endpoints. In some patients, the additional follow-up has been as long as 3 years, whereas in others it has been only 8 months. Some of the patients who were in the untreated control group were started on therapy and others remained untreated. One of the re maining three patients on whom we have no further in formation had a cerebral venous malformation, which accounted for his field defects, whereas the remaining two patients were lost to follow-up. Of the 39 patients who were followed, 26 (67%) were clinically labeled as having glaucoma, 7 as a result of the photographically confirmed disc changes, I 6 as a result of further confirmed field de fects or their progression, and 3 because after their disc hemorrhages, field defects or disc changes subsequently developed. In the remaining 13 patients, the field defects were slight and even when confirmed on follow-up showed no progression, so that we were clinically uncertain as to their significance; three patients had a disc hemorrhage as endpoint and so far no other disc or field changes have taken place. Of the 26 patients who were clinically con firmed to have glaucoma, I 6 were in the treatment group of the study and 10 were in the untreated control group. Of the I 6 visual field study endpoints, I 2 were treated in the study and 4 were not, whereas of the 7 patients whose endpoints were the development of changes in the disc, only 2 were in the treated group and 5 were in the un treated control group. Further follow-up will almost cer tainly yield more definitive cases ofglaucoma. The clinical information does not change the statistical conclusions obtained with the rigorous protocol described in this study.
DISCUSSION At the present time, there is no agreement on whether medical treatment prevents or delays the onset of glau comatous damage in patients with elevated lOP. Long term follow-up has .shown that, each year, visual field de fects and/or optic disc changes develop in approximately 1% of patients with elevated lOP. The current study, which enrolled ocular hypertensive patients with additional risk factors to develop damage, showed a 4.9% per year inci dence for the development of glaucomatous end points: 3.4% developed field defects, 0.6% showed a disc hem orrhage, and 0.9% showed a disc change. Our figures
should, however, be compared with the 3.3% incidence rate found by Epstein et al 14 and 3.3% per year found by Kass et al. 15 Our population had 31 % of patients with a family history of damaging disease, 29% with a cup-to disc ratio of0.5 or greater at entry, and 20% with a baseline entry pressure of 30 mmHg or greater. Therefore, our population was at high risk and may have had some pre clinical disc features such as a uniformly enlarged cup when enrolled. The recent long-term prospective studies reported by Kass et al 15 and Epstein et al 14 both suggest that pressure reduction significantly decreases the inci dence of subsequent visual field defects in patients with elevated lOP. We enrolled a larger number of patients in the prospective study and randomly assigned them to a treatment with timolol group or a nontreatment group. Our study was done entirely with computerized perimetry, which minimizes observer bias and by disc photography, which was interpreted in a masked manner. The results of the study suggest that although the lOP was significantly lowered by the use of timolol, there was no significant difference in the incidence of glaucomatous field defects between the treated and untreated groups. The mean pressure reduction obtained in our study was 4.54 mmHg, which is of the same order obtained with timolol by Kass et al 15 and Epstein et al. 14 The mean level of lOP in the treated group in our study was 21.77 mmHg. This also was of the same order as in the other studies. It is, of course, possible that a greater pressure reduction than ob tained with timolol might have shown different results. Our study was undertaken at a time when timolol was first introduced and had a much better likelihood of pa tient compliance because of its lack of miosis and other ocular side effects and also at a time when computerized perimetry first became available, which allowed visual field data to be obtained with minimal observer bias. The use of photography of the optic nerve head in addition to ophthalmoscopy and the masked reading of the disc pho tographs allowed a more objective interpretation of any disc changes. We demanded three normal baseline fields, which included 135 central threshold estimations each time and excluded any patient who had a depression of 5 decibels in any of these fields. Our endpoint criterion for a field defect demanded that the same point have a depression confirmed three times to reduce false-positive results to a minimum. To date, we know from follow-up that at least 67% were true-positive results, a minimum estimate. Retrospectively, it is unfortunate that only ti molol was used for ·pressure reduction, but it was the only 13-blocker available at the time. Our study suggests that the pressure reduction obtained may not protect the sus ceptible individual from the development oflocalized vi sual field defects and possibly disc changes as well. This cannot be applied in general to pressure reduction, as it may only mean that pressure reduction produced by the nonspecific 13-blocker that we used and the pressure level that was obtained does not protect the susceptible individual from visual field defects. In our untreated group, there was a relationship between the mean lOP and the survival time to disc change: the higher the pres 305
