Intraocular Pressure Reduction in Normal,tension Glaucoma Patients Michael Schulzer, MD, PhD, The Normal Tension Glaucoma Study Group Background: In a collaborative study, patients with untreated normal-tension glaucoma were randomly assigned to a marked intraocular pressure reduction group or to a no therapy group. It was anticipated that medical therapy and laser trabeculoplasty would generally not achieve adequate pressure lowering and that fistulizing surgery would be required. This hypothesis was examined using current observations in the study. Methods: Patients randomized to the therapy group had a pressure reduction of at least 30% from their last prerandomization level. This was achieved within 6 months by means of fistulizing surgery or with pilocarpine and/or laser trabeculoplasty. Betablockers and adrenergic agonists were excluded from both eyes. Results: Of 30 patients with documented stable 30% pressure reduction, 17 (57%) achieved this with topical medication and/or laser trabeculoplasty: 8 with pilocarpine alone, 2 with laser trabeculoplasty alone, and 7 with laser trabeculoplasty after initial topical medication. The remaining 13 (43%) patients required a single fistulizing procedure. There was no statistically significant difference between the mean follow-up time for the nonfistulized group (533.8 ± 437.6 days) and for the fistulized group (502.7 ± 344.7 days). Both treatment groups had similar baseline profiles. Conclusion: Marked pressure reduction can be achieved and maintained on a longterm basis by means other than fistulizing surgery in a large proportion of patients with untreated normal-tension glaucoma. Ophthalmology 1992;99:1468-1470
We are currently conducting a collaborative randomized controlled clinical trial of the effectiveness of intraocular pressure reduction in slowing the progression offield loss in normal-tension glaucoma. This study is sponsored by the Foundation for Glaucoma Research in San Francisco, and currently involves 26 centers from throughout the United States, Canada, Japan, the Netherlands, and Finland. It has been reported 1,2 that therapy is ineffective in preventing visual field loss in patients with normal-tension Originally received: November 25, 1991. Revision accepted: March 9, 1992. From the Department of Medicine, the Department of Statistics, and the Department of Ophthalmology, University of British Columbia, Vancouver, and the Bascom Palmer Eye Institute, Department ofOphthalmology, University of Miami, School of Medicine, Miami. Supported in part by The Foundation for Glaucoma Research, San Francisco, California. Presented at the American Academy of Ophthalmology Annual Meeting, Anaheim, October 1991. Reprint requests to Michael Schulzer, MD, PhD, Department of Medicine, University of British Columbia, Laurel Pavilion, 910 W 10th Ave, Vancouver, British Columbia V5Z 4E3, Canada.
1468
glaucoma. However, it remains unclear whether this poor outcome results from ineffectiveness of pressure lowering in haIting progressive visual field loss, or from the difficulty in achieving adequate pressure lowering from baseline levels when the pressure is in the normal range to begin with. For this reason, our study is designed to examine potential visual benefits when 30% lowering of pressure is not simply attempted but actually achieved. These benefits, if proven, are to be compared with the potentially adverse visual effects from the aggressive therapy that might be required to achieve this pressure-lowering goal. We had expected that medical therapy and laser trabeculoplasty usually would not achieve adequate pressure lowering in cases of normal-tension g1aucoma3 and that incisional surgery would be required. Our current observations negate this assumption and are reported below.
Materials and Methods To be eligible, patients with normal-tension glaucoma must have glaucomatous excavation of the optic disc and characteristic''\'isual field loss by automated static thresh-
Schulzer et al . lOP Reduction in Normal-tension Glaucoma old perimetry (a localized defect with a cluster of adjacent 3 nonedge points depressed 5 decibels [dB] from the average normal value for age, and a nucleus of at least 1 point depressed 10 dB from the normal value for age). There must be no history of intraocular pressure (lOP) greater than 24 mmHg and on 10 baseline measurements after a washout period of 1 month, the median must be 20 mmHg or less, with 9 of the 10 readings 22 mmHg or less and all readings 24 mmHg or less. Randomization occurs if or when the visual field is shown to be a progressive one, or if the disc changes or a disc hemorrhage occurs, or the field defect impinges on and threatens fixation. Only one eye of each patient is entered into the study and is randomly assigned either to an untreated control group or to a group that is to have its pressure reduced. After randomization, the visual field is evaluated every 3 months until it reaches an end point, which consists of a defined subtle but definite progression in visual field loss or a change of the optic nerve head. Disc hemorrhage is not considered an end point. Randomization to the "treatment" group requires an lOP reduction of at least 30% from the last prerandomization levels. Pressure reduction must be achieved within 6 months and may be attained with fistulizing surgery or with pilocarpine and/or laser trabeculoplasty. Throughout the study period, beta-blockers and adrenergic agonists, because of their potential vasoactive actions, were excluded from both eyes. Systemic carbonic anhydrase inhibitors were not used to treat the opposite eye if the study eye had been randomized to the untreated control group.
Statistical Methods The means of continuous, symmetrically distributed variables were compared with t tests. Continuous variables that violated basic regularity assumptions were transformed logarithmically to satisfy requirements for parametric analysis. Categorical variables were compared with contingency tables (chi-square).
Results Up to this time, we have randomized 41 patients to the "treatment" group. In 30 of these patients, stable 30% pressure reductions already have been documented. Because our center does not receive information about the type or success of treatment until stabilization has been achieved, we have as yet no data on the remaining 11 patients. We report here on fistulizing surgery versus medical therapy and laser trabeculoplasty as a means of achieving and maintaining the stable pressure reduction of at least 30% in these patients. Of the 30 patients who have achieved stable 30% pressure reduction, requiring no further corrective intervention, 17 achieved this and maintained it with topical medication and/or a laser trabeculoplasty; 13 required a single fistulizing procedure. Of the 17 patients not requiring fistulizing surgery, 8 were maintained successfully on pilocarpine alone, 2 with laser trabeculoplasty alone,
and 7 required laser trabeculoplasty after initial topical medication. Of the 13 fistulized patients, 10 preceded the filtering surgery with pilocarpine and/or laser trabeculoplasty on randomization to the "treatment" group: 1 of them received only pilocarpine, 5 were treated only with lasers, and 4 received pilocarpine followed by laser trabeculoplasty, before fistulizing surgery was ultimately required to achieve and to maintain the stable reduced pressure. The median time interval for these 10 patients from initial therapy to final fistulizing surgery was 3 months (mean time, 5 ± 6.9 months). The remaining three patients in the fistulizing surgery group received filtering therapy directly after they were randomized. The mean follow-up time of the non fistulized group (from time of stabilization to present) was 533.8 days (±437.6); the corresponding mean time interval for the fistulized group was 502.7 days (±344.7); this difference was not statistically significant. Table 1 indicates that the fistulized and the nonfistulized groups had similar baseline profiles, with only a marginal difference in mean corrected pattern standard deviation (CPS D) (P = 0.05), where the mean CPSD of the fistulized group was slightly larger. Although the prerandomization lOP levels were statistically comparable in the two groups, the mean percent drop in pressure accomplished with fistulizing surgery was significantly greater than that achieved with topical therapy and laser (fistulizing group: 44.9% [± 13.3]; nonfistulizing group: 35.7% [±7.1]; P = 0.022).
Discussion In designing the normal-tension glaucoma study, we had expected that incisional surgical intervention would usually be required to reduce the lOP of normal-tension glaucoma patients by at least 30% and to maintain it at that level. Therefore, we had not anticipated that we would achieve a success rate of 57% (17 of 30) by topical therapy and laser alone, and, indeed, a success rate of 27% (8 of 30) with pilocarpine alone. It is quite possible that these rates underestimate the theoretical success rate that might be achieved without incisional surgery, since the choice of method of intervention in randomized eyes (medication, laser trabeculoplasty, or fistulizing procedure) was left to the discretion of each collaborating investigator; in 3 of the 13 fistulized cases, medication had not been attempted before surgery. Although our protocol called for repeated incisional surgical interventions if needed to achieve the 30% reduction of pressure, a single surgical intervention succeeded in all 13 cases in achieving and maintaining a stable pressure reduction. The incisional surgical and the topical medication and laser trabeculoplasty groups had similar demographic and ocular profiles and differed only in the degree of pressure reduction achieved (45% reduction in the incisional surgical group versus 36% in the nonfistulized group). We conclude that marked pressure reduction of at least 30% can be achieved and maintained on a long-term basis (mean follow-up time, 534 days) by means other than fistulizing surgery in a large proportion of untreated nor-
1469
Ophthalmology
Volume 99, Number 9, September 1992
Table 1. Profile Comparison Between the Fistulized and the Nonfistulized Groups Fistulized Group (n
Age (yrs) Prerandomization intraocular pressure (mmHg) Percent rop drop Visual acuity Cup-to-disc ratio Vertical Horizontal Mean deviation Short-term fluctuation Corrected pattern standard deviation
lOP
=
13)
=
=
17)
Mean
Standard Deviation
Range
Mean
Standard Deviation
Range
PValue
68.5
7.8
55- 79
69.4
8.8
45-81
0.75
15.5 44.9 0.85
2.1 13.3 0.15
12.0-19.0 27.8-69.0 0.67- 1.00
16.8 35.7 0.88
2.8 7 .1 0.14
12.0-21.0 25.6- 54.2 0.67-1.00
0.20 0.Q2 0.83
0.81 0.73 - 11.5 2.2
0.14 0.22 5.9 1.4
0.50-1.00 0.40-1.00 (-20.1)-(-1.4) 0.6-5.7
0.82 0.76 -9.0 2 .2
0.13 0.15 5.6 1.0
0.40-1.00 0.30-0.90 (-17.6)-(-1.2) 1.1-4.5
0.80 0.53 0.27 0.48
12.0
3.5
5.8-15.9
9 .0
3.4
intraocular pressure.
mal-tension glaucoma patients. It follows that nonincisional surgical treatment can be seriously considered when attempting to reduce pressure in that group of patients. We want to emphasize that our results have been obtained from otherwise untreated patients. Had these patients already received other medications, the pilocarpine and/or laser effects may have been smaller, but we have no information to confirm or deny this in our studies. It also should be stressed at this point that although we have documented that both methods of therapy were quite successful in lowering the pressure, we have not yet documented that lowering the pressure is of benefit in halting visual loss in normal-tension glaucoma. We also do not know how often or to what degree aggressive therapy will produce adverse visual effects, for example from miosis, long-term cataract formation, or macular edema. This is still being addressed by the ongoing clinical trial.
Appendix Members of the Normal Tension Glaucoma Study Group: Dr. P. J. Airaksinen, Dr. W. L. M. Alward, Dr. M. Amyot, Dr. D. R. Anderson, Dr. G . Balazsi, Dr. P. Blondeau, Dr. L. F. Cashwell, Dr. J. Cohen, Dr. D.Desjardins, Dr. C. Dickens, Dr.
1470
Nonfistulized Group (n
2.5-14.5
0.05
G . R. Douglas, Dr. S. M. Drance, Dr. F. Feldman, Dr. H . C. Geijssen, Dr. A. Grajewski, Dr. E. Greve, Dr. J . Hetherington, Dr. D. Heuer, Dr. E. Hodapp, Dr. H .D. Hoskins, Dr. A. Iwach, Dr. H . Jampel, Dr. O. Kasner, Dr. Y. Kitazawa, Dr. R. Komulainen, Dr. R. Levene, Dr. J . Liebmann, Dr. F. S. Mikelberg, Dr. R. Mills, Dr. D. Minckler, Dr. M. Motolko, Dr. I. Pollack, Dr. H. Quigley, Dr. R. Ritch, Dr. E. G. Rosanelli, Dr. A. Schwartz, Dr. S. Shirato, Dr. G. Skuta, Dr. G. Tomita, Dr. G. Trope, Dr. A. Tuulonen, Dr. J. Wilensky. Data and Safety M onitoring Committee: Dr. D. R. Anderson, Dr. J. G. Clarkson, Dr. S. M. Drance, Dr. S. Litinsky, Dr. R. Prineas, Dr. A. W. Rose, Ms. Joyce Schiffman, Dr. M. Schulzer, Mrs. Tara Steele.
References I. Chumbley LC, Brubaker RF. Low-tension glaucoma. Am J OphthalmoI1976;81:761-7. 2. Gliklich RE, Steinmann WC, Spaeth GL. Visual field change in low-tension glaucoma over a five-year follow-up. Ophthalmology 1989;96:316-20. 3. Abedin S, Simmons RJ, Grant WM. Progressive low-tension glaucoma. Treatment to stop glaucomatous cupping and field loss when these progress despite normal intraocular pressure. Ophthalmology 1982;89: 1-6.
We are currently conducting a collaborative randomized controlled clinical trial of the effectiveness of intraocular pressure reduction in slowing the progression offield loss in normal-tension glaucoma. This study is sponsored by the Foundation for Glaucoma Research in San Francisco, and currently involves 26 centers from throughout the United States, Canada, Japan, the Netherlands, and Finland. It has been reported 1,2 that therapy is ineffective in preventing visual field loss in patients with normal-tension Originally received: November 25, 1991. Revision accepted: March 9, 1992. From the Department of Medicine, the Department of Statistics, and the Department of Ophthalmology, University of British Columbia, Vancouver, and the Bascom Palmer Eye Institute, Department ofOphthalmology, University of Miami, School of Medicine, Miami. Supported in part by The Foundation for Glaucoma Research, San Francisco, California. Presented at the American Academy of Ophthalmology Annual Meeting, Anaheim, October 1991. Reprint requests to Michael Schulzer, MD, PhD, Department of Medicine, University of British Columbia, Laurel Pavilion, 910 W 10th Ave, Vancouver, British Columbia V5Z 4E3, Canada.
1468
glaucoma. However, it remains unclear whether this poor outcome results from ineffectiveness of pressure lowering in haIting progressive visual field loss, or from the difficulty in achieving adequate pressure lowering from baseline levels when the pressure is in the normal range to begin with. For this reason, our study is designed to examine potential visual benefits when 30% lowering of pressure is not simply attempted but actually achieved. These benefits, if proven, are to be compared with the potentially adverse visual effects from the aggressive therapy that might be required to achieve this pressure-lowering goal. We had expected that medical therapy and laser trabeculoplasty usually would not achieve adequate pressure lowering in cases of normal-tension g1aucoma3 and that incisional surgery would be required. Our current observations negate this assumption and are reported below.
Materials and Methods To be eligible, patients with normal-tension glaucoma must have glaucomatous excavation of the optic disc and characteristic''\'isual field loss by automated static thresh-
Schulzer et al . lOP Reduction in Normal-tension Glaucoma old perimetry (a localized defect with a cluster of adjacent 3 nonedge points depressed 5 decibels [dB] from the average normal value for age, and a nucleus of at least 1 point depressed 10 dB from the normal value for age). There must be no history of intraocular pressure (lOP) greater than 24 mmHg and on 10 baseline measurements after a washout period of 1 month, the median must be 20 mmHg or less, with 9 of the 10 readings 22 mmHg or less and all readings 24 mmHg or less. Randomization occurs if or when the visual field is shown to be a progressive one, or if the disc changes or a disc hemorrhage occurs, or the field defect impinges on and threatens fixation. Only one eye of each patient is entered into the study and is randomly assigned either to an untreated control group or to a group that is to have its pressure reduced. After randomization, the visual field is evaluated every 3 months until it reaches an end point, which consists of a defined subtle but definite progression in visual field loss or a change of the optic nerve head. Disc hemorrhage is not considered an end point. Randomization to the "treatment" group requires an lOP reduction of at least 30% from the last prerandomization levels. Pressure reduction must be achieved within 6 months and may be attained with fistulizing surgery or with pilocarpine and/or laser trabeculoplasty. Throughout the study period, beta-blockers and adrenergic agonists, because of their potential vasoactive actions, were excluded from both eyes. Systemic carbonic anhydrase inhibitors were not used to treat the opposite eye if the study eye had been randomized to the untreated control group.
Statistical Methods The means of continuous, symmetrically distributed variables were compared with t tests. Continuous variables that violated basic regularity assumptions were transformed logarithmically to satisfy requirements for parametric analysis. Categorical variables were compared with contingency tables (chi-square).
Results Up to this time, we have randomized 41 patients to the "treatment" group. In 30 of these patients, stable 30% pressure reductions already have been documented. Because our center does not receive information about the type or success of treatment until stabilization has been achieved, we have as yet no data on the remaining 11 patients. We report here on fistulizing surgery versus medical therapy and laser trabeculoplasty as a means of achieving and maintaining the stable pressure reduction of at least 30% in these patients. Of the 30 patients who have achieved stable 30% pressure reduction, requiring no further corrective intervention, 17 achieved this and maintained it with topical medication and/or a laser trabeculoplasty; 13 required a single fistulizing procedure. Of the 17 patients not requiring fistulizing surgery, 8 were maintained successfully on pilocarpine alone, 2 with laser trabeculoplasty alone,
and 7 required laser trabeculoplasty after initial topical medication. Of the 13 fistulized patients, 10 preceded the filtering surgery with pilocarpine and/or laser trabeculoplasty on randomization to the "treatment" group: 1 of them received only pilocarpine, 5 were treated only with lasers, and 4 received pilocarpine followed by laser trabeculoplasty, before fistulizing surgery was ultimately required to achieve and to maintain the stable reduced pressure. The median time interval for these 10 patients from initial therapy to final fistulizing surgery was 3 months (mean time, 5 ± 6.9 months). The remaining three patients in the fistulizing surgery group received filtering therapy directly after they were randomized. The mean follow-up time of the non fistulized group (from time of stabilization to present) was 533.8 days (±437.6); the corresponding mean time interval for the fistulized group was 502.7 days (±344.7); this difference was not statistically significant. Table 1 indicates that the fistulized and the nonfistulized groups had similar baseline profiles, with only a marginal difference in mean corrected pattern standard deviation (CPS D) (P = 0.05), where the mean CPSD of the fistulized group was slightly larger. Although the prerandomization lOP levels were statistically comparable in the two groups, the mean percent drop in pressure accomplished with fistulizing surgery was significantly greater than that achieved with topical therapy and laser (fistulizing group: 44.9% [± 13.3]; nonfistulizing group: 35.7% [±7.1]; P = 0.022).
Discussion In designing the normal-tension glaucoma study, we had expected that incisional surgical intervention would usually be required to reduce the lOP of normal-tension glaucoma patients by at least 30% and to maintain it at that level. Therefore, we had not anticipated that we would achieve a success rate of 57% (17 of 30) by topical therapy and laser alone, and, indeed, a success rate of 27% (8 of 30) with pilocarpine alone. It is quite possible that these rates underestimate the theoretical success rate that might be achieved without incisional surgery, since the choice of method of intervention in randomized eyes (medication, laser trabeculoplasty, or fistulizing procedure) was left to the discretion of each collaborating investigator; in 3 of the 13 fistulized cases, medication had not been attempted before surgery. Although our protocol called for repeated incisional surgical interventions if needed to achieve the 30% reduction of pressure, a single surgical intervention succeeded in all 13 cases in achieving and maintaining a stable pressure reduction. The incisional surgical and the topical medication and laser trabeculoplasty groups had similar demographic and ocular profiles and differed only in the degree of pressure reduction achieved (45% reduction in the incisional surgical group versus 36% in the nonfistulized group). We conclude that marked pressure reduction of at least 30% can be achieved and maintained on a long-term basis (mean follow-up time, 534 days) by means other than fistulizing surgery in a large proportion of untreated nor-
1469
Ophthalmology
Volume 99, Number 9, September 1992
Table 1. Profile Comparison Between the Fistulized and the Nonfistulized Groups Fistulized Group (n
Age (yrs) Prerandomization intraocular pressure (mmHg) Percent rop drop Visual acuity Cup-to-disc ratio Vertical Horizontal Mean deviation Short-term fluctuation Corrected pattern standard deviation
lOP
=
13)
=
=
17)
Mean
Standard Deviation
Range
Mean
Standard Deviation
Range
PValue
68.5
7.8
55- 79
69.4
8.8
45-81
0.75
15.5 44.9 0.85
2.1 13.3 0.15
12.0-19.0 27.8-69.0 0.67- 1.00
16.8 35.7 0.88
2.8 7 .1 0.14
12.0-21.0 25.6- 54.2 0.67-1.00
0.20 0.Q2 0.83
0.81 0.73 - 11.5 2.2
0.14 0.22 5.9 1.4
0.50-1.00 0.40-1.00 (-20.1)-(-1.4) 0.6-5.7
0.82 0.76 -9.0 2 .2
0.13 0.15 5.6 1.0
0.40-1.00 0.30-0.90 (-17.6)-(-1.2) 1.1-4.5
0.80 0.53 0.27 0.48
12.0
3.5
5.8-15.9
9 .0
3.4
intraocular pressure.
mal-tension glaucoma patients. It follows that nonincisional surgical treatment can be seriously considered when attempting to reduce pressure in that group of patients. We want to emphasize that our results have been obtained from otherwise untreated patients. Had these patients already received other medications, the pilocarpine and/or laser effects may have been smaller, but we have no information to confirm or deny this in our studies. It also should be stressed at this point that although we have documented that both methods of therapy were quite successful in lowering the pressure, we have not yet documented that lowering the pressure is of benefit in halting visual loss in normal-tension glaucoma. We also do not know how often or to what degree aggressive therapy will produce adverse visual effects, for example from miosis, long-term cataract formation, or macular edema. This is still being addressed by the ongoing clinical trial.
Appendix Members of the Normal Tension Glaucoma Study Group: Dr. P. J. Airaksinen, Dr. W. L. M. Alward, Dr. M. Amyot, Dr. D. R. Anderson, Dr. G . Balazsi, Dr. P. Blondeau, Dr. L. F. Cashwell, Dr. J. Cohen, Dr. D.Desjardins, Dr. C. Dickens, Dr.
1470
Nonfistulized Group (n
2.5-14.5
0.05
G . R. Douglas, Dr. S. M. Drance, Dr. F. Feldman, Dr. H . C. Geijssen, Dr. A. Grajewski, Dr. E. Greve, Dr. J . Hetherington, Dr. D. Heuer, Dr. E. Hodapp, Dr. H .D. Hoskins, Dr. A. Iwach, Dr. H . Jampel, Dr. O. Kasner, Dr. Y. Kitazawa, Dr. R. Komulainen, Dr. R. Levene, Dr. J . Liebmann, Dr. F. S. Mikelberg, Dr. R. Mills, Dr. D. Minckler, Dr. M. Motolko, Dr. I. Pollack, Dr. H. Quigley, Dr. R. Ritch, Dr. E. G. Rosanelli, Dr. A. Schwartz, Dr. S. Shirato, Dr. G. Skuta, Dr. G. Tomita, Dr. G. Trope, Dr. A. Tuulonen, Dr. J. Wilensky. Data and Safety M onitoring Committee: Dr. D. R. Anderson, Dr. J. G. Clarkson, Dr. S. M. Drance, Dr. S. Litinsky, Dr. R. Prineas, Dr. A. W. Rose, Ms. Joyce Schiffman, Dr. M. Schulzer, Mrs. Tara Steele.
References I. Chumbley LC, Brubaker RF. Low-tension glaucoma. Am J OphthalmoI1976;81:761-7. 2. Gliklich RE, Steinmann WC, Spaeth GL. Visual field change in low-tension glaucoma over a five-year follow-up. Ophthalmology 1989;96:316-20. 3. Abedin S, Simmons RJ, Grant WM. Progressive low-tension glaucoma. Treatment to stop glaucomatous cupping and field loss when these progress despite normal intraocular pressure. Ophthalmology 1982;89: 1-6.
