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From the Eye Clinic, Institute of Biomedical Sciences, San Paolo Hospital, University of Milan, Italy.
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Abstract |
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METHODS. In this crossover trial, 20 patients with POAG (n = 10) or OHT (n = 10) were treated with timolol, latanoprost, and dorzolamide for 1 month. The treatment sequence was randomized. All patients underwent measurements for four 24-hour tonometric curves: at baseline and after each 1-month period of treatment. The patients were admitted to the hospital, and IOP was measured by two well-trained evaluators masked to treatment assignment. Measurements were taken at 3, 6, and 9 AM and noon and at 3, 6, and 9 PM and midnight by handheld electronic tonometer (TonoPen XL; Bio-Rad, Glendale, CA) with the patient supine and sitting, and a Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland) with the patient sitting at the slit lamp. Systemic blood pressure was recorded at the same times. The between-group differences were tested for significance by means of parametric analysis of variance. The circadian IOP curve of a small group of untreated healthy young subjects was also recorded using the same procedures. To compare the circadian IOP rhythms in the POAG-OHT and control groups, the acrophases for each subject were calculated.
RESULTS. When Goldmann sitting values were considered, all the drugs significantly reduced IOP in comparison with baseline at all times, except for timolol at 3 AM. Latanoprost was more effective in lowering IOP than timolol at 3, 6, and 9 AM (P = 0.03), noon (P = 0.01), 9 PM, and midnight (P = 0.05) and was more effective than dorzolamide at 9 AM, noon (P = 0.03), and 3 and 6 PM (P = 0.04). Timolol was more effective than dorzolamide at 3 PM (P = 0.05), whereas dorzolamide performed better than timolol at midnight and 3 AM (P = 0.05). An ancillary finding of this study was that in the group of healthy subjects, the pattern of IOP curve was different that in patients with eye disease.
CONCLUSIONS. Latanoprost seemed to lead to a fairly uniform circadian reduction in IOP, whereas timolol seemed to be less effective during the nighttime hours. Dorzolamide was less effective than latanoprost but led to a significant reduction in nocturnal IOP. The reason for the difference in the pattern of the IOP curve of healthy subjects is currently unknown and deserves further investigation.
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Introduction |
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The purpose of this study was to compare the effect of three of the most widely used ocular hypotensive drugs on the circadian rhythm of IOP in patients with POAG or OHT.
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Methods |
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Visual fields were considered normal on the basis of normal global mean defect (MD) and corrected pattern SD (CPSD) field indices confirmed by at least two consecutive tests (Humphrey perimeter, 30-2 central threshold program; Humphrey Instruments, San Leandro, CA). To be deemed normal, the optic disc had to have intact rims with no disc hemorrhages, notches, localized pallor, or asymmetry of more than 0.3 in the cup-to-disc ratios (vertical or horizontal) of the two eyes. The retinal nerve fiber layer (evaluated with the Scanning Laser Ophthalmoscope 101; Rodenstock, Ottobrunn, Germany) was considered normal if a normal striation pattern was visible in all the peripapillary sectors, giving rise to a uniform light–silver reflex.
Glaucomatous visual fields had abnormal MD and CPSD field indices. For ethical reasons, patients with visual field defects within the central 10° were not included. Glaucomatous optic discs had a cup-to-disc ratio of more than 0.7. Nerve fiber layer defects included wedge defects (i.e., darker focal areas in which the visibility of the normal striation pattern was reduced or lost) that were wider than a first-order branch vein, which originated at the disc border and arched from the disc to the periphery, and diffuse defects (i.e., a diffuse and generalized rarefaction of the normal striation pattern that seemed to blur into a uniform, dull, granular whitish gray; in these areas, the walls of the denuded blood vessels stood out sharply instead of being buried in the retinal nerve fiber).
The exclusion criteria included baseline untreated IOP higher than 30 mm Hg confirmed on two occasions within 1 week; angle-closure glaucoma; corneal abnormalities preventing reliable IOP measurement, including photorefractive keratectomy; previous filtration surgery; a life-threatening or debilitating disease limiting the patient’s ability to participate in the trial; secondary causes of elevated IOP, such as the use of corticosteroids, iridocyclitis, or ocular trauma; conditions for which the trial drugs are contraindicated; absence of vision in one eye; and pregnancy. Significant disturbances of wake–sleep rhythms and/or the regular consumption of hypnotic drugs reported by the patients were also considered reasons for exclusion.
