- Email: [email protected]
Comparison of the intraocular pressure-lowering effect of latanoprost and timolol in patients with chronic angle closure glaucoma
Comparison of the Intraocular Pressurelowering Effect of Latanoprost and Timolol in Patients with Chronic Angle Closure Glaucoma A Preliminary Study Tin Aung, FRCS,1,2 Hon T. Wong, MBSS,1 Chee C. Yip, FRCS,1 Joy Y. N. Leong, MN,3 Yiong-Huak Chan, PhD,3 Paul T. K. Chew, FRCS2 Objective: To compare the intraocular pressure (IOP)–reducing effect and side effects of 0.005% latanoprost once daily to 0.5% timolol twice daily in patients with primary chronic angle closure glaucoma (CACG). Design: Randomized, double-masked two-center clinical trial. Participants: Thirty-two Asian patients with CACG, defined as glaucomatous optic neuropathy with a compatible visual field defect and at least 6 clock hours of synechial angle closure on gonioscopy were recruited. All patients had previous peripheral iridotomy (PI) with IOP ⬎21 mmHg after PI and were thereafter controlled (IOP ⬍22 mmHg) with one or two pressure-reducing drugs. Intervention: After a washout period, the patients were randomized to a 2-week treatment period with either placebo in the morning and 0.005% latanoprost in the evening or 0.5% timolol twice daily. Main Outcome Measures: The short-term IOP reduction of latanoprost and timolol in patients with CACG. IOP was measured at baseline, and after 2, 7, and 14 days of treatment. In addition, the short-term ocular and systemic adverse events of the two drugs were evaluated. Results: Thirty patients completed the study. Two patients in the timolol group were withdrawn because of inadequate IOP control. Compared with baseline, the IOP after 2 weeks of treatment was statistically significantly reduced by 8.8 ⫾ 1.1 mmHg (mean ⫾ SEM, P ⬍ 0.001) in the latanoprost group, and by 5.7 ⫾ 0.9 mmHg (P ⬍ 0.001) in the timolol group. The difference in IOP reduction between the two treatment groups was 3.1 ⫾ 1.5 mm Hg in favor of latanoprost (P ⫽ 0.04). The main ocular adverse events reported in both treatment groups were conjunctival hyperemia and discomfort. Conclusions: In this preliminary study, a significantly greater IOP reduction was achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily in patients with CACG. The results suggest that latanoprost may be a therapeutic choice for the medical treatment of primary CACG. Ophthalmology 2000;107: 1178 –1183 © 2000 by the American Academy of Ophthalmology. Latanoprost, a prostaglandin F2␣-analog, has proven to be an effective ocular hypotensive drug.1–7 Its main mechanism for reducing intraocular pressure (IOP) is an increase in the uveoscleral outflow. Latanoprost has not been found Originally received: June 4, 1999. Accepted: January 25, 2000. Manuscript no. 99288. 1 Tan Tock Seng Hospital, Singapore. 2 National University Hospital, Singapore and Singapore National Eye Centre, Singapore. 3 Clinical Trials and Epidemiology Research Unit, Singapore. This study was supported in part by a grant from the Singapore Eye Research Institute. Presented in part at the Asia Pacific Academy of Ophthalmology, Manila, Philippines, March 1999, and at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 1999.
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© 2000 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
to alter the aqueous humor production to a clinically significant extent.8 –9 When administered to monkey eyes, latanoprost markedly increased uveoscleral outflow,10 and a corresponding effect has indirectly been demonstrated in humans.8 In long-term studies, 0.005% latanoprost applied once daily reduced IOP at least as effectively as the -ad-
The authors have no financial interest related to the manuscript including stock or ownership of a business entity connected to a product described in the article, paid consulting for the company or competing companies, patent rights to a drug or piece of equipment, or personal or family ownership or potential rights to any company or competing companies and have no interest in marketing any product, drug, instrument or equipment discussed in the manuscript. Reprint requests to Paul T. K. Chew, FRCS, Department of Ophthalmology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. ISSN 0161-6420/00/$–see front matter PII S0161-6420(00)00073-7
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma Table 1. Schedule of Examinations and Procedures Baseline Examination
Within 3 Weeks of Baseline
Medical and ocular history Visual acuity Refraction Slit-lamp examination Intraocular pressure Ophthalmoscopy Gonioscopy Visual field Iris photographs Blood pressure and pulse Symptomatology
X X X X X X X X X X X
renergic receptor antagonist timolol in patients with primary open-angle glaucoma or ocular hypertension.2–5 Glaucoma is the second leading cause of vision loss in the world, accounting for approximately 5.1 million of the blind people in the world, with nearly half of these residing in China and the Asia Pacific countries.11–12 Primary angle closure glaucoma is considered the most common form of glaucoma in Asia,13 whereas primary open-angle glaucoma (POAG) is the predominant condition among Caucasians and Africans.14 Most glaucoma research has been focused on populations with a preponderance of POAG, whereas treatment modalities or drug therapies for chronic angle closure glaucoma (CACG) remain less studied. In CACG, gradual asymptomatic angle closure results in diminished aqueous outflow through the angles and a subsequent rise of the IOP. A peripheral iridotomy is usually performed to treat the pupillary block, and topical medications are added to reduce the pressure if the iridectomy alone is insufficient. Information about the most efficacious topical therapy available is insufficient, and ophthalmologists empirically use topical -adrenergic receptor antagonists or a cholinergic agonist such as pilocarpine, as first-line drugs in CACG. It is not known whether latanoprost is effective in reducing IOP when the anterior chamber angles are partly or fully closed. The purpose of this study was to compare the short-term effect on IOP of latanoprost and timolol in patients with CACG. In addition, ocular and systemic safety variables were monitored and reported throughout the study.
Materials and Methods This two-center study was carried out at the Tan Tock Seng Hospital and the National University Hospital, Singapore, and was designed as a 2-week, randomized, double-masked comparison of latanoprost treatment to timolol treatment in patients with CACG. The relatively short study period of 2 weeks was chosen for safety reasons because no data were available on the efficacy of latanoprost in CACG, and this was a preliminary study investigating its effect in this condition. After obtaining approval from the ethics committees of each center and by the Ministry of Health of Singapore, a signed informed consent was obtained from all patients before study enrollment. The study was performed according to the Declaration of Helsinki and the Singapore “Good Clinical Practice” guidelines.
9
AM
5
PM
X X X
X X
Day 2
Day 7
9
9
AM
AM
X
X
X
X X
X X
X
X X
X X
Day 14 9
AM
X X X X X X
5
PM
X
X X X
Patients 40 years of age or older with unilateral or bilateral primary CACG were eligible. CACG was defined as glaucomatous optic neuropathy with a compatible visual field defect and at least 6 clock hours of synechial angle closure on gonioscopy. Glaucomatous optic neuropathy was defined as a cup/disc ratio of ⱖ0.5. A threshold examination of the central 24 degrees of visual field (24-2 program) showing a glaucoma hemifield test (GHT) “outside normal limits” and a cluster of four contiguous points on the pattern deviation plot depressed at P ⬍ 5% level (occurring in age-matched normal subjects) not crossing the horizontal meridian were considered compatible with glaucoma. Test reliability was determined by the instrument’s algorithm (fixation losses ⱕ20%, false positives ⱕ33%, and false negatives ⱕ33%). The patients should also have had a previous peripheral iridotomy (PI), an IOP greater than 21 mmHg after the PI, and current control with one or two pressure-reducing medications on two consecutive visits (retrospectively ascertained). Eligible patients were required to complete a minimum washout period before randomization: 3 weeks for -adrenergic antagonists, 3 weeks for prostaglandins, 2 weeks for adrenergic agonists, 5 days for cholinergic agonists, and 5 days for carbonic anhydrase inhibitors. Patients requiring bilateral treatment had to fulfill all eligibility criteria for both eyes to be included. However, if only one eye fulfilled the inclusion criteria, that eye was included as study eye, but the fellow eye could be treated with allocated study therapy provided that no exclusion criteria were met. Exclusion criteria were previous intraocular surgery (PI excluded), previous trauma to the eye with damage of the anterior chamber angle, advanced glaucoma (defined as cup/disc ratio ⱖ0.9 and/or perimetric evidence of visual field loss within 10 degrees of macula fixation in one or more quadrants) at risk for progression during the washout period, the fellow eye on treatment with another IOP-reducing drug, previous corneal infection or corneal abnormalities, uveitis or dry eyes, current use of contact lenses, oral drugs known to affect the IOP, or known allergy to benzalkonium chloride. Also, a history of asthma or chronic obstructive lung disease; congestive cardiac failure; bradycardia; heart block; cerebrovascular, hepatic, or metabolic disease (except diabetes mellitus) were considered reasons for exclusion. Pregnant or nursing women or women considering pregnancy were also excluded, as well as patients with a history of noncompliance or patients who participated in another therapeutic drug study within 1 month. The schedule of examinations and procedures is presented in Table 1. At the prestudy visit, medical and ocular history were taken. Visual acuity and refraction, slit-lamp examination, ophthalmoscopy, and measurement of the IOP were performed. Gonioscopy and perimetry were also carried out. This visit took place within 3 weeks before the study start, and the patients were included after these eligibility assessments. The current therapy
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Ophthalmology Volume 107, Number 6, June 2000 was then withdrawn before study start according to the previously described washout periods for different drugs. The patients were then randomized to two parallel study groups: one group was assigned to treatment with placebo in the morning and 0.005% latanoprost in the evening, and the other group received 0.5% timolol twice daily. During the study period there were four scheduled visits: at baseline and at 2 days, 7 days, and 14 days. The IOP was measured with a Goldmann applanation tonometer. Three measurements were performed in each eye, and the mean of the three measurements was used in the statistical analyses. Best-corrected Snellen visual acuity and refractive error, systemic blood pressure, and pulse rate were determined at each visit, and a slit-lamp examination was performed. The presence of cells and flare in the anterior chamber was investigated during slit-lamp examination. Flare was graded as none, moderate, or severe, and cells present in a slit of 2-mm width were graded as none (1–2 cells), mild (3–5 cells), moderate (6 –20 cells) or severe (ⱖ20 cells). At the prestudy visit and at the 14-day visit, gonioscopy and ophthalmoscopy were carried out, and iris photographs were taken. Patients were instructed to administer one drop of the allocated medication at 8 AM and 8 PM each day. On visit days (days 2, 7, and 14), the morning drop was administered at 7 AM before clinic visit. The first application began at 8 PM on day 0 (baseline) and the last application at 7 AM on day 14 (last visit). Patients were instructed on punctal occlusion after administering the drops. Adverse events were monitored carefully throughout the study. Patients were queried at each visit regarding adverse events by standard clinician inquiry. An adverse event was defined as any undesirable event occurring in a subject regardless of whether it was considered related to the investigational drug. A serious adverse event was defined as an event that was potentially fatal, life threatening, permanently disabling, requiring hospitalization, or requiring intervention to prevent permanent impairment or damage.
Statistical Evaluation The trial size of 16 patients randomly assigned to timolol and 16 to latanoprost was calculated to be sufficient to detect a difference in IOP between the two treatments of 3.5 mmHg as determined at week 2, with a two-sided test size of 5% and power 80%. It was anticipated that the between-treatment groups SD ⫽ 3 mmHg. Differences in IOP between treatment groups and reduction of IOP within treatment groups were determined with Student’s t test and the analysis of variance (ANOVA). The normality of data distribution was tested using the Shapiro-Wilk test of normality. The IOP was defined as the mean value of the measurements at 9:00 AM and 5:00 PM. If both eyes of a patient were studied, the mean IOP of both eyes was used in the analysis.
Results Of the 32 patients included in the study, 16 patients were randomly assigned to the latanoprost treatment group and 16 to the timolol treatment group. The patient characteristics of the two treatment groups are presented in Table 2. No major difference was found between the two treatment groups with respect to age, race, or gender. Of the patients included, 29 completed the study. Two patients were withdrawn from the timolol treatment group because of an IOP greater than 30 mmHg on the second day of the study. These patients had been previously treated with combined therapy of timolol ⫹ dorzolamide and timolol ⫹ latanoprost, respectively. Another patient from the timolol treatment group discontinued the
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Table 2. Demographic Characteristics of the Patients in the Two Parallel Treatment Groups Characteristics Age (yrs) Mean ⫾ SD Range Gender Female Male Race Chinese Malay Indian
Latanoprost (n ⴝ 16)
Timolol (n ⴝ 16)
64 ⫾ 7 49–77
64 ⫾ 8 50–77
8 8
8 8
12 3 1
14 2 0
n ⫽ number of patients; SD ⫽ standard deviation.
study after 1 week because of conjunctival injection and pain in the nonstudy eye. This patient’s IOP measurements after 7 days of treatment were used in the statistical analysis. The mean IOP at each measurement for the two treatment groups is presented in Table 3. Compared with baseline measurements, the IOP reduction at day 14 was statistically significant in both treatment groups (P ⬍ 0.001). In the latanoprost group the mean IOP reduction at day 14 was 8.8 ⫾ 1.1 mmHg (mean ⫾ SEM, P ⬍ 0.001; 34.2%) from a mean IOP baseline of 25.7 ⫾ 0.9 mmHg, and the corresponding figures for the timolol group were 5.7 ⫾ 0.9 mmHg (P ⬍ 0.001; 22.6%) from a mean IOP baseline of 25.2 ⫾ 1.1 mmHg. A significantly greater IOP reduction of 3.1 ⫾ 1.5 mmHg (95% confidence interval: 0.1– 6.0) was achieved in the latanoprost group compared with the timolol treatment group (P ⫽ 0.04). In Figure 1 the IOP reduction (mean ⫾ SEM) at day 14 compared with baseline is shown. The distribution of IOP change for both groups did not deviate from the normality assumption (Shapiro-Wilk test). The degree of angle closure was classified into two groups: a closure of 6 to 9 clock hours and a closure of 10 to 12 clock hours. All 16 patients in the latanoprost group had an angle closure of 6 to 9 clock hours, whereas 10 of the patients in the timolol group had an angle closure of 6 to 9 clock hours and the remaining four had a more extensive closure of 10 to 12 clock hours. However, the ANOVA analysis could not reveal any statistically significant relationship between degree of angle closure and IOP reduction (P ⫽ 0.197). Previous medication was another inclusion criteria that could vary among the patients included because they could be Table 3. Intraocular Pressure (mean ⫾ SD) in the Two Parallel Study Groups at Each Measurement Time Baseline 9 AM 5 PM Day 2 9 AM Day 7 9 AM Day 14 9 AM 5 PM
Latanoprost (n ⴝ 16)
Timolol (n ⴝ 14)
27.2 ⫾ 3.8 24.2 ⫾ 3.8
26.8 ⫾ 4.5 23.5 ⫾ 4.3
16.4 ⫾ 3.7
21.2 ⫾ 6.8
16.0 ⫾ 4.3
19.1 ⫾ 3.0
17.0 ⫾ 4.7 16.8 ⫾ 5.8
20.0 ⫾ 2.6 18.9 ⫾ 2.8
n ⫽ number of patients; SD ⫽ standard deviation.
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma
Figure 1. The intraocular pressure (IOP) reduction (mean ⫾ SEM) at 2 weeks compared with baseline.
on one or two IOP-reducing drugs before inclusion into the study. The previous medications for the different treatment groups in the study are listed in Table 4. In the latanoprost group there were five patients taking two ocular hypotensive medications, whereas in the timolol group there were seven. No statistically significant relationship between previous medication and IOP reduction could, however, be found in the ANOVA analysis (P ⫽ 0.305). Figure 2 shows scatterplots of prestudy IOP versus final IOP for different degrees of angle closure and number of previous medications. The graphs show that there was no relationship between the degree of angle closure and IOP reduction and between the number of previous medications and IOP reduction in the subjects. Ocular and systemic adverse events are presented in Table 5. Most of the events were reported as mild. In two patients in the latanoprost group and one patient in the timolol group, three to five cells (mild event) were found in the anterior chamber. No flare was found in any of these patients, and they had no ocular symptoms. At the follow-up visit after the end of the study, there were no cells in the anterior chamber on examination, and no other objective or subjective symptoms were reported. No serious adverse events were reported. Iris photographs and slit-lamp examinations did not reveal any changes in iris pigmentation. There were no changes in systemic blood pressure or pulse rate.
Discussion In this study, 2 weeks of treatment with 0.005% latanoprost once daily or 0.5% timolol twice daily significantly reduced Table 4. Number of Patients with Different Medications before Study Inclusion in the Two Parallel Study Groups Drug
Latanoprost
Timolol
Acetazolamide Betaxolol Latanoprost Pilocarpine Timolol Unoprostone
0 0 0 6 4 1
1 1 2 2 1 0
Betaxolol ⫹ pilocarpine Timolol ⫹ dorzolamide Timolol ⫹ pilocarpine
0 1 4
1 3 3
the IOP from the untreated baseline in patients with CACG. In the latanoprost group the IOP reduction was 34% (8.8 mmHg), whereas it was 23% (5.7 mmHg) in the timolol group. Thus, latanoprost was significantly better than timolol in reducing the IOP in these CACG patients. Interestingly, in CACG, the extent of the IOP-reducing effect of latanoprost once daily was similar to that seen in POAG and ocular hypertension.2– 4,6 The concern that latanoprost might not exert its pressure-reducing effect when the anterior chamber angles were partly closed could possibly be dismissed. As to whether latanoprost will be effective when the angles are fully closed remains unanswered because no patient had such an angle in the latanoprost group. The mechanism of action of latanoprost in eyes with closed angles is not known. One possibility is that latanoprost gains access to the ciliary body by way of the open part of the anterior chamber angle; another possibility is that it acts through a pathway in the uveoscleral outflow not yet fully understood. The effect of latanoprost on eyes with different degrees of angle closure could not be analyzed because all patients randomly assigned to the latanoprost group had 6 to 9 clock hours of angle closure. The inclusion criteria for this study were chosen to select a subgroup of patients with a less severe form of CACG (which was medically controlled). The reason for choosing this subgroup was concern for the IOP during the washout period and also for the efficacy of latanoprost in CACG because latanoprost acts by increasing uveoscleral outflow, which might be compromised in this type of glaucoma. The short duration of the study and small sample size were also to satisfy patient safety concerns. This small sample size might be open to bias and make the two groups unbalanced, as was found eventually with regard to the degree of angle closure and the number of prestudy medications. All 16 patients receiving latanoprost treatment had an angle closure of 6 to 9 clock hours, whereas 10 of the patients receiving timolol treatment had an angle closure of 6 to 9 clock hours, and 4 of them had a closure of 10 to 12 clock hours. This was taken into consideration in the statistical analysis, and no significant relationship between degree of angle closure and IOP reduction could be found. Another indication of severity of the disease could be the number of IOP-reducing drugs needed for adequate pressure control. Although a slight discrepancy was found between the groups, no significant relationship between number of previous medications and IOP reduction was found. However, the authors acknowledge that the results of the ANOVA statistics could have been affected by the small number of patients studied. Because prostaglandins are known to be released in the inflammatory response, cells and flare in the anterior chamber were regularly monitored during the study period as an indication of increased permeability of the blood-aqueous barrier. In the three 6-month latanoprost phase III studies, no difference was found between latanoprost and timolol in the incidence of cells and flare,2– 4 and in a study of 1-year treatment with latanoprost, only slight aqueous flare and a few cells were reported in a small number of patients.6 In
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Figure 2. Scatterplots of prestudy IOP versus final IOP for different degrees of angle closure and number of previous medications.
several other clinical studies,9,15–18 no signs of breakdown of the blood-aqueous barrier were found. In this study, two Table 5. Number of Patients with Ocular or Systemic Adverse Events Reported During the Study (Withdrawn Patients Included) Adverse Event
Latanoprost
Timolol
Ocular Conjunctival hyperemia Discomfort Cells in the anterior chamber Blurred vision Itching Punctate corneal erosions
6 4 2 1 1 0
5 2 1 2 1 1
Systemic Headache
0
1
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patients in the latanoprost group and one patient in the timolol group had a small number of cells (3–5 cells) in the anterior chamber during the treatment period. No flare was present, and no subjective ocular symptoms were present. In all three patients the cells were no longer present after the end of the study. Other side effects were transient and reported as mild in both the latanoprost and the timolol groups. In conclusion, a significantly greater IOP reduction was achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily in patients with CACG. In this preliminary study, a small group of patients was treated for a period of 2 weeks, and more extensive studies need to be performed to evaluate the drug for long-term treatment in different degrees of CACG. However, the results of this study suggest that latanoprost may be a therapeutic choice for the medical treatment of primary CACG.
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma
References 1. Alm A, Widengard I, Kjellgren D, et al. Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol 1995;79:12– 6. 2. Alm A, Stjernschantz J. Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group. Ophthalmology 1995;102:1743–52. 3. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. A sixmonth, masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:138 – 47. 4. Watson P, Stjernschantz J. A six month randomized doublemasked study comparing latanoprost with timolol in openangle glaucoma and ocular hypertension. The Latanoprost Study Group. Ophthalmology 1996;103:126 –37. 5. Mishima HK, Masuda K, Kitazawa Y, et al. A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12-week study. Arch Ophthalmol 1996;114:929 –32. 6. Camras CB, Alm A, Watson P, Stjernschantz J. Latanoprost, a prostaglandin analog, for glaucoma treatment. Efficacy and safety after 1 year of treatment in 198 patients. The Latanoprost Study Groups. Ophthalmology 1996;103:1916 –24. 7. Watson PG. Latanoprost. Two years’ experience of its use in the United Kingdom. Latanoprost Study Group. Ophthalmology 1998;105:82–7. 8. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2␣ analogue, on aqueous humor dynamics in human eyes. Ophthalmology 1993;100:1297–304. 9. Ziai N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2␣ ana-
10.
11.
12. 13.
14.
15.
16.
17.
18.
logue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993;111:1351– 8. Stjernschantz J, Sele´n G, Sjo¨quist B, Resul B. Preclinical pharmacology of latanoprost, a phenyl-substituted PGF2␣ analogue. Adv Prostaglandin Thromboxane Leukot Res 1995; 23:513– 8. Thylefors B, Ne´grel AD, Pararajasegaram R, Dadzie KY. Global data on blindness [review]. Bull World Health Organ 1995;73:115–21. Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol 1996;80:389 –93. Foster PJ, Baasanhu J, Alsbirk PH, et al. Glaucoma in Mongolia. A population based survey in Ho¨vsgo¨l Province, Northern Mongolia. Arch Ophthalmol 1996;114:1235– 41. Congdon N, Wang F, Tielsch JM. Issues in the epidemiology and population based screening of primary angle-closure glaucoma [review]. Surv Ophthalmol 1992;36:411–23. Hotehama Y, Mishima HK, Kitazawa Y, Masuda K. Ocular hypotensive effect of PhXA41 in patients with ocular hypertension or primary open-angle glaucoma. Jpn J Ophthalmol 1993;37:270 – 4. Linde´n C, Nuija E, Alm A. Effects on IOP restoration and blood-aqueous barrier after long term treatment with latanoprost in open angle glaucoma and ocular hypertension. Br J Ophthalmol 1997;81:370 –2. Widengård I, Ma¨epea O, Alm A. Effects of latanoprost and dipivefrin, alone or combined, on intraocular pressure and on blood-aqueous barrier permeability. Br J Ophthalmol 1998; 82:404 – 6. Diestelhorst M, Roters S, Krieglstein GK. The effect of latanoprost 0.005% once daily versus 0.0015% twice daily on intraocular pressure and aqueous humor protein concentration in glaucoma patients. A randomized, double-masked comparison with timolol 0.5%. Graefes Arch Clin Exp Ophthalmol 1997;235:20 – 6.
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© 2000 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
to alter the aqueous humor production to a clinically significant extent.8 –9 When administered to monkey eyes, latanoprost markedly increased uveoscleral outflow,10 and a corresponding effect has indirectly been demonstrated in humans.8 In long-term studies, 0.005% latanoprost applied once daily reduced IOP at least as effectively as the -ad-
The authors have no financial interest related to the manuscript including stock or ownership of a business entity connected to a product described in the article, paid consulting for the company or competing companies, patent rights to a drug or piece of equipment, or personal or family ownership or potential rights to any company or competing companies and have no interest in marketing any product, drug, instrument or equipment discussed in the manuscript. Reprint requests to Paul T. K. Chew, FRCS, Department of Ophthalmology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. ISSN 0161-6420/00/$–see front matter PII S0161-6420(00)00073-7
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma Table 1. Schedule of Examinations and Procedures Baseline Examination
Within 3 Weeks of Baseline
Medical and ocular history Visual acuity Refraction Slit-lamp examination Intraocular pressure Ophthalmoscopy Gonioscopy Visual field Iris photographs Blood pressure and pulse Symptomatology
X X X X X X X X X X X
renergic receptor antagonist timolol in patients with primary open-angle glaucoma or ocular hypertension.2–5 Glaucoma is the second leading cause of vision loss in the world, accounting for approximately 5.1 million of the blind people in the world, with nearly half of these residing in China and the Asia Pacific countries.11–12 Primary angle closure glaucoma is considered the most common form of glaucoma in Asia,13 whereas primary open-angle glaucoma (POAG) is the predominant condition among Caucasians and Africans.14 Most glaucoma research has been focused on populations with a preponderance of POAG, whereas treatment modalities or drug therapies for chronic angle closure glaucoma (CACG) remain less studied. In CACG, gradual asymptomatic angle closure results in diminished aqueous outflow through the angles and a subsequent rise of the IOP. A peripheral iridotomy is usually performed to treat the pupillary block, and topical medications are added to reduce the pressure if the iridectomy alone is insufficient. Information about the most efficacious topical therapy available is insufficient, and ophthalmologists empirically use topical -adrenergic receptor antagonists or a cholinergic agonist such as pilocarpine, as first-line drugs in CACG. It is not known whether latanoprost is effective in reducing IOP when the anterior chamber angles are partly or fully closed. The purpose of this study was to compare the short-term effect on IOP of latanoprost and timolol in patients with CACG. In addition, ocular and systemic safety variables were monitored and reported throughout the study.
Materials and Methods This two-center study was carried out at the Tan Tock Seng Hospital and the National University Hospital, Singapore, and was designed as a 2-week, randomized, double-masked comparison of latanoprost treatment to timolol treatment in patients with CACG. The relatively short study period of 2 weeks was chosen for safety reasons because no data were available on the efficacy of latanoprost in CACG, and this was a preliminary study investigating its effect in this condition. After obtaining approval from the ethics committees of each center and by the Ministry of Health of Singapore, a signed informed consent was obtained from all patients before study enrollment. The study was performed according to the Declaration of Helsinki and the Singapore “Good Clinical Practice” guidelines.
9
AM
5
PM
X X X
X X
Day 2
Day 7
9
9
AM
AM
X
X
X
X X
X X
X
X X
X X
Day 14 9
AM
X X X X X X
5
PM
X
X X X
Patients 40 years of age or older with unilateral or bilateral primary CACG were eligible. CACG was defined as glaucomatous optic neuropathy with a compatible visual field defect and at least 6 clock hours of synechial angle closure on gonioscopy. Glaucomatous optic neuropathy was defined as a cup/disc ratio of ⱖ0.5. A threshold examination of the central 24 degrees of visual field (24-2 program) showing a glaucoma hemifield test (GHT) “outside normal limits” and a cluster of four contiguous points on the pattern deviation plot depressed at P ⬍ 5% level (occurring in age-matched normal subjects) not crossing the horizontal meridian were considered compatible with glaucoma. Test reliability was determined by the instrument’s algorithm (fixation losses ⱕ20%, false positives ⱕ33%, and false negatives ⱕ33%). The patients should also have had a previous peripheral iridotomy (PI), an IOP greater than 21 mmHg after the PI, and current control with one or two pressure-reducing medications on two consecutive visits (retrospectively ascertained). Eligible patients were required to complete a minimum washout period before randomization: 3 weeks for -adrenergic antagonists, 3 weeks for prostaglandins, 2 weeks for adrenergic agonists, 5 days for cholinergic agonists, and 5 days for carbonic anhydrase inhibitors. Patients requiring bilateral treatment had to fulfill all eligibility criteria for both eyes to be included. However, if only one eye fulfilled the inclusion criteria, that eye was included as study eye, but the fellow eye could be treated with allocated study therapy provided that no exclusion criteria were met. Exclusion criteria were previous intraocular surgery (PI excluded), previous trauma to the eye with damage of the anterior chamber angle, advanced glaucoma (defined as cup/disc ratio ⱖ0.9 and/or perimetric evidence of visual field loss within 10 degrees of macula fixation in one or more quadrants) at risk for progression during the washout period, the fellow eye on treatment with another IOP-reducing drug, previous corneal infection or corneal abnormalities, uveitis or dry eyes, current use of contact lenses, oral drugs known to affect the IOP, or known allergy to benzalkonium chloride. Also, a history of asthma or chronic obstructive lung disease; congestive cardiac failure; bradycardia; heart block; cerebrovascular, hepatic, or metabolic disease (except diabetes mellitus) were considered reasons for exclusion. Pregnant or nursing women or women considering pregnancy were also excluded, as well as patients with a history of noncompliance or patients who participated in another therapeutic drug study within 1 month. The schedule of examinations and procedures is presented in Table 1. At the prestudy visit, medical and ocular history were taken. Visual acuity and refraction, slit-lamp examination, ophthalmoscopy, and measurement of the IOP were performed. Gonioscopy and perimetry were also carried out. This visit took place within 3 weeks before the study start, and the patients were included after these eligibility assessments. The current therapy
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Ophthalmology Volume 107, Number 6, June 2000 was then withdrawn before study start according to the previously described washout periods for different drugs. The patients were then randomized to two parallel study groups: one group was assigned to treatment with placebo in the morning and 0.005% latanoprost in the evening, and the other group received 0.5% timolol twice daily. During the study period there were four scheduled visits: at baseline and at 2 days, 7 days, and 14 days. The IOP was measured with a Goldmann applanation tonometer. Three measurements were performed in each eye, and the mean of the three measurements was used in the statistical analyses. Best-corrected Snellen visual acuity and refractive error, systemic blood pressure, and pulse rate were determined at each visit, and a slit-lamp examination was performed. The presence of cells and flare in the anterior chamber was investigated during slit-lamp examination. Flare was graded as none, moderate, or severe, and cells present in a slit of 2-mm width were graded as none (1–2 cells), mild (3–5 cells), moderate (6 –20 cells) or severe (ⱖ20 cells). At the prestudy visit and at the 14-day visit, gonioscopy and ophthalmoscopy were carried out, and iris photographs were taken. Patients were instructed to administer one drop of the allocated medication at 8 AM and 8 PM each day. On visit days (days 2, 7, and 14), the morning drop was administered at 7 AM before clinic visit. The first application began at 8 PM on day 0 (baseline) and the last application at 7 AM on day 14 (last visit). Patients were instructed on punctal occlusion after administering the drops. Adverse events were monitored carefully throughout the study. Patients were queried at each visit regarding adverse events by standard clinician inquiry. An adverse event was defined as any undesirable event occurring in a subject regardless of whether it was considered related to the investigational drug. A serious adverse event was defined as an event that was potentially fatal, life threatening, permanently disabling, requiring hospitalization, or requiring intervention to prevent permanent impairment or damage.
Statistical Evaluation The trial size of 16 patients randomly assigned to timolol and 16 to latanoprost was calculated to be sufficient to detect a difference in IOP between the two treatments of 3.5 mmHg as determined at week 2, with a two-sided test size of 5% and power 80%. It was anticipated that the between-treatment groups SD ⫽ 3 mmHg. Differences in IOP between treatment groups and reduction of IOP within treatment groups were determined with Student’s t test and the analysis of variance (ANOVA). The normality of data distribution was tested using the Shapiro-Wilk test of normality. The IOP was defined as the mean value of the measurements at 9:00 AM and 5:00 PM. If both eyes of a patient were studied, the mean IOP of both eyes was used in the analysis.
Results Of the 32 patients included in the study, 16 patients were randomly assigned to the latanoprost treatment group and 16 to the timolol treatment group. The patient characteristics of the two treatment groups are presented in Table 2. No major difference was found between the two treatment groups with respect to age, race, or gender. Of the patients included, 29 completed the study. Two patients were withdrawn from the timolol treatment group because of an IOP greater than 30 mmHg on the second day of the study. These patients had been previously treated with combined therapy of timolol ⫹ dorzolamide and timolol ⫹ latanoprost, respectively. Another patient from the timolol treatment group discontinued the
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Table 2. Demographic Characteristics of the Patients in the Two Parallel Treatment Groups Characteristics Age (yrs) Mean ⫾ SD Range Gender Female Male Race Chinese Malay Indian
Latanoprost (n ⴝ 16)
Timolol (n ⴝ 16)
64 ⫾ 7 49–77
64 ⫾ 8 50–77
8 8
8 8
12 3 1
14 2 0
n ⫽ number of patients; SD ⫽ standard deviation.
study after 1 week because of conjunctival injection and pain in the nonstudy eye. This patient’s IOP measurements after 7 days of treatment were used in the statistical analysis. The mean IOP at each measurement for the two treatment groups is presented in Table 3. Compared with baseline measurements, the IOP reduction at day 14 was statistically significant in both treatment groups (P ⬍ 0.001). In the latanoprost group the mean IOP reduction at day 14 was 8.8 ⫾ 1.1 mmHg (mean ⫾ SEM, P ⬍ 0.001; 34.2%) from a mean IOP baseline of 25.7 ⫾ 0.9 mmHg, and the corresponding figures for the timolol group were 5.7 ⫾ 0.9 mmHg (P ⬍ 0.001; 22.6%) from a mean IOP baseline of 25.2 ⫾ 1.1 mmHg. A significantly greater IOP reduction of 3.1 ⫾ 1.5 mmHg (95% confidence interval: 0.1– 6.0) was achieved in the latanoprost group compared with the timolol treatment group (P ⫽ 0.04). In Figure 1 the IOP reduction (mean ⫾ SEM) at day 14 compared with baseline is shown. The distribution of IOP change for both groups did not deviate from the normality assumption (Shapiro-Wilk test). The degree of angle closure was classified into two groups: a closure of 6 to 9 clock hours and a closure of 10 to 12 clock hours. All 16 patients in the latanoprost group had an angle closure of 6 to 9 clock hours, whereas 10 of the patients in the timolol group had an angle closure of 6 to 9 clock hours and the remaining four had a more extensive closure of 10 to 12 clock hours. However, the ANOVA analysis could not reveal any statistically significant relationship between degree of angle closure and IOP reduction (P ⫽ 0.197). Previous medication was another inclusion criteria that could vary among the patients included because they could be Table 3. Intraocular Pressure (mean ⫾ SD) in the Two Parallel Study Groups at Each Measurement Time Baseline 9 AM 5 PM Day 2 9 AM Day 7 9 AM Day 14 9 AM 5 PM
Latanoprost (n ⴝ 16)
Timolol (n ⴝ 14)
27.2 ⫾ 3.8 24.2 ⫾ 3.8
26.8 ⫾ 4.5 23.5 ⫾ 4.3
16.4 ⫾ 3.7
21.2 ⫾ 6.8
16.0 ⫾ 4.3
19.1 ⫾ 3.0
17.0 ⫾ 4.7 16.8 ⫾ 5.8
20.0 ⫾ 2.6 18.9 ⫾ 2.8
n ⫽ number of patients; SD ⫽ standard deviation.
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma
Figure 1. The intraocular pressure (IOP) reduction (mean ⫾ SEM) at 2 weeks compared with baseline.
on one or two IOP-reducing drugs before inclusion into the study. The previous medications for the different treatment groups in the study are listed in Table 4. In the latanoprost group there were five patients taking two ocular hypotensive medications, whereas in the timolol group there were seven. No statistically significant relationship between previous medication and IOP reduction could, however, be found in the ANOVA analysis (P ⫽ 0.305). Figure 2 shows scatterplots of prestudy IOP versus final IOP for different degrees of angle closure and number of previous medications. The graphs show that there was no relationship between the degree of angle closure and IOP reduction and between the number of previous medications and IOP reduction in the subjects. Ocular and systemic adverse events are presented in Table 5. Most of the events were reported as mild. In two patients in the latanoprost group and one patient in the timolol group, three to five cells (mild event) were found in the anterior chamber. No flare was found in any of these patients, and they had no ocular symptoms. At the follow-up visit after the end of the study, there were no cells in the anterior chamber on examination, and no other objective or subjective symptoms were reported. No serious adverse events were reported. Iris photographs and slit-lamp examinations did not reveal any changes in iris pigmentation. There were no changes in systemic blood pressure or pulse rate.
Discussion In this study, 2 weeks of treatment with 0.005% latanoprost once daily or 0.5% timolol twice daily significantly reduced Table 4. Number of Patients with Different Medications before Study Inclusion in the Two Parallel Study Groups Drug
Latanoprost
Timolol
Acetazolamide Betaxolol Latanoprost Pilocarpine Timolol Unoprostone
0 0 0 6 4 1
1 1 2 2 1 0
Betaxolol ⫹ pilocarpine Timolol ⫹ dorzolamide Timolol ⫹ pilocarpine
0 1 4
1 3 3
the IOP from the untreated baseline in patients with CACG. In the latanoprost group the IOP reduction was 34% (8.8 mmHg), whereas it was 23% (5.7 mmHg) in the timolol group. Thus, latanoprost was significantly better than timolol in reducing the IOP in these CACG patients. Interestingly, in CACG, the extent of the IOP-reducing effect of latanoprost once daily was similar to that seen in POAG and ocular hypertension.2– 4,6 The concern that latanoprost might not exert its pressure-reducing effect when the anterior chamber angles were partly closed could possibly be dismissed. As to whether latanoprost will be effective when the angles are fully closed remains unanswered because no patient had such an angle in the latanoprost group. The mechanism of action of latanoprost in eyes with closed angles is not known. One possibility is that latanoprost gains access to the ciliary body by way of the open part of the anterior chamber angle; another possibility is that it acts through a pathway in the uveoscleral outflow not yet fully understood. The effect of latanoprost on eyes with different degrees of angle closure could not be analyzed because all patients randomly assigned to the latanoprost group had 6 to 9 clock hours of angle closure. The inclusion criteria for this study were chosen to select a subgroup of patients with a less severe form of CACG (which was medically controlled). The reason for choosing this subgroup was concern for the IOP during the washout period and also for the efficacy of latanoprost in CACG because latanoprost acts by increasing uveoscleral outflow, which might be compromised in this type of glaucoma. The short duration of the study and small sample size were also to satisfy patient safety concerns. This small sample size might be open to bias and make the two groups unbalanced, as was found eventually with regard to the degree of angle closure and the number of prestudy medications. All 16 patients receiving latanoprost treatment had an angle closure of 6 to 9 clock hours, whereas 10 of the patients receiving timolol treatment had an angle closure of 6 to 9 clock hours, and 4 of them had a closure of 10 to 12 clock hours. This was taken into consideration in the statistical analysis, and no significant relationship between degree of angle closure and IOP reduction could be found. Another indication of severity of the disease could be the number of IOP-reducing drugs needed for adequate pressure control. Although a slight discrepancy was found between the groups, no significant relationship between number of previous medications and IOP reduction was found. However, the authors acknowledge that the results of the ANOVA statistics could have been affected by the small number of patients studied. Because prostaglandins are known to be released in the inflammatory response, cells and flare in the anterior chamber were regularly monitored during the study period as an indication of increased permeability of the blood-aqueous barrier. In the three 6-month latanoprost phase III studies, no difference was found between latanoprost and timolol in the incidence of cells and flare,2– 4 and in a study of 1-year treatment with latanoprost, only slight aqueous flare and a few cells were reported in a small number of patients.6 In
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Figure 2. Scatterplots of prestudy IOP versus final IOP for different degrees of angle closure and number of previous medications.
several other clinical studies,9,15–18 no signs of breakdown of the blood-aqueous barrier were found. In this study, two Table 5. Number of Patients with Ocular or Systemic Adverse Events Reported During the Study (Withdrawn Patients Included) Adverse Event
Latanoprost
Timolol
Ocular Conjunctival hyperemia Discomfort Cells in the anterior chamber Blurred vision Itching Punctate corneal erosions
6 4 2 1 1 0
5 2 1 2 1 1
Systemic Headache
0
1
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patients in the latanoprost group and one patient in the timolol group had a small number of cells (3–5 cells) in the anterior chamber during the treatment period. No flare was present, and no subjective ocular symptoms were present. In all three patients the cells were no longer present after the end of the study. Other side effects were transient and reported as mild in both the latanoprost and the timolol groups. In conclusion, a significantly greater IOP reduction was achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily in patients with CACG. In this preliminary study, a small group of patients was treated for a period of 2 weeks, and more extensive studies need to be performed to evaluate the drug for long-term treatment in different degrees of CACG. However, the results of this study suggest that latanoprost may be a therapeutic choice for the medical treatment of primary CACG.
Aung et al 䡠 Latanoprost and Timolol in Chronic Angle Closure Glaucoma
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