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sure the shorter the survival time. The survival time to disc changes also was related to the mean lOP change from baseline; the greater the fall from baseline the longer the survival. In this untreated group, there also was are lationship between the baseline cup-to-disc ratio and the survival time of the visual field: the greater the cup-to disc ratio, the shorter the survival time to field change. The overall level ofiOP during the entire follow-up period in the untreated group did not relate to the survival time to visual field defect. In the untreated group, the mean lOP change from baseline was significantly related (P = 0.0206) to the survival time to visual field defect in a surprising way; the greater the mean fall of lOP from baseline, the shorter the survival time. The criteria for detecting visual field defects adopted by Kass et al, 15 Epstein et al, 14 and in our studies were developed to identify only scotomas that are localized vi sual field defects. In none of the studies was a generalized, diffuse loss of visual function pursued. Fortunately, we also performed a static meridional cut every degree up to 30° from fixation in the 270° meridian. In a previous article, 10 we analyzed a subsample of those patients in whom localized visual field defects did not develop and who completed 6 years of follow-up and found that there was no difference in the thresholds over time in the treated and untreated groups. In the optic nerve, the current study shows that all the disc changes showed a generalized en largement of the cup and, therefore, a reduction in the neuroretinal rim. This is an indication of diffuse loss of nerve fibers. In the description of the optic nerve head changes observed by Kass et al, 15 most changes also were diffuse in nature, even though in some of them it was the upper or lower rim that changed, but not in a localized way. It is possible, therefore, that pressure reduction with timolol does not influence the development of localized visual field defects, yet pressure may influence the changes at the optic disc. Further study is required to establish whether the fact that almost all the disc changes were diffuse diminutions of the rim while the field defects were localized scotomas was responsible for this difference. If it is confirmed that pressure is related to diffuse change but not to localized change, this could have important implications in the understanding of the pathogenesis of glaucomatous damage. The statistical design of the study by Kass et al 15 as sumed that pressure reduction would either be protective or not and did not allow for the possibility that pressure reduction or the drug might be detrimental. Therefore, a one-tailed sign test was used by the authors in their anal ysis, although a two-tailed sign test would have been more appropriate for this type of study, in which case none of their P-values would have attained any statistical signifi cance at a 0.05 level. Their survival curves also are based on the two eyes of the same individuals and are highly correlated. Therefore, standard survival analysis may not be applied. Epstein et al, 14 however, had an almost identical design to our study, but most of the perimetry in their study was manual and was only later changed to automatic perini 306
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etry. They had five patients, all in the untreated group, who had high lOPs and were called failures and appear to be included in the analysis as endpoints. Therefore, their criteria for endpoints are different from ours. With out those five patients, their untreated survival curves would be much closer to the treated survival curve. Fur thermore, in their analysis, all two-eyed subjects had their data averaged, which would tend to weaken any potential relationships between the survival time ofa failed eye and its corresponding covariates such as pressure or cup-to disc ratio. This may explain some of the apparently con tradictory results obtained by the two studies. We also have analyzed our survival times by including the high lOPs as endpoints; this has not altered our survival anal ysis. In the Discussion sections in both the article by Epstein et al 14 and the article by Kass et al, 15 very strong guidelines were given for practicing ophthalmologists to institute treatment of the suspect glaucoma eye because of the pro tective nature of the treatment. Our study, which was per formed in an almost identical manner to their studies, has not confirmed their findings. The incidence of visual field defects and probably disc changes in our study was not influenced by the treatment. In the untreated group, a relationship between the pressure level and the devel opment of changes in the disc over time was established. Therefore, we consider it important to further study on the relationship of pressure reduction to the underlying development ofglaucoma. Our clinical follow-up of these patients has not changed the conclusions reached from the rigorous study protocol. We would also like to suggest that if there is more than one mechanism of developing damage in glaucoma, as has been suggested, 16 there may be one group of patients who are pressure-sensitive and another group in whom pressure may be a lesser factor. Therefore, the differences between the various studies may be due to the chance composition of each study population as opposed to the differences in outcome. This may have some important implications for pressure reduction in the management of glaucoma and suspect glaucoma pa tients.
REFERENCES 1. Quigley HA, Addicks EM. Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci 1980; 19: 137 52. 2. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Ed ward Jackson Memorial Lecture Am J Ophthalmol 1989; 108:485 95. 3. Becker B, Morton WR. Topical epinephrine in glaucoma suspects. Am J Ophthalmol1966; 62:272-7. 4. Shin DH, Kolker AE, Kass MA, et at. Long-term epinephrine therapy of ocular hypertension. Arch Ophthalmol1976; 94:2059-60. 5. Kitazawa Y. Prophylactic therapy of ocular hypertension: a prospective study. Trans Ophthalmol Soc NZ 1981; 33:30-2.
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6. Graham PA. The definition of pre-glaucoma. A prospective study. Trans Ophthalmol Soc UK 1969; 88:153-65. 7. N0rskov K. Routine tonometry in ophthalmic practice. II. Five-year follow-up. Acta Ophthalmol 1970; 48:873-95. 8. Levene RZ. Uniocular miotic therapy. Trans Am Acad Ophthalmol Otolaryngol 1975; 79:376-80. 9. David R, Livingston DG, Luntz MH. Ocular hypertension- a long-term follow-up of treated and untreated patients. Br J Ophthalmol 1977; 61 :668-74. ' 10. Chauhan BC, Drance SM, Douglas GR. The effect of long-term intra ocular pressure reduction on the differential light sensitivity in glaucoma suspects. Invest Ophthalmol Vis Sci 1988; 29:1478-85. 11. Chisholm lA, Stead S, Tan L, Melenchuk JW. Prognostic indicators in ocular hypertension. Can J Ophthalmol 1980; 15:4-8.
12. Werner EB, Drance SM, Schulzer M. Trabeculectomy and the pro gression of glaucomatous visual field loss. Arch Ophthalmol 1977; 95:1374-7. 13. Dake CL, Greve EL. Four year follow-up of glaucoma operation. lnt Ophthalmol 1979; 1:139-45. 14. Epstein DL, Krug JH Jr, Hertzmark E, et al. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology 1989; 96:1460-7. 15. Kass MA, Gordon MO, Hoff MR, et al. Topical tirnolol administration reduced the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial. Arch Ophthalmol1989; 107:1590-8. 16. Schulzer M, Drance SM, Carter J, et al. Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 1990; 74:196-200.
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Abstract: One hundred forty-three patients with intraocular pressures (lOPs) above 22 mmHg and without visual field defects or any obvious evidence of optic nerve damage were randomly assigned to either a timolol treatment group or no treatment in a 6-year prospective clinical trial. Endpoints were defined as reproducible visual field defects on automatic perimetry, disc hemorrhages, or stereophotographically documented optic nerve head changes. Endpoints de veloped in 42 patients: 28 visual field defects, 8 changes in disc appearance, and 6 disc hemorrhages. Of the 42 patients, 20 were treated and 22 were not. Survival analysis showed no statistically significant differences in failure time to any endpoints between the two groups. In the untreated group, the time to failure of disc change was related to the mean lOP during the study and also to the changes in the lOP from baseline. A significant correlation was found between initial cup-to-disc ratio and survival time to visual field defects in the untreated group. Ophthalmology 1991; 98:301-307
The causal relationship between elevated intraocular pressure (lOP) and glaucoma-like changes at the optic nerve head has been established. 1 Anderson, 2 in his Jack son memorial lecture, examined the relationship between lOP and open-angle glaucoma and also the idea that other risk factors must be present. The evidence for success with medical pressure reduction in cases of damaged glaucoma eyes is still controversial, 3- 11 although the evidence that surgical pressure reduction favorably influences progres sion has been established. 12 • 13 Even if it were clearly es tablished that medical pressure reduction improved the prognosis for progression ofdamage in the glaucoma eye, the question as to whether medical pressure reduction in glaucoma suspects is beneficial would depend on, among other things, the number of people among the suspects who were at risk either from the height of the pressure
alone or from the presence of other factors that would make them susceptible to damage. The management of patients with ocular hypertension has been even more controversial and the published re ports on this subject are almost equally divided between those who find early medical treatment to be effective4 •5 and those who find no clear benefit from treatment. 6- 11 Two recent studies have shown that pressure reduction in glaucoma suspects with topical timolol favorably in fluences the subsequent development of glaucomatous damage. 14•15 The current study was undertaken 10 years ago with the same end in mind, namely to establish whether pressure reduction with timolol favorably altered the incidence of glaucomatous damage in glaucoma sus pects.
SUBJECTS AND METHODS Originally received: May 14, 1990. Revision accepted: November 7, 1990. From the Department of Ophthalmology and Medicine, University of British Columbia, Vancouver. Supported in part by a grant from Merck Sharp & Dohme Laboratories and Medical Research Council of Canada grant #1578. Presented in part at the Glaucoma Society of the International Congress of Ophthalmology, Bali, March 1990. Reprint requests to Stephen M. Drance, MD, Department of Ophthalmology, University of British Columbia, 2550 Willow St. Vancouver, British Columbia V5Z 3N9, Canada.
Our goal was to enroll 300 patients with elevated lOP and a greater risk of developing glaucomatous damage. Only 143 such patients were enrolled, two ofwhom failed to meet the criteria and four of whom failed to complete baseline evaluations (Table 1). For entry into the study, patients had to be between 45 and 70 years ofage. Thirty one percent of patients had a family history ofglaucoma. The untreated lOPs, measured with the Goldmann ap planation tonometer, had to be 22 mmHg or higher on at least three separate days. Twenty percent of patients 301
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Table 1. Outcome of Individuals in Trial
Recruited patients Did not meet criteria Completed 6 years Endpoints Dropouts Adverse drug reaction Died Intraocular pressure Branch vein occlusion Unreliable fields
Total
Treated
Untreated
143 2 63 42 22 2 3 5
70 2 28 21 12 2 2 2
73
1 3
35 21 10 1 3 1 2
had entry pressures of 30 mmHg or greater. All patients had to have previous normal manual visual fields on the Goldmann perimeter using the modified Armaly tech nique on at least two separate successive occasions. Pa tients had to have no obvious signs of acquired disc change characteristic of glaucoma. All cup-to-disc ratios were ac cepted, providing they were symmetric and there were no features of localized acquired disc change. Twenty-nine percent of patients had a cup-to-disc ratio of0.5 or greater. Patients were excluded from the study ifthey had evidence of ocular infections, intraocular surgery, or trauma within 3 months before the study. Also excluded were patients who wore contact lenses; had active keratitis within 3 months of starting the study; had increased intraocular pressure due to trauma or abnormalities preventing reli able tonometry; had disease states that could produce vi sual field loss such as multiple sclerosis, diabetic retinop athy, retinitis pigmentosa, or ischemic optic neuropathy; had bronchial asthma or chronic obstructive lung disease; patients who were of child-bearing age; and patients who had a resting pulse rate of 50 beats per minute or less or evidence of cardiac failure. Patients on systemic /3-blockers or clonidine or who were judged to be unreliable or poor compliers and those with unreliable visual fields or a visual acuity of 20/70 or less because of cataract also were ex cluded. Patients with severe systemic illnesses and those whose pupils did not dilate sufficiently for photography of the posterior pole also were excluded. After obtaining informed consent, all patients were randomly assigned to a timolol treatment group or to no treatment at all. The timolol treatment patients started with 0.25% timolol for 1 month, followed by 0.5% timolol for 1 month. The con centration that produced the greater pressure reduction was chosen for the patient. Those patients who started on 0.25% timolol and whose pressures appeared to gradually rise were placed on 0.5% timolol during the study. A full history of ocular symptoms, presence of other diseases, family history of glaucoma and other diseases, as well as a history of all topical and systemic drug ad ministration was obtained. The baseline ocular exami nation included visual acuity, slit-lamp examination, ophthalmoscopy, color-stereo photography, and three ex aminations on automatic perimeters, performed at least 2 days apart. Results of the three visual field tests had to 302
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be normal for inclusion in the study. Blood pressure, rest ing pulse rate, and a 2-hour postprandial blood sugar were measured and an electrocardiogram was recorded. At the start of the study, the Perimetron (Coherent Radiation, Palo Alto, CA) was the only available computerized pe rimeter. Kinetic isotopers to a I 2E, II 4E, and V 4E stim ulus were plotted on the perimeter. A special program for threshold static testing at 135 locations in the inner 30° was employed and any fields with points with a 0.5-decibel loss or a 5o nasal step were labeled as not normal and excluded. Approximately 6 months after the start of the study, the Peritest automatic perimeter (Rodenstock, Munich, Germany) became available. Subsequently, this instrument was used both for the initial screening of new patients and for all follow-up perimetry measurements. One patient, who showed normal results on baseline on the Perimetron, showed an abnormal reproducible point 6 decibels depressed on the first Peritest follow-up ex amination and was excluded from the study. Each patient was clinically re-evaluated once a month for 4 months; re-evaluation included tests for visual acuity, perimetry, tonometry, disc examination, blood pressure, and pulse recording. A glaucomatous visual field defect on the Peritest was reported in the presence of any two adjacent points with a depression of 6 decibels or more, any single isolated point with a depression of 10 decibels in the central 30°, any point immediately above or below the nasal horizontal with a depression of 0.6 decibels or more, any point within 5o of fixation with a depression of 0.4 decibels or more, and adjacent peripheral points depressed 10 decibels or more, providing this was not part of a generalized depression. After each follow-up exami nation, the visual fields were masked for evaluation. If the field was labeled abnormal by the predetermined cri teria, the test was repeated. For the abnormality to be confirmed, the second field had to show that the same point or points were "abnormal." In that case, the patient was re-examined on an Octopus 201 (Interzeag, North boro, MA) with programs 31, 32, 42, or later with Hum phrey programs 30-1, 30-2, and 68. Ifthe previously con firmed abnormal points on the two Peritest examinations also were abnormal on the Octopus or Humphrey perim eter, the visual field was called abnormal and the study was terminated for that patient or eye. If the field defect was not confirmed either on re-examination or third ex amination, the patient returned for the next four follow up visits. All discs were photographed annually and eval uated in masked fashion. The horizontal and vertical cup to-disc ratios were first recorded from the photograph, and then a comparison with the initial baseline photog raphy was made to identify any changes in the disc ap pearance. The masked photographic evidence of change of the disc constituted another endpoint and the patient discontinued the study. The occurrence of a disc hem orrhage also constituted an endpoint. The data were subjected to product-limit (Kaplan Meier) time-to-failure survival analysis, using log-rank tests to compare the survival experience ofthe two groups with respect to each failure event (disc change, disc hem orrhage, disc change or hemorrhage, field change, any of
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the above). Comparisons between the treated and un treated groups and between censored and failed individ uals were performed with respect to continuous covariates and continuous demographic variables using t tests and with chi-square tests on categorical variables. In addition, survival to each endpoint also was analyzed in the two groups using Cox's proportional hazards method adjusting for the following covariates: baseline lOP, mean postbaseline lOP over the follow-up period, mean lOP change (baseline- mean follow-up pressure), logarithm ofvariance ofpostbaseline lOP measurements, and baseline cup-to-disc ratio. When both eyes ofa patient were included in the study, the first eye to fail was ana lyzed, with its own covariate values. When neither eye failed, a random eye was selected for analysis. The time from first eye failure to second eye failure also was ana lyzed and compared in the two groups.
RESULTS The study was started in 1980 and the last patient com pleted 6 years offollow-up in December 1989. Of the 143 patients recruited into the study, 73 were assigned to the untreated control group and 70 to the treated group (Ta ble 1). Two patients failed to meet our entrance criteria, both from the treatment group (one had drusen of the optic nerve, and one had previous angle-closure glaucoma). Table 2. Covariate Values for Followed Patients* Controls (n = 70)
Treated (n = 67)
p
F 37 39 0.48 M 28 33 Family history of glaucoma Yes 21 21 0.85 No 49 46 Age (yrs) 59.28 ± 9.16 61.27 ± 11.61 0.27 Mean baseline lOP 26.1 ± 3.18 26.31 ± 3.49 0.69 (mmHg) Mean follow-up (post26.28 ± 4.34 21.77 ± 3.22 <0.001 baseline) lOP (mmHg) Mean lOP change from -0.19 ± 3.31 4.54 ± 3.89 <0.001 baseline (baseline lOP minus mean follow-up lOP) (mmHg) Mean baseline cup-to-disc 0.34 ± 0.17 0.35 ± 0.16 0.70 ratio Baseline systolic blood 138.74 ± 34.6 131.57 ± 37.10 0.24 pressure (mmHg) Baseline diastolic blood 81.06 ± 17.28 80.37 ± 20.48 0.83 pressure (mmHg) Baseline pulse rate per 71.54 ± 19.16 70.84 ± 18.39 0.83 minute lOP = intraocular pressure. * For continuous variables, means and standard deviations are given.
Table 3. Endpoints Field defects (28) Disc changes (8) Disc hemorrhages (6) Total
15 treated 13 controls 2 treated 6 controls 3 treated 3 controls
42
Four patients failed to complete the baseline examination, three in the control group and one in the treatment group, so that 137 patients were followed: 70 controls and 67 treated patients. The baseline characteristics of the treated and untreated groups are described in Table 2 and showed no statistically significant differences. Thirty-six patients were lost or discontinued during follow-up for reasons shown in Table 1. There were no significant differences between the dropouts and those who completed the study, except for the cup-to-disc ratio, which was larger among the dropouts: the mean cup-to-disc ratio of the dropouts was 0.36 ± 0.17, whereas the mean cup-to-disc ratio of the completed group was 0.29 ± 0.14 (P < 0.03). End points developed in 42 of the remaining 105 patients who were followed, and the remaining 63 patients completed the 6-year study. Among the dropouts, all deaths and reported sicknesses were unrelated to the use of topical ,6-blockers. The adverse reactions were due to topical ti molol. Of the five high lOPs that resulted in a discontin uation of the study, three occurred in patients in the un treated control group and two in patients in the treated group. In four patients, pressures rose to levels higher than 35 mmHg (27 to 40 mmHg, 39 to 50 mmHg, 27 to 45 mmHg, and 22 to 41 mmHg) and in the fifth patient (31 to 33 mmHg), a clinical decision that the pressures were too high was made. This was a patient on treatment in whom pilocarpine was added. At the present time, glau coma has not developed in any of these patients, but they were treated more intensively. Of the 42 endpoints, 28 were due to the development of abnormal visual fields using the predetermined criteria (Table 3). Eight were found photographically to have a change in the disc ap pearance and six were found to have a disc hemorrhage. Of the 42 patients, 20 were in the treatment group and 22 were in the untreated group. Among the 28 visual field defects, 15 were treated and 13 were not, whereas of the 8 patients with changes in the discs, 2 were treated and 6 were not. Among the six patients with disc hemorrhages, three were treated and three were not. The mean lOP during the study ofthe treatment group was 21.77 ± 3.22 mmHg, whereas the mean lOP of the control group was 26.28 ± 4.34 mmHg. These mean val ues were significantly lower in the treated group (P < 0.001). The mean pressures are illustrated in Figure 1, and the mean pressure differences and corresponding 95% confidence intervals at each observation time are given in Table 4. Survival analysis (Fig 2) showed that the treated group had a mean survival time of 2061 days before end point, whereas the untreated group had a mean survival 303
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time of 1942 days. These differences were not statistically significant. With our sample size and the number of pos itive events, a difference of 1 year survival would have been detected over 80% of the time and a difference in survival of 3 years would have been detected 100% of the time. The survival analysis was repeated on an "intent-to treat" basis, including the six patients who were random ized but not followed. A similar analysis also was per formed with the five patients who had been withdrawn from the study due to excessive lOP elevation analyzed as endpoints rather than as censored observations. In all cases, there was no statistically significant difference be tween the two survival curves. There also was no statistically significant difference in the survival curves of the two groups of the failure times between the first eye reaching endpoint and the second eye reaching endpoint when endpoint was reached in both. Analysis using Cox's model confirmed that even after ad justment for the covariates of lOP and cup-to-disc ratio, no significant difference could be detected in the survival pattern of the two groups with respect to any of the end points studied. However, highly significant interactions Table 4. Mean and 95% Confidence Intervals for the Intraocular Pressure Differences (mmHg) for the Followed Patients (Untreated Minus Treated) during the Study Time
Mean Difference
Baseline 6 months 12 months 18 months 24 months 30 months 36 months 42 months 48 months 54 months 60 months 66 months 72 months
-0.23 4.49 5.47 5.02 3.86 4.77 4.23 4.08 2.56 2.65 5.20 3.68 4.19
> ~ "'5 E
0.6
:::J
() 0.4.1__2L00----6_.0_0____ 1O.L.0_0---1-14L00----18-L0-0---2....200
Days
Fig 1. Mean intraocular pressures at each observation time in the followed patients, treated and untreated controls.
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E
E
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Confidence Interval (-1.35, (3.06, (4.10, (3.63, (2.08, (3.06, (2.37, (1.81' (0.40, (0.36, (2.52, (1.36, (2.03,
0.89) 5.92) 6.85) 6.42) 5.63) 6.47) 6.08) 6.35) 4.73) 4.94) 7.89) 6.01) 6.36)
Fig 2. Product-limit survival curves in the followed patients, treated and untreated controls. Endpoints are defined as developments offield defects, disc changes, or disc hemorrhages. Dropouts and cases followed to the end of the study without developing an endpoint are analyzed as censored observations.
were found between the survival experiences in the two groups and various covariates. In patients in the timolol-treated group, survival time to any of the endpoint criteria was found not to be sta tistically correlated with any of the covariates (i.e., the baseline cup-to-disc ratio, the baseline lOP level, the mean follow-up lOP level during treatment, or the mean lOP change). In the untreated group, however, survival correlated significantly with several of the co variates. In. particu~ar, for failure due to the development of change m the d1sc, defined as photographically demonstrable diminution of the neuroretinal rim, the untreated group showed a highly significant (P = 0.0004) correlation between survival time and the overall mean lOP level during the follow-up pe riod with shorter survival times corresponding to higher me;n lOP levels. The time until failure due to change in the disc in the untreated group also was correlated (P = 0.0042) with the mean change in lOP from baseline, so that a mean fall in lOP from baseline corresponded to a longer survival time and a mean rise corresponded to a shorter survival time. Table 2 indicates that the untreated group showed no significant systematic change in pressure from baseline over the follow-up period but had a wide range of pressure variations, with a standard deviation of mean pressure change (3.31 mmHg) similar to that of the treated group (3.89 mmHg). No significant correlation between survival and any of the covariates was found in either group when the devel opment of disc hemorrhage was considered as an end point. When the endpoint of visual field failure was con sidered, the survival time in the untreated group showed a highly significant (P = 0.0047) correlation with the initial cup-to-disc ratio, a larger ratio corresponding to a shorter survival time. Survival time to field change was not related to the overall mean lOP follow-up level. There was a cor relation in the untreated group (P = 0.026) between the mean change in lOP from baseline and survival time to visual field change; a mean fall in lOP from baseline sur
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prisingly corresponded to a shorter survival time, and a mean rise from baseline corresponded to a longer survival time. Fluctuations in lOP within patients over the follow-up period showed no statistical correlation with survival to any endpoint in either of the two groups.
CLINICAL FOLLOW-UP We have followed clinically 39 of the 42 patients who reached any of the study endpoints. In some patients, the additional follow-up has been as long as 3 years, whereas in others it has been only 8 months. Some of the patients who were in the untreated control group were started on therapy and others remained untreated. One of the re maining three patients on whom we have no further in formation had a cerebral venous malformation, which accounted for his field defects, whereas the remaining two patients were lost to follow-up. Of the 39 patients who were followed, 26 (67%) were clinically labeled as having glaucoma, 7 as a result of the photographically confirmed disc changes, I 6 as a result of further confirmed field de fects or their progression, and 3 because after their disc hemorrhages, field defects or disc changes subsequently developed. In the remaining 13 patients, the field defects were slight and even when confirmed on follow-up showed no progression, so that we were clinically uncertain as to their significance; three patients had a disc hemorrhage as endpoint and so far no other disc or field changes have taken place. Of the 26 patients who were clinically con firmed to have glaucoma, I 6 were in the treatment group of the study and 10 were in the untreated control group. Of the I 6 visual field study endpoints, I 2 were treated in the study and 4 were not, whereas of the 7 patients whose endpoints were the development of changes in the disc, only 2 were in the treated group and 5 were in the un treated control group. Further follow-up will almost cer tainly yield more definitive cases ofglaucoma. The clinical information does not change the statistical conclusions obtained with the rigorous protocol described in this study.
DISCUSSION At the present time, there is no agreement on whether medical treatment prevents or delays the onset of glau comatous damage in patients with elevated lOP. Long term follow-up has .shown that, each year, visual field de fects and/or optic disc changes develop in approximately 1% of patients with elevated lOP. The current study, which enrolled ocular hypertensive patients with additional risk factors to develop damage, showed a 4.9% per year inci dence for the development of glaucomatous end points: 3.4% developed field defects, 0.6% showed a disc hem orrhage, and 0.9% showed a disc change. Our figures
should, however, be compared with the 3.3% incidence rate found by Epstein et al 14 and 3.3% per year found by Kass et al. 15 Our population had 31 % of patients with a family history of damaging disease, 29% with a cup-to disc ratio of0.5 or greater at entry, and 20% with a baseline entry pressure of 30 mmHg or greater. Therefore, our population was at high risk and may have had some pre clinical disc features such as a uniformly enlarged cup when enrolled. The recent long-term prospective studies reported by Kass et al 15 and Epstein et al 14 both suggest that pressure reduction significantly decreases the inci dence of subsequent visual field defects in patients with elevated lOP. We enrolled a larger number of patients in the prospective study and randomly assigned them to a treatment with timolol group or a nontreatment group. Our study was done entirely with computerized perimetry, which minimizes observer bias and by disc photography, which was interpreted in a masked manner. The results of the study suggest that although the lOP was significantly lowered by the use of timolol, there was no significant difference in the incidence of glaucomatous field defects between the treated and untreated groups. The mean pressure reduction obtained in our study was 4.54 mmHg, which is of the same order obtained with timolol by Kass et al 15 and Epstein et al. 14 The mean level of lOP in the treated group in our study was 21.77 mmHg. This also was of the same order as in the other studies. It is, of course, possible that a greater pressure reduction than ob tained with timolol might have shown different results. Our study was undertaken at a time when timolol was first introduced and had a much better likelihood of pa tient compliance because of its lack of miosis and other ocular side effects and also at a time when computerized perimetry first became available, which allowed visual field data to be obtained with minimal observer bias. The use of photography of the optic nerve head in addition to ophthalmoscopy and the masked reading of the disc pho tographs allowed a more objective interpretation of any disc changes. We demanded three normal baseline fields, which included 135 central threshold estimations each time and excluded any patient who had a depression of 5 decibels in any of these fields. Our endpoint criterion for a field defect demanded that the same point have a depression confirmed three times to reduce false-positive results to a minimum. To date, we know from follow-up that at least 67% were true-positive results, a minimum estimate. Retrospectively, it is unfortunate that only ti molol was used for ·pressure reduction, but it was the only 13-blocker available at the time. Our study suggests that the pressure reduction obtained may not protect the sus ceptible individual from the development oflocalized vi sual field defects and possibly disc changes as well. This cannot be applied in general to pressure reduction, as it may only mean that pressure reduction produced by the nonspecific 13-blocker that we used and the pressure level that was obtained does not protect the susceptible individual from visual field defects. In our untreated group, there was a relationship between the mean lOP and the survival time to disc change: the higher the pres 305
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sure the shorter the survival time. The survival time to disc changes also was related to the mean lOP change from baseline; the greater the fall from baseline the longer the survival. In this untreated group, there also was are lationship between the baseline cup-to-disc ratio and the survival time of the visual field: the greater the cup-to disc ratio, the shorter the survival time to field change. The overall level ofiOP during the entire follow-up period in the untreated group did not relate to the survival time to visual field defect. In the untreated group, the mean lOP change from baseline was significantly related (P = 0.0206) to the survival time to visual field defect in a surprising way; the greater the mean fall of lOP from baseline, the shorter the survival time. The criteria for detecting visual field defects adopted by Kass et al, 15 Epstein et al, 14 and in our studies were developed to identify only scotomas that are localized vi sual field defects. In none of the studies was a generalized, diffuse loss of visual function pursued. Fortunately, we also performed a static meridional cut every degree up to 30° from fixation in the 270° meridian. In a previous article, 10 we analyzed a subsample of those patients in whom localized visual field defects did not develop and who completed 6 years of follow-up and found that there was no difference in the thresholds over time in the treated and untreated groups. In the optic nerve, the current study shows that all the disc changes showed a generalized en largement of the cup and, therefore, a reduction in the neuroretinal rim. This is an indication of diffuse loss of nerve fibers. In the description of the optic nerve head changes observed by Kass et al, 15 most changes also were diffuse in nature, even though in some of them it was the upper or lower rim that changed, but not in a localized way. It is possible, therefore, that pressure reduction with timolol does not influence the development of localized visual field defects, yet pressure may influence the changes at the optic disc. Further study is required to establish whether the fact that almost all the disc changes were diffuse diminutions of the rim while the field defects were localized scotomas was responsible for this difference. If it is confirmed that pressure is related to diffuse change but not to localized change, this could have important implications in the understanding of the pathogenesis of glaucomatous damage. The statistical design of the study by Kass et al 15 as sumed that pressure reduction would either be protective or not and did not allow for the possibility that pressure reduction or the drug might be detrimental. Therefore, a one-tailed sign test was used by the authors in their anal ysis, although a two-tailed sign test would have been more appropriate for this type of study, in which case none of their P-values would have attained any statistical signifi cance at a 0.05 level. Their survival curves also are based on the two eyes of the same individuals and are highly correlated. Therefore, standard survival analysis may not be applied. Epstein et al, 14 however, had an almost identical design to our study, but most of the perimetry in their study was manual and was only later changed to automatic perini 306
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etry. They had five patients, all in the untreated group, who had high lOPs and were called failures and appear to be included in the analysis as endpoints. Therefore, their criteria for endpoints are different from ours. With out those five patients, their untreated survival curves would be much closer to the treated survival curve. Fur thermore, in their analysis, all two-eyed subjects had their data averaged, which would tend to weaken any potential relationships between the survival time ofa failed eye and its corresponding covariates such as pressure or cup-to disc ratio. This may explain some of the apparently con tradictory results obtained by the two studies. We also have analyzed our survival times by including the high lOPs as endpoints; this has not altered our survival anal ysis. In the Discussion sections in both the article by Epstein et al 14 and the article by Kass et al, 15 very strong guidelines were given for practicing ophthalmologists to institute treatment of the suspect glaucoma eye because of the pro tective nature of the treatment. Our study, which was per formed in an almost identical manner to their studies, has not confirmed their findings. The incidence of visual field defects and probably disc changes in our study was not influenced by the treatment. In the untreated group, a relationship between the pressure level and the devel opment of changes in the disc over time was established. Therefore, we consider it important to further study on the relationship of pressure reduction to the underlying development ofglaucoma. Our clinical follow-up of these patients has not changed the conclusions reached from the rigorous study protocol. We would also like to suggest that if there is more than one mechanism of developing damage in glaucoma, as has been suggested, 16 there may be one group of patients who are pressure-sensitive and another group in whom pressure may be a lesser factor. Therefore, the differences between the various studies may be due to the chance composition of each study population as opposed to the differences in outcome. This may have some important implications for pressure reduction in the management of glaucoma and suspect glaucoma pa tients.
REFERENCES 1. Quigley HA, Addicks EM. Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure elevation on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci 1980; 19: 137 52. 2. Anderson DR. Glaucoma: the damage caused by pressure. XLVI Ed ward Jackson Memorial Lecture Am J Ophthalmol 1989; 108:485 95. 3. Becker B, Morton WR. Topical epinephrine in glaucoma suspects. Am J Ophthalmol1966; 62:272-7. 4. Shin DH, Kolker AE, Kass MA, et at. Long-term epinephrine therapy of ocular hypertension. Arch Ophthalmol1976; 94:2059-60. 5. Kitazawa Y. Prophylactic therapy of ocular hypertension: a prospective study. Trans Ophthalmol Soc NZ 1981; 33:30-2.
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6. Graham PA. The definition of pre-glaucoma. A prospective study. Trans Ophthalmol Soc UK 1969; 88:153-65. 7. N0rskov K. Routine tonometry in ophthalmic practice. II. Five-year follow-up. Acta Ophthalmol 1970; 48:873-95. 8. Levene RZ. Uniocular miotic therapy. Trans Am Acad Ophthalmol Otolaryngol 1975; 79:376-80. 9. David R, Livingston DG, Luntz MH. Ocular hypertension- a long-term follow-up of treated and untreated patients. Br J Ophthalmol 1977; 61 :668-74. ' 10. Chauhan BC, Drance SM, Douglas GR. The effect of long-term intra ocular pressure reduction on the differential light sensitivity in glaucoma suspects. Invest Ophthalmol Vis Sci 1988; 29:1478-85. 11. Chisholm lA, Stead S, Tan L, Melenchuk JW. Prognostic indicators in ocular hypertension. Can J Ophthalmol 1980; 15:4-8.
12. Werner EB, Drance SM, Schulzer M. Trabeculectomy and the pro gression of glaucomatous visual field loss. Arch Ophthalmol 1977; 95:1374-7. 13. Dake CL, Greve EL. Four year follow-up of glaucoma operation. lnt Ophthalmol 1979; 1:139-45. 14. Epstein DL, Krug JH Jr, Hertzmark E, et al. A long-term clinical trial of timolol therapy versus no treatment in the management of glaucoma suspects. Ophthalmology 1989; 96:1460-7. 15. Kass MA, Gordon MO, Hoff MR, et al. Topical tirnolol administration reduced the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial. Arch Ophthalmol1989; 107:1590-8. 16. Schulzer M, Drance SM, Carter J, et al. Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 1990; 74:196-200.
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