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The glaucoma laser trial
ELSEVIER
Clinical Eye and Vision Care 8 (1996) 51-54
News and views
The glaucoma laser trial Timothy Harkins VA Medical
Center,
4801 Linwood
1. Introduction Glaucoma is an important cause of visual loss and its management can be frustrating. Despite an increasing arsenal of topical medications to control intraocular pressure (IOP), none of these medications is without shortcomings. Significant improvements have been made in filtering surgery, but a less invasive procedure would be preferred. Argon laser trabeculoplasty (ALT) does lower IOP and is a suitable treatment option for many patients. It is unclear, however, when ALT should be performed. The Glaucoma Laser Trial (GLT) was designed to compare the safety and efficacy of ALT to topical medications for controlling IOP in newly diagnosed primary open angle glaucoma (POAG) [l-61. 2. Study design The glaucoma laser trial was a randomized, controlled, multicentered study that involved 271 patients [1,2]. Each patient was newly diagnosed with primary open angle glaucoma. Once a patient was entered into the study, each eye was randomly assigned to a different therapy. One eye was treated with 360” of ALT (performed in two sessions separated by 4 weeks). At each session, 180” of trabecular meshwork was treated with 45-50 burns, 50 pm in size, with a 0.1 second pulse of argon blue-green laser. The beam was focused at the junction of the pigmented and non-pigmented anterior trabecular meshwork. The power was adjusted to the threshold of bubble formation (600-1200 mW). Patients used a topical anti-inflammatory agent four times per day for 6 days following each procedure. The other eye was treated with ocular hypotensive medicines. The medicine prescribed first - 0.5% timolol - was predetermined by the study design. If patients failed with timolol, the subsequent steps in medical therapy (and their order) were also predetermined. The steps are summarized in Table 1. A
Boulevard,
Kansas
City, MO 64128,
USA
patientcould be on any of four medicines alone (timolol, dipivefrin, low-dose pilocarpine, or high-dose pilocarpine), or on combination therapy of high-dose pilocarpine with either timolol or dipivefrin. Three outcome measures have been reported. The first was frequency of complications secondary to ALT - specifically IOP rises, the development of peripheral anterior synechia (PAS), and anterior segment inflammation. The second compared the abilities of ALT and medications to lower IOP to a target pressure. The third compared the effects of ALT and medical therapies on visual field progression. 3. AL,T complications There was a 5 mmHg IOP rise in 34% of patients, and 12% had a rise of 10 mmHg or more at one or both sessions [3]. IOP rises occur frequently enough that they should be anticipated, sought out, and reversed. They can also be virtually eliminated with pre-laser and post-laser use of 1% apraclonidine [7]. PAS of at least 1” developed in 46% of patients, and 33% of patients had PAS that extended to the trabecular meshwork. PAS formation was more likely in patients with brown hides and if the laser burns were placed too posteriorly. The authors did not give more detail about the size or extent of the PAS formation, just that a PAS of at least 1” was observed in these patients. Rare PAS of 1” in a patient would be unimportant, but multiple PAS might adversely affect outflow and IOP. Though the authors did not give more detail about the extent of PAS formation in their patients, they state that their formation does not contraindicate future use of ALT. In their 2-year report, the authors showed that the ALT patients with PAS required fewer medications to control IOP than those without PAS, implying their formation is of little consequence [4]. Despite the use of anti-inflammatory agents, anterior segment inflammation was present in 7% of
0953-4431/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PlI:SO953-4431(96)00155-5
Table I Medication
i-able 2 ._’ year data: IOP control
steps
step 1: step 2: step 3: step 4: step 5: step 6:
0.5% timolol 0.1% dipivefrin Low-dose pilocarpine High-dose pilocarpinc Timolol with pilocarpine Dipivefrin with pilocarpine
patients 1 week after their ALT. The authors did not report on the severity of the inflammation. They also did not study whether the anti-inflammatory agents reduced the rate and severity of post-laser iritis, but intuition tells us that they would help. ALT is a relatively safe, but not entirely benign procedure. Its short-term complications include IOP rises and inflammation. It seems wise to reduce the likelihood of these complications with pre- and postlaser 1% apraclonidine, and with topical anti-inflammatory agents for 1 week after the procedure. 4. IOP control
In 1990, the GLT research group reported their two year results of IOP control. Criteria for failure were: (1) IOP greater than 22 or a reduction less than 20% from baseline; (2) visual field deterioration; (3) optic nerve deterioration; or (4) adverse reactions to the medicine [4]. After 2 years, 44% of patients treated with ALT alone had adequate IOP reduction. 56% of laser treated eyes needed additional medical therapy during the first 2 years. In eyes which did not receive laser, 51% were adequately controlled for 2 years on a single medicine (timolol, dipivefrin, or pilocarpine) and 66% were controlled on one or two medicines. The 2-year data showed that the majority of ALT patients needed medication to control their IOP, but that ALT did reduce the number of medicines required for many patients. Table 2 shows that 44% of patients who had laser were controlled without any medicine, 84% were controlled with a single medicine added to laser (51% of non-laser patients were controlled on a single medicine) and 89% were controlled by two medicines added to laser (66% of non-laser patients were controlled by two medicines). The argument that timolol could crossover and lower the IOP in the laser treated eye was adequately answered. The crossover effect was only 0.5 mmHg not enough to alter the results of IOP or visual field data [51. 5. Visual field changes
In 1995, the GLT research group published their
Percent
of patients
requiring
one or two medicines
Medicine ALT One Two
only medicine medicines
for
first
N/A 51 Ch 66%
3.5 year data comparing visual field deterioration in patients treated with laser first to those treated with medicine first [6]. Unfortunately, the data do not tell us how the visual fields fared if patients were treated with laser alone, because 64% of laser first patients received additional therapy during the 3.5 years. We do know that 36% of eyes required only laser (and presumably did not have visual field deterioration), 64% required the addition of medicine, and that 7% required filtering surgery or oral medication. Patients treated with medicine first also required filtering surgery or oral medication 7% of the time. As stated, most laser first patients received additional therapy, so the visual field results of these patients do not tell us how patients did with laser alone. The results do not compellingly argue for or against laser first therapy. The average mean threshold for laser first eyes was 0.3 db higher than for medicine first eyes - a statistically, but not clinically significant number. ‘Confirmed’ deterioration (two consecutive fields that were worse than baseline) occurred in 23% of laser first eyes and in 31% of medicine first eyes. At first glance, this seems important, but most ‘confirmed’ field losses in fact subsequently returned to baseline status. Persistent visual field loss occurred in far fewer patients - 12% of laser first eyes and 14% of medicine first eyes. This was not a statistically significant difference. Curiously, in each group the visual field appeared to improve more often than it appeared to deteriorate. Disturbingly, the patients who had progression had the same IOP reduction as those who did not progress. 6. Clinical implications
Our obligation in evaluating the GLT is to determine how it will effect our clinical decisions. The results have taught us that ALT is a safe procedure, that sometimes it succeeds as sole glaucoma therapy, that its initial use can reduce the need for single or multiple medicines, and it taught us something about the interpretation of visual field data (clinically and in large studies). Severe complications from ALT are uncommon. Significant IOP rises can occur, but they are consider-
T Harkins
/Clinical
Eye and Vision
ably less common if 1% apraclonidine is used. Iritis occurs, and post-laser anti-inflammatories are indicated. The only long term complication is the formation of PAS, which did not adversely affect IOP control. In 36% of the cases, ALT (as a single therapy) successfully controlled pressure and prevented visual field loss for 3.5 years. If the initial question was to ‘evaluate the efficacy and safety of ALT as oppossed to topical medication for controlling IOP in patients with newly diagnosed POAG [41’, because of the adverse effects of topical medicines, then it failed 64% of the time. The use of medicines might have been delayed, but most patients still needed them, and they were still confronted by their risks. However, the adverse effects of topical medications are real, and they can range from inconvenient to serious. Using ALT did eliminate the need for medicines in some patients, and it reduced the number required in others. The GLT does not compellingly demonstrate that laser should become an automatic first line therapy in all newly diagnosed POAG. No treatment should be considered an automatic first line therapy for glaucoma. We should consider every option for each of our patients, argue the risks and benefits of each option, and make a wise choice for the best therapy for that patient. The GLT showed us that laser first is successful often enough that it should be considered as an option for initial therapy (along with considering every available medicine and filtering surgery). In some cases it will be the best choice and we will recommend it; in others a different option will be better. The GLT also serves as a reminder that following patients with visual fields can be misleading. This is true in large studies, but we must also recall the lesson when managing the individual patient. The GLT research group recognized that an apparent visual field progression can be due to true deterioration or due to fluctuation in the patient’s ability to perform this difficult test. Before a change was interpreted as a true progression, it had to meet specific characteristics, and then had to be ‘confirmed’ by repeat examination. Even this rigid strategy failed too often - over half of the ‘confirmed’ progressions subsequently reversed. The GLT research group argued that therapy could have improved the fields in their patients, but fluctuation in performance is the more likely cause. This should create skepticism when interpreting the results of any glaucoma study that uses visual field progression as an outcome measure. We should also be careful in interpreting visual field data for individual patients, when the difference between stability (or
Care 8 (1996151-54
53
simple fluctuation) and true progression dictates a change in therapy. Depending overconfidently on perimetry data can lead to poor decisions. While automated perimetry is an important tool in glaucoma management, it remains flawed - the test is too subjective and too difficult. However, until better techniques are developed, we must make wise decisions for our patients despite imperfect information. Addendum
In December, 1995 the 7 year result of the GLT were published [8]. These results are valuable because they represent a long term follow-up of the GLT. However, they do not change the observations that could be made based on the 3.5 year results. As expected, the effect of the laser on IOP dissipated as the years after treatment increased. The longer term results (n = 271 in each group) showed that 20% of laser first patients were satisfactorily controlled without any medications; 84% of laser first patients were controlled with topical medications alone (69% of medicine first patients were controlled with topical medications alone); 100% of laser first patients received laser (23% of medicine first patients received laser); and 8% of laser first patients required filtering suregery (11% of medicine first patients required filtering surgery). The two treatment groups had no clinically significant difference in visual field or optic nerve progression, nor were there any long term complications from the laser procedure. The conclusions that can be made for the GLT’s 7 year results are the same as those made from the 3.5 year results (but more meaningful). ALT performed as an initial therapy for glaucoma is quite safe. It adequately lowered the pressure often enough to warrant consideration as initial therapy (especially in non-compliant patients), but not often enough to make it a first line therapy for all open angle glaucoma patients. References [II Glaucoma Laser Trial Research Group. The Glaucoma Laser trial (GLT):3. Designs and methods. Control. Clin. Trials 1991;12:504-524. [21 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):5. Subgroup differences at enrollment. Ophthalmic Surg. 1993;4:232-240. [31 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLTN. Acute effects of argon laser trabeculoplasty on intraocular pressure. Arch. Ophthalmol. 1989;107:1135-1142. [41 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):2. Results of argon laser trabeculoplasty versus topical medicines. Ophthalmology 1990;97:1403-1413.
[5]
[6]
Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLTk4. Contralateral effects of timolol on the intraocular pressure of eyes treated with ALT. Ophthalmic Surg. 1991;22:324-329. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):6. Treatment group differences in visual field
[7] i8]
changes. Am. J. Ophthalmol. I995:l N:ltJ-22. Harkins 7. Apraclonidine. Clin. Eye Vis. Care 3995;7:43 -47. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study:7 Results. Am. J. Ophthalmol. 1995:13tl:718 -7’31.
Clinical Eye and Vision Care 8 (1996) 51-54
News and views
The glaucoma laser trial Timothy Harkins VA Medical
Center,
4801 Linwood
1. Introduction Glaucoma is an important cause of visual loss and its management can be frustrating. Despite an increasing arsenal of topical medications to control intraocular pressure (IOP), none of these medications is without shortcomings. Significant improvements have been made in filtering surgery, but a less invasive procedure would be preferred. Argon laser trabeculoplasty (ALT) does lower IOP and is a suitable treatment option for many patients. It is unclear, however, when ALT should be performed. The Glaucoma Laser Trial (GLT) was designed to compare the safety and efficacy of ALT to topical medications for controlling IOP in newly diagnosed primary open angle glaucoma (POAG) [l-61. 2. Study design The glaucoma laser trial was a randomized, controlled, multicentered study that involved 271 patients [1,2]. Each patient was newly diagnosed with primary open angle glaucoma. Once a patient was entered into the study, each eye was randomly assigned to a different therapy. One eye was treated with 360” of ALT (performed in two sessions separated by 4 weeks). At each session, 180” of trabecular meshwork was treated with 45-50 burns, 50 pm in size, with a 0.1 second pulse of argon blue-green laser. The beam was focused at the junction of the pigmented and non-pigmented anterior trabecular meshwork. The power was adjusted to the threshold of bubble formation (600-1200 mW). Patients used a topical anti-inflammatory agent four times per day for 6 days following each procedure. The other eye was treated with ocular hypotensive medicines. The medicine prescribed first - 0.5% timolol - was predetermined by the study design. If patients failed with timolol, the subsequent steps in medical therapy (and their order) were also predetermined. The steps are summarized in Table 1. A
Boulevard,
Kansas
City, MO 64128,
USA
patientcould be on any of four medicines alone (timolol, dipivefrin, low-dose pilocarpine, or high-dose pilocarpine), or on combination therapy of high-dose pilocarpine with either timolol or dipivefrin. Three outcome measures have been reported. The first was frequency of complications secondary to ALT - specifically IOP rises, the development of peripheral anterior synechia (PAS), and anterior segment inflammation. The second compared the abilities of ALT and medications to lower IOP to a target pressure. The third compared the effects of ALT and medical therapies on visual field progression. 3. AL,T complications There was a 5 mmHg IOP rise in 34% of patients, and 12% had a rise of 10 mmHg or more at one or both sessions [3]. IOP rises occur frequently enough that they should be anticipated, sought out, and reversed. They can also be virtually eliminated with pre-laser and post-laser use of 1% apraclonidine [7]. PAS of at least 1” developed in 46% of patients, and 33% of patients had PAS that extended to the trabecular meshwork. PAS formation was more likely in patients with brown hides and if the laser burns were placed too posteriorly. The authors did not give more detail about the size or extent of the PAS formation, just that a PAS of at least 1” was observed in these patients. Rare PAS of 1” in a patient would be unimportant, but multiple PAS might adversely affect outflow and IOP. Though the authors did not give more detail about the extent of PAS formation in their patients, they state that their formation does not contraindicate future use of ALT. In their 2-year report, the authors showed that the ALT patients with PAS required fewer medications to control IOP than those without PAS, implying their formation is of little consequence [4]. Despite the use of anti-inflammatory agents, anterior segment inflammation was present in 7% of
0953-4431/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PlI:SO953-4431(96)00155-5
Table I Medication
i-able 2 ._’ year data: IOP control
steps
step 1: step 2: step 3: step 4: step 5: step 6:
0.5% timolol 0.1% dipivefrin Low-dose pilocarpine High-dose pilocarpinc Timolol with pilocarpine Dipivefrin with pilocarpine
patients 1 week after their ALT. The authors did not report on the severity of the inflammation. They also did not study whether the anti-inflammatory agents reduced the rate and severity of post-laser iritis, but intuition tells us that they would help. ALT is a relatively safe, but not entirely benign procedure. Its short-term complications include IOP rises and inflammation. It seems wise to reduce the likelihood of these complications with pre- and postlaser 1% apraclonidine, and with topical anti-inflammatory agents for 1 week after the procedure. 4. IOP control
In 1990, the GLT research group reported their two year results of IOP control. Criteria for failure were: (1) IOP greater than 22 or a reduction less than 20% from baseline; (2) visual field deterioration; (3) optic nerve deterioration; or (4) adverse reactions to the medicine [4]. After 2 years, 44% of patients treated with ALT alone had adequate IOP reduction. 56% of laser treated eyes needed additional medical therapy during the first 2 years. In eyes which did not receive laser, 51% were adequately controlled for 2 years on a single medicine (timolol, dipivefrin, or pilocarpine) and 66% were controlled on one or two medicines. The 2-year data showed that the majority of ALT patients needed medication to control their IOP, but that ALT did reduce the number of medicines required for many patients. Table 2 shows that 44% of patients who had laser were controlled without any medicine, 84% were controlled with a single medicine added to laser (51% of non-laser patients were controlled on a single medicine) and 89% were controlled by two medicines added to laser (66% of non-laser patients were controlled by two medicines). The argument that timolol could crossover and lower the IOP in the laser treated eye was adequately answered. The crossover effect was only 0.5 mmHg not enough to alter the results of IOP or visual field data [51. 5. Visual field changes
In 1995, the GLT research group published their
Percent
of patients
requiring
one or two medicines
Medicine ALT One Two
only medicine medicines
for
first
N/A 51 Ch 66%
3.5 year data comparing visual field deterioration in patients treated with laser first to those treated with medicine first [6]. Unfortunately, the data do not tell us how the visual fields fared if patients were treated with laser alone, because 64% of laser first patients received additional therapy during the 3.5 years. We do know that 36% of eyes required only laser (and presumably did not have visual field deterioration), 64% required the addition of medicine, and that 7% required filtering surgery or oral medication. Patients treated with medicine first also required filtering surgery or oral medication 7% of the time. As stated, most laser first patients received additional therapy, so the visual field results of these patients do not tell us how patients did with laser alone. The results do not compellingly argue for or against laser first therapy. The average mean threshold for laser first eyes was 0.3 db higher than for medicine first eyes - a statistically, but not clinically significant number. ‘Confirmed’ deterioration (two consecutive fields that were worse than baseline) occurred in 23% of laser first eyes and in 31% of medicine first eyes. At first glance, this seems important, but most ‘confirmed’ field losses in fact subsequently returned to baseline status. Persistent visual field loss occurred in far fewer patients - 12% of laser first eyes and 14% of medicine first eyes. This was not a statistically significant difference. Curiously, in each group the visual field appeared to improve more often than it appeared to deteriorate. Disturbingly, the patients who had progression had the same IOP reduction as those who did not progress. 6. Clinical implications
Our obligation in evaluating the GLT is to determine how it will effect our clinical decisions. The results have taught us that ALT is a safe procedure, that sometimes it succeeds as sole glaucoma therapy, that its initial use can reduce the need for single or multiple medicines, and it taught us something about the interpretation of visual field data (clinically and in large studies). Severe complications from ALT are uncommon. Significant IOP rises can occur, but they are consider-
T Harkins
/Clinical
Eye and Vision
ably less common if 1% apraclonidine is used. Iritis occurs, and post-laser anti-inflammatories are indicated. The only long term complication is the formation of PAS, which did not adversely affect IOP control. In 36% of the cases, ALT (as a single therapy) successfully controlled pressure and prevented visual field loss for 3.5 years. If the initial question was to ‘evaluate the efficacy and safety of ALT as oppossed to topical medication for controlling IOP in patients with newly diagnosed POAG [41’, because of the adverse effects of topical medicines, then it failed 64% of the time. The use of medicines might have been delayed, but most patients still needed them, and they were still confronted by their risks. However, the adverse effects of topical medications are real, and they can range from inconvenient to serious. Using ALT did eliminate the need for medicines in some patients, and it reduced the number required in others. The GLT does not compellingly demonstrate that laser should become an automatic first line therapy in all newly diagnosed POAG. No treatment should be considered an automatic first line therapy for glaucoma. We should consider every option for each of our patients, argue the risks and benefits of each option, and make a wise choice for the best therapy for that patient. The GLT showed us that laser first is successful often enough that it should be considered as an option for initial therapy (along with considering every available medicine and filtering surgery). In some cases it will be the best choice and we will recommend it; in others a different option will be better. The GLT also serves as a reminder that following patients with visual fields can be misleading. This is true in large studies, but we must also recall the lesson when managing the individual patient. The GLT research group recognized that an apparent visual field progression can be due to true deterioration or due to fluctuation in the patient’s ability to perform this difficult test. Before a change was interpreted as a true progression, it had to meet specific characteristics, and then had to be ‘confirmed’ by repeat examination. Even this rigid strategy failed too often - over half of the ‘confirmed’ progressions subsequently reversed. The GLT research group argued that therapy could have improved the fields in their patients, but fluctuation in performance is the more likely cause. This should create skepticism when interpreting the results of any glaucoma study that uses visual field progression as an outcome measure. We should also be careful in interpreting visual field data for individual patients, when the difference between stability (or
Care 8 (1996151-54
53
simple fluctuation) and true progression dictates a change in therapy. Depending overconfidently on perimetry data can lead to poor decisions. While automated perimetry is an important tool in glaucoma management, it remains flawed - the test is too subjective and too difficult. However, until better techniques are developed, we must make wise decisions for our patients despite imperfect information. Addendum
In December, 1995 the 7 year result of the GLT were published [8]. These results are valuable because they represent a long term follow-up of the GLT. However, they do not change the observations that could be made based on the 3.5 year results. As expected, the effect of the laser on IOP dissipated as the years after treatment increased. The longer term results (n = 271 in each group) showed that 20% of laser first patients were satisfactorily controlled without any medications; 84% of laser first patients were controlled with topical medications alone (69% of medicine first patients were controlled with topical medications alone); 100% of laser first patients received laser (23% of medicine first patients received laser); and 8% of laser first patients required filtering suregery (11% of medicine first patients required filtering surgery). The two treatment groups had no clinically significant difference in visual field or optic nerve progression, nor were there any long term complications from the laser procedure. The conclusions that can be made for the GLT’s 7 year results are the same as those made from the 3.5 year results (but more meaningful). ALT performed as an initial therapy for glaucoma is quite safe. It adequately lowered the pressure often enough to warrant consideration as initial therapy (especially in non-compliant patients), but not often enough to make it a first line therapy for all open angle glaucoma patients. References [II Glaucoma Laser Trial Research Group. The Glaucoma Laser trial (GLT):3. Designs and methods. Control. Clin. Trials 1991;12:504-524. [21 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):5. Subgroup differences at enrollment. Ophthalmic Surg. 1993;4:232-240. [31 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLTN. Acute effects of argon laser trabeculoplasty on intraocular pressure. Arch. Ophthalmol. 1989;107:1135-1142. [41 Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):2. Results of argon laser trabeculoplasty versus topical medicines. Ophthalmology 1990;97:1403-1413.
[5]
[6]
Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLTk4. Contralateral effects of timolol on the intraocular pressure of eyes treated with ALT. Ophthalmic Surg. 1991;22:324-329. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT):6. Treatment group differences in visual field
[7] i8]
changes. Am. J. Ophthalmol. I995:l N:ltJ-22. Harkins 7. Apraclonidine. Clin. Eye Vis. Care 3995;7:43 -47. Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial (GLT) and Glaucoma Laser Trial Follow-up Study:7 Results. Am. J. Ophthalmol. 1995:13tl:718 -7’31.