The trial had a crossover design with the patients in medical treatment undergoing a 4-week wash-out before the baseline circadian tonometric curve was recorded. The nature and purpose of the trial was explained in detail to all participants, and their informed consent was obtained before drug wash-out was initiated. The study protocol adhered to the tenets of the Declaration of Helsinki.
The patients were randomized to receive one of the following treatment sequences: 1) A, B, C; 2) A, C, B; 3) B, A, C; 4) B, C, A; 5) C, A, B; 6) C, B, A, where A was timolol 0.5% (Timoptic; Merck, Darmstadt, Germany), B was latanoprost 0.005% (Xalatan; Pharmacia Upjohn, Kalamazoo, MI), and C was dorzolamide 2% (Trusopt, Merck). Randomization was obtained using a list of random numbers. The patients were given the masked bottles and instructed to instill the eyedrops according to the study protocol: twice daily for drug A (8 AM and 8 PM), once daily for drug B (9 PM), and three times daily for drug C (8 AM, 2 PM, and 8 PM). The duration of treatment with each trial drug was 1 month, after which a circadian tonometric curve was recorded. Four circadian tonometric curves were therefore obtained for each patient: one baseline and three different treatment curves.
For recording of the circadian tonometric curves, the patients were
admitted to the hospital in the morning (at 7 AM) and stayed for the
following 24 hours. During hospital stays, they were allowed a normal
lifestyle, including reading, watching television, and playing cards.
They had normal hospital meals without any beverage restrictions,
including small amounts of beer or wine and coffee or tea. The patients
were also given an ad hoc questionnaire designed to assess their
reactions to the hospital stay, anxiety due to measurements, and
quality of sleep. The awake period lasted from approximately 6:30 AM to
11:00 PM. A complete ophthalmic examination (including corneal
pachymetry) was performed, and any information about systemic and local
tolerance of the drug was recorded. IOP was measured at 3, 6, and 9 AM
and noon and at 3, 6, and 9 PM and midnight. While patients were in the
hospital, drugs were administered by the study personnel according to
the protocol. For the daytime measurements (9 AM to 9 PM), the patients
were asked to relax in bed for approximately 15 minutes, after which
supine IOP was measured in both eyes. Subsequently, the omeral
blood pressure was assessed, and patients were then asked to sit on the
bed for another measurement of IOP. The interval between IOP
measurements in the supine and sitting positions did not exceed 5
minutes. After walking approximately 10 m, the patients reached
the nearest examination room where a third IOP value was measured at
the slit lamp. During the night (midnight to 6 AM), the patients were
awakened approximately 10 minutes before IOP and blood pressure were
measured by the same procedure at midnight and 3 and 6 AM. The IOP
measurements were made using a handheld electronic tonometer (TonoPen
XL; Bio-Rad, Glendale, CA) with the patient in supine and sitting
positions, and a Goldmann applanation tonometer with the patient
sitting at the slit lamp. All the measurements were performed by two
well-trained evaluators who were masked to the treatment assignments,
and measurements were tested for consistency and agreement (
=
0.82) before beginning the study.
The study outcome was the difference in IOP between the groups. If both eyes were eligible, only one eye (chosen at random) was used for analytical purposes.
The sample size calculation was based on the assumption that a
difference in mean IOP of 2.5 mm Hg is clinically relevant.
Approximately 2O patients were needed, given an 
= 0.05,
1-ß = 0.90, and an SD = 2 mm Hg. The between-group
differences were tested for significance by means of parametric
analysis of variance (ANOVA) with Bonferroni’s method used to adjust
P. The normality of the data distribution was checked by
means of the Shapiro–Francia W' test in all cases. Correlation was
used to test the possible association between continuous variables.
As a preliminary step, to evaluate the normal circadian IOP curve without treatment, a group of seven healthy young volunteers (aged 23–26 years) was recruited from among the medical students attending the Eye Clinic of San Paolo Hospital and underwent the same evaluation procedures as the POAG-OHT group.
To compare the circadian IOP rhythms in the POAG-OHT and control groups, the acrophases (timing of the fitted peak) for each subject were calculated as the best fitting 24-hour cosine for the eight IOP averages of both eyes.6 The supine values of the patients with POAG-OHT at baseline were compared with those of the young volunteers. Differences in the median values of the acrophases were tested using the two-tailed Mann–Whitney test. All analyses were performed by computer (SPSS ver. 6.0 for Macintosh; SPSS, Chicago, IL).
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Results |
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Figures 2 and 3 show the electronic tonometer measurements in the supine and sitting positions. The shape of the curves was consistent with those obtained using the Goldmann tonometer, and the differences in drug efficacy were maintained. The statistical significance of the between-drug comparisons is shown in Figures 2 and 3 . As previously found,2 Goldmann tonometer readings agreed well with the electronic tonometer readings in the sitting position (r = 0.90), whereas the IOP measured by electronic tonometer with the patients supine were slightly higher. The mean supine versus sitting IOPs were, respectively, 23.7 ± 1.9 mm Hg versus 22.5 ± 1.7 mm Hg at baseline, 19.4 ± 1.6 mm Hg versus 18.5 ± 1.2 mm Hg with timolol, 17.5 ± 1.0 mm Hg versus 16.8 ± 0.9 with latanoprost, and 20.0 ± 1.1 mm Hg versus 19.1 ± 1.6 mm Hg with dorzolamide. When the data are considered as a whole, the supine IOPs were significantly higher than the sitting IOPs only at noon and at 3 PM (P = 0.04). The mean diurnal versus nocturnal difference in IOP between the supine and sitting IOPs were 1.4 ± 1 mm Hg and 0.9 ± 1.1 mm Hg, respectively. This difference was not statistically significant.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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All the drugs led to a statistically significant decrease in IOP in comparison with baseline. Latanoprost was the most effective ocular hypotensive agent and, as reported in previous studies,2 3 4 its effect appeared to be fairly uniform throughout the circadian cycle. However, its efficacy was slightly but not significantly greater during the day. Similar behavior was more marked with timolol, which had a nocturnal efficacy only approximately half that obtained during the day. Finally, dorzolamide was less effective than both latanoprost and timolol during the day but maintained its efficacy during the night, when it was superior to timolol. Previous observations may help to explain the results of this trial. A number of studies indicate that the rate of aqueous flow during sleep is much lower than during waking hours,17 18 19 20 21 and that drugs affecting aqueous flow can have different effects at different times of day.17 19 22 23 Timolol, which has a substantial effect when tested during the day,1 24 25 26 27 has been found to have no measurable effect at night.19 28 29 This has been attributed to the existence of a baseline rate of flow that cannot be further suppressed by any drug, or to the absence of timolol-blocking activity in the sleeping eye.17 30 31 However, acetazolamide and apraclonidine both suppress the rate of aqueous flow in the sleeping eye,28 32 and in this study dorzolamide (a derivative of acetazolamide) maintained its effect on IOP during the night. Previous studies have shown that the effect of latanoprost (which reduces IOP by increasing uveoscleral outflow) is present throughout the circadian cycle.2 3 4 In the present crossover trial, latanoprost seemed to be more effective during the day than during the night (-6.8 ± 1.3 mm Hg versus -4.9 ± 1.0 mm Hg, respectively). Although not significant, this difference may be related to nocturnal variations in ciliary muscle tone that could affect uveoscleral outflow, as is suggested by the ability of prostaglandins to relax the ciliary muscle and thus increase the uveoscleral outflow.2 33
The circadian curves recorded using the TonoPen and Goldmann measurements in the sitting and supine positions were basically similar but, as expected, the sitting values were lower than the TonoPen supine measurements (a statistically significant difference was found at noon and at 3 PM), probably because of the increase in venous pressure in the supine position. The results of this study, however, show a smaller postural effect on IOP than was expected. This probably occurred because the interval between supine and sitting IOP measurements did not exceed 5 minutes. The brief time between the two recordings was considered to shorten, as much as possible, the awake time during the sleep period.
The circadian curves obtained in the patients with POAG or OHT at baseline and under treatment followed the pattern of the curve traditionally quoted in the literature as the day-type curve, which is characterized by a peak in the morning (between 8 and 10 AM) and a trough at night.5 This pattern was particularly evident in the case of the supine measurements. A day-type curve was not observed, however, in the small control group of healthy young subjects, who showed higher pressures during the night than during the day. This pattern is similar to that reported by Liu et al.6 in a recent study of healthy volunteers examined under strictly controlled experimental conditions, which showed a peak at 5:30 AM and a trough at 9:30 PM.
The reasons for this difference can only be hypothesized. It is possible that the different characteristics of the two groups in age (20 versus 60 years) and health may have played a role. Another explanation could reside in the experimental conditions applied by Liu et al., particularly in relation to the effect of exposure to light during IOP assessment, although in another recent study by Liu et al.,34 environmental light at night had no significant effect on the nocturnal IOP elevation in healthy young adults. That our healthy subjects were examined under the same conditions as those used for the patients with POAG or OHT and behaved similar to those of Liu et al. seems to indicate that more cogent reasons are involved.
An association between baseline supine IOP measