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Crossover Comparison of Timolol and Latanoprost in Chronic Primary Angle-closure Glaucoma
Ramanjit Sihota, MD, FRCS;
Rohit Saxena, MD;
H. C. Agarwal, MD;
Vikas Gulati, MD
Arch Ophthalmol. 2004;122:185-189.
ABSTRACT
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Objective To compare latanoprost and timolol maleate as primary therapy in 60 eyes with chronic primary angle-closure glaucoma after a laser iridotomy.
Methods We performed a prospective, randomized, crossover study of 60 eyes of 30 patients with chronic primary angle-closure glaucoma after laser iridotomy. Patients were randomized to 2 groups: those taking latanoprost once daily or those taking timolol twice daily. Three months after treatment with the first drug, the second drug was substituted. The circadian rhythm of intraocular pressure (IOP) was recorded before the start of therapy, at 3 months, and at 7 months. The fourth month was the washout period for the first drug.
Results The mean baseline IOP was 23.5 ± 2.1 mm Hg, which decreased by 8.2 ± 2.0 mm Hg with latanoprost (P<.001) and by 6.1 ± 1.7 mm Hg with timolol (P = .01). The decrease in IOP was greater for patients taking latanoprost (P<.001). Latanoprost was significantly more effective in eyes having morning and afternoon peaks of IOP. A total of 43 eyes (72%) of patients taking latanoprost and 26 (43%) on timolol achieved a reduction of more than 30% from baseline IOP.
Conclusion There were greater mean and peak IOP reductions achieved with 0.005% latanoprost once daily compared with 0.5% timolol twice daily.
INTRODUCTION
Latanoprost, a phenyl-substituted prostaglandin analogue, has been studied extensively for its intraocular pressure (IOP)-lowering efficacy and adverse effects in cases of primary open-angle glaucoma.1-3 Numerous studies4-5 have also compared its effect with that of timolol maleate in cases of primary open-angle glaucoma. Chronic primary angle-closure glaucoma constitutes a significant proportion of all glaucomas, especially in Asia.  -Blockers and pilocarpine nitrate have been routinely used for the medical therapy of chronic primary angle-closure glaucoma after an iridotomy; however, the role of newer antiglaucoma medications like latanoprost needs evaluation. The formation of peripheral anterior synechiae in chronic primary angle-closure glaucoma could diminish access to the uveoscleral outflow, the major mechanism of action of latanoprost. To our knowledge, no long-term, crossover study has evaluated latanoprost and timolol with respect to their efficacy in cases of chronic primary angle-closure glaucoma. The aim of the present study was to compare the effect of latanoprost administered once at night with timolol administered twice daily in a masked, crossover study in chronic primary angle-closure glaucoma eyes.
METHODS
The study was designed as a prospective, randomized, crossover trial comparing the efficacy and adverse effects of timolol and latanoprost as monotherapy in freshly diagnosed cases of eyes having chronic primary angle-closure glaucoma after an Nd:YAG laser iridotomy. Consecutive adult patients with bilateral, untreated, chronic primary angle-closure glaucoma were included in the study after providing informed consent. Human investigation guidelines were adhered to. All patients had an occludable angle, with peripheral anterior synechiae involving more than 180°, a baseline IOP of more than 21 mm Hg without any antiglaucoma medication on more than 2 occasions, and optic nerve head and visual field changes commensurate with the diagnosis of glaucoma. All patients had a patent peripheral iridotomy.
Exclusion criteria included prior medical or surgical intervention for the control of IOP, any previous ocular surgery, any other intraocular disorder, or any condition preventing reliable applanation tonometry. Patients using systemic -blockers were excluded. Known hypersensitivity to any component of the drugs to be used, patients who were unable to adhere to the follow-up protocol, or those with systemic or ocular problems that contraindicated the use of either of the 2 study drugs were also excluded. Patients with a baseline IOP of more than 35 mm Hg or cases with advanced glaucoma (defined as cupping ratio of 0.9 and/or perimetric evidence of visual field loss within 10° of fixation in one or more quadrants) were also excluded from the study.
At the time of enrollment in the study, a complete medical and ocular history was taken, and any concurrent medical therapies were recorded. A systemic examination was performed to evaluate the cardiovascular and respiratory status. A comprehensive ocular examination was performed, including best-corrected visual acuity, slitlamp examination, biomicroscopic fundus evaluation, 3-hourly applanation tonometry from 7 AM to 10 PM on a single day using a Goldmann applanation tonometer, and full threshold automated perimetry on the 30-2 program of Humphrey field analyzer.
The patients were then randomized into 2 parallel study groups: one group received 0.005% latanoprost at 10 PM once daily, and the other group received 0.5% timolol maleate at 8 AM and 8 PM. Follow-up examination was performed at 3 weeks, 6 weeks, and 3 months after the start of therapy. Best-corrected visual acuity, IOP recording, and fundus evaluation were performed at each follow-up visit. After 3 months, the second medication was substituted (ie, patients in the latanoprost group started taking timolol and vice versa). The first month of treatment with the second drug (ie, the fourth month of the trial) was deemed the washout period for the first drug used during the first 3 months of therapy. Additional follow-up was performed at 3 weeks, 6 weeks, and 3 months after the washout period.
A circadian recording of IOP and full threshold automated perimetry were repeated at 3 and 7 months after enrollment in the study (ie, 3 months following the use of each drug). The timings of the diurnal recording of IOP were 7 AM, 10 AM, 1 PM, 4 PM, 7 PM, and 10 PM; on all occasions the IOP recorded was performed by applanation tonometry in the sitting position by a single masked observer. Patients were recalled on an outpatient basis every 3 hours on 1 day.
At each of the follow-up visits, the patient's eye was examined with slitlamp biomicroscopy to rule out any uveitis, iris color changes, or any eyelash changes. The patients were also asked in detail about any adverse ocular and systemic events that occurred during the treatment. A subsequent systemic examination with heart rate and blood pressure measurement was performed at each follow-up visit.
The efficacy of the 2 drugs was evaluated with respect to the dampening of the range of diurnal variation in IOP, its effect on the different types of circadian cycles, and drug efficacy regarding baseline peak IOP. The effectiveness of the 2 drugs was also evaluated with respect to age, sex, and the presence or absence of diabetes and hypertension.
Peak pressure was defined as the highest pressure recorded in each individual circadian rhythm. Trough pressure was defined as the lowest pressure recorded in each individual circadian rhythm. A change in the timing of the peak pressures recorded at baseline and on diurnal measurements of IOP at 3 and 7 months was recorded in each individual. It was considered negative if the peak IOP in the circadian rhythm on treatment was previously earlier compared with the timing of the baseline peak and positive if it occurred later.
Each baseline circadian rhythm was classified as morning type, noon type, and evening type, depending on the timing of the peak pressures recorded in that diurnal curve. Morning type was defined as peak pressures at 7 AM or 10 AM. Noon type was defined as peak pressures at 1 PM or 4 PM. Evening type was defined as peak pressures at 7 PM or 10 PM.
Statistical analysis was performed with STATA Intercooled statistical software, version 6.0 (Stata Corp, College Station, Tex) using the unpaired t test and 2-way analysis of variance. Data are presented as mean ± SD.
RESULTS
Sixty eyes of 30 patients were enrolled in the study during an enrollment period of 3 months. The mean age of the patients was 57.7 ± 7.4 years (age range, 46-76 years). There were 18 men and 12 women. The prevalence of diabetes mellitus was 30%, and the prevalence of hypertension was 13%. Both the diseases were controlled with oral medication. None of the patients were taking oral -blockers for control of elevated blood pressures. The mean cup-disc ratio was 0.6 ± 0.8. Peripheral anterior synechiae extended from 180° to 270° in all the eyes studied.
The mean of the baseline IOP was 23.5 ± 2.1 mm Hg and was decreased to 15.3 ± 1.8 mm Hg (34.9%) with latanoprost (P<.01) and to 17.4 ± 1.7 mm Hg (26.0%) with timolol (P<.01). The baseline circadian rhythm of IOP and the IOP with latanoprost and timolol are detailed in Table 1 and Figure 1. Both the drugs significantly reduced IOP compared with baseline at all points on the diurnal curve. Latanoprost was significantly more effective in lowering IOP than timolol at 7 AM, 10 AM, 1 PM, 4 PM, and 7 PM. At 10 PM patients taking latanoprost recorded lower IOPs compared with those taking timolol, but the difference between the 2 drugs was not statistically significant (P = .25).
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Table 1. Diurnal Variation of Intraocular Pressure (IOP) at Baseline and After 3 Months of Therapy With Latanoprost and Timolol in 60 Eyes
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Baseline intraocular pressure (IOP) and IOP after 3 months of therapy with latanoprost and timolol maleate at different times during the day. Error bars indicate 95% confidence intervals.
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The average of the peak pressures recorded in the 60 individual baseline IOP curves was 27.5 ± 2.7 mm Hg. The average of the highest IOP recorded in each of the subsequent individual circadian rhythms was 18.1 ± 2.4 mm Hg after treatment with latanoprost for 3 months and 20.4 ± 2.5 mm Hg after treatment with timolol for 3 months; both the drugs showed a significant reduction compared with baseline peak pressures (P<.01). The peak IOP reduction was greater for latanoprost compared with timolol (P<.01).
The average of the trough IOP recorded in each of the individual baseline IOP curves was 20.2 ± 2.1 mm Hg. The average of the trough IOP that was recorded at any point of time on each of the diurnal curves was 12.5 ± 2.1 mm Hg with latanoprost (P<.01) and 14.4 ± 2.9 mm Hg with timolol (P<.01). The IOP reduction was greater for patients taking latanoprost compared with those taking timolol (P<.01).
In each of the individual diurnal curves, the alteration in timing of IOP peaks on therapy with both the drugs was compared with the time of the peak IOP on the baseline diurnal curve of the same patient. The average of this shift in the time of the peak pressures was recorded for both the drugs used (Table 2). The results showed that with timolol there was no significant time shift of the peak IOP compared with baseline in all the 3 types of circadian rhythms, and overall the peak IOP was recorded 0.15 ± 0.4 hours later than that recorded in the baseline curve. Latanoprost caused the peak IOP to occur 3.3 ± 1.79 hours later in the day, especially for those with a morning or afternoon peak.
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Table 2. Time Shift of Baseline Peak Intraocular Pressure After Treatment in 60 Eyes*
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The circadian rhythm recorded on baseline evaluation was divided into 3 categories: those with peaks in the morning (30 eyes, 50%), noon (20 eyes, 33.3%), or evening (10 eyes, 16.7%). Evaluating measurements of IOP at the time of the baseline peak, the decrease in the IOP after the use of latanoprost or timolol was analyzed in each of the 3 types of circadian patterns (Table 3). Timolol caused a similar decrease in IOP in all the 3 types of circadian rhythms, whereas latanoprost caused a mean percentage decrease in IOP of 40.9% ± 5.5% in those with a morning peak, 34.8% ± 6.3% for afternoon peaks, and 31.9% ± 6.5% in eyes having a peak at night. This difference in the efficacy of latanoprost in patients with a night peak (31.9%) compared with patients with a morning peak (40.9%) was statistically significant (P<.01).
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Table 3. Change in Mean Intraocular Pressure (IOP) on Therapy in 60 Eyes With Different Circadian Rhythms*
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Different age groups, the sex of the patient, the presence or absence of hypertension or diabetes, and the height of the baseline peak, trough, and mean IOP did not affect the pressure reduction achieved with either drug. The effect of the 2 drugs was similar whether used first or second in the study.
The numbers of patients who did not achieve a mean IOP of 21 mm Hg or less with treatment were 6 (10%) in the timolol group and 1 in the latanoprost group. A peak IOP of more than 21 mm Hg was seen in 15 cases (25%) in the timolol group and 4 cases (7%) in the latanoprost group. An IOP reduction of less than 20% was noted in 5 cases (8%) after latanoprost treatment and in 13 (22%) after timolol treatment. A pressure reduction of 30% or more from baseline was observed in 43 eyes (72%) of patients taking latanoprost compared with 26 (43%) of those taking timolol (P<.001) (Table 4). The patient whose condition was uncontrolled with latanoprost showed a mild elevation of IOP to 25 mm Hg, which was confirmed on stopping use of and rechallenging with latanoprost.
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Table 4. Percentage Reduction in Mean Intraocular Pressure (IOP) After 3 Months of Therapy With Latanoprost and Timolol in 60 Eyes
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No significant adverse effects were observed during the study period. Four patients taking latanoprost complained of discomfort during the study period, 2 patients taking latanoprost complained of conjunctival hyperemia, and 2 patients reported foreign body sensation after instilling timolol drops. None of the adverse effects were significant enough to result in discontinuation of therapy. There was no significant change in the pulse rate and blood pressure of patients taking any of the medications used in our study compared with the baseline.
COMMENT
In chronic primary angle-closure glaucoma, a peripheral iridotomy helps to relieve the pupillary block and further attacks of angle closure; however, medication is required to control the chronically elevated IOP caused by obstruction of aqueous outflow secondary to synechial angle closure and trabecular meshwork damage.6 Previous studies7-8 have noted that patients with chronic angle-closure glaucoma in whom disc and field changes had occurred were not likely to have their condition controlled with an iridectomy but required a trabeculectomy to control their IOP. Pilocarpine and -blockers have been the mainstay of therapy for chronic angle-closure glaucoma9-10 and were seen to control the IOP in 30% of chronic primary angle-closure glaucoma eyes.10
There are many new antiglaucoma drugs now available, the most efficacious being prostaglandin analogues, which act by increasing the uveoscleral outflow. Access to the uveoscleral pathway is through the ciliary muscle bundles into the supraciliary and suprachoroidal spaces from which it is drained through sclera. The presence of peripheral anterior synechiae could possibly hamper the flow of aqueous into this pathway and perhaps decrease the efficacy of drugs such as prostaglandin analogues.
The efficacy of latanoprost has been compared with timolol in multiple studies, but to the best of our knowledge, there has been no previous long-term, crossover study regarding their effect on peak IOPs in cases of primary angle-closure glaucoma. The current study was undertaken to evaluate and compare the efficacy of latanoprost with timolol in eyes with chronic primary angle-closure glaucoma. The 2 medications have a different viscosity and different administration regimens that made masking difficult. Because the same patients were tested with both drugs, confounding factors were minimized.
We noted the mean reduction of IOP to be 8.2 ± 0.4 mm Hg with latanoprost and 6.1 ± 0.2 mm Hg with timolol. A similar reduction was reported by Aung et al11 in a small number of eyes studied for 2 weeks; latanoprost reduced the IOP by 8.8 ± 1.1 mm Hg compared with 5.7 ± 0.7 mm Hg by timolol. Hedman and Alm12 reported a mean decrease of 7.7 ± 0.1 mm Hg in a meta-analysis of primary open-angle glaucoma eyes compared with a mean decrease of 8.7 ± 2.2 mm Hg in our study, starting from similar baseline IOPs.
A previous study13 has shown that patients with IOP consistently below 15 mm Hg had a higher chance of remaining stable. However, because different patients have different baseline pressures and different target pressures, it may be reasonable to lower the IOP by at least 30% of baseline pressures to prevent progression of field loss.14 The effect of latanoprost on mean IOP was clinically more significant than timolol in our study in causing a reduction of more than 30% from baseline. This decrease of more than 30% from baseline was seen in 72% of primary angle-closure glaucoma eyes of patients taking latanoprost and 43% of primary angle-closure glaucoma eyes of patients taking timolol.
We evaluated the circadian rhythm in eyes with chronic primary angle-closure glaucoma before and after therapy with latanoprost and timolol. Our study noted a significantly higher reduction of peak and trough IOP with latanoprost compared with timolol. There was thus a greater dampening of the circadian rhythm of IOP with latanoprost in chronic primary angle-closure glaucoma eyes. The evening efficacy of latanoprost and timolol was similar. Orzalesi et al15 and Racz et al16 have also noted that latanoprost leads to a more uniform circadian rhythm in primary open-angle glaucoma eyes. Hedman and Alm12 found latanoprost to be more effective than timolol in primary open-angle glaucoma eyes when morning, noon, and afternoon IOPs were averaged to determine the diurnal IOP. In our study, latanoprost used at night was less effective in the control of baseline IOP peaks that occurred in the evening (7-10 PM). Timolol was equally effective in all types of circadian rhythms and appeared to work around the clock, albeit to a lesser extent.
It is important to schedule the follow-up of glaucoma patients around the time that the highest IOP is expected. We studied the temporal change of the highest recorded IOP in eyes after the use of latanoprost and timolol. The time shift of peak IOPs in eyes of patients taking timolol was insignificant in all types of circadian rhythms. Of patients taking latanoprost, the peak IOP in eyes with morning and afternoon baseline peaks were shifted 3 to 7 hours later in the day. This could be due to its efficacy waning with time. The time difference noted by us could be kept in mind when scheduling follow-up visits. In conclusion, latanoprost was clinically more effective than timolol because it lowered the IOP to a greater extent and dampened the circadian rhythm of IOP.
AUTHOR INFORMATION
Corresponding author: Ramanjit Sihota, MD, FRCS, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi 110029, India (e-mail: rjsihota{at}hotmail.com).
Submitted for publication June 6, 2003; final revision received August 17, 2003; accepted September 15, 2003.
The principal author takes full responsibility for the integrity of the data and the reliability of the data analysis.
From the Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. The authors have no relevant financial interest in this article.
REFERENCES
1. Camras CB, Alm A, Watson P, Stjernschantz J, Latanoprost Study Groups. Latanoprost, a prostaglandin analogue, for glaucoma treatment: efficacy and safety after 1 year of treatment in 198 patients. Ophthalmology. 1996;103:1916-1924.
2. Watson PG, Latanoprost Study Groups. Latanoprost: two years experience of its use in the United Kingdom. Ophthalmology. 1998;105:82-87.
3. Suzuki M, Mishima HK, Masuda K, Araic M, Kitazawa Y, Azuma I. Efficacy and safety of latanoprost eye drops for glaucoma treatment: a 1-year study in Japan. Jpn J Ophthalmol. 2000;44:33-38.
PUBMED
4. Camras CB, United States Latanoprost Study Groups. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six month, masked, multicentric trial in the United States. Ophthalmology. 1996;103:138-147.
ISI
| PUBMED
5. Watson P, Stjernschantz J, Latanoprost Study Group. A six month randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103:126-137.
ISI
6. Sihota R, Lakshmaiah NC, Walia KB, Sharma S, Pailoor J, Agarwal HC. The trabecular meshwork in acute and chronic angle-closure glaucoma. Indian J Ophthalmol. 2001;49:255-260.
PUBMED
7. Gelber EC, Anderson DR. Surgical decisions in chronic angle-closure glaucoma. Arch Ophthalmol. 1976;94:1481-1484.
ABSTRACT
8. Playfair TJ, Watson PG. Management of chronic or intermittent primary angle-closure glaucoma: a long-term follow-up of the results of peripheral iridectomy used as an initial procedure. Br J Ophthalmol. 1979;63:23-28.
FREE FULL TEXT
9. Steinbach PD, Gruia DG. Long-term study of chronic glaucoma treated with beta blockers (timolol). Klin Monatsbl Augenheilkd. 1987;190:534-538.
PUBMED
10. Sihota R, Agarwal HC. Profile of the subtypes of angle-closure glaucoma in a tertiary hospital in India. Indian J Ophthalmol. 1998;46:25-29.
PUBMED
11. Aung T, Wong HT, Yip CC, Leong JY, Chan YH, Chew PT. Comparison of the intraocular pressure lowering effect of latanoprost and timolol in patients with chronic angle-closure glaucoma: a preliminary study. Ophthalmology. 2000;107:1178-1183.
12. Hedman K, Alm A. A pooled data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol. 2000;10:95-104.
PUBMED
13. Hovding G, Aasved H. Prognostic factors in development of manifest open-angle glaucoma: a long term follow up study of hypertensive and normotensive eyes. Acta Ophthalmol (Copenh). 1986;64:601-608.
PUBMED
14. Asrani S, Zeimer R, Wilinsky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients of glaucoma. J Glaucoma. 2000;9:134-142.
ISI
| PUBMED
15. Orzalesi N, Rossetti L, Invernizzi T, Bottoli A, Auteitano A. Effect of timolol, latanoprost and dorzolamide on circadian intraocular pressure in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci. 2000;41:2566-2572.
FREE FULL TEXT
16. Racz P, Ruzsonyi MR, Nagy ZT, et al. Around-the-clock (circadian) intraocular pressure reduction with once-daily application of 0.005% latanoprost by itself or in combination with timolol. Arch Ophthalmol. 1996;114:268-273.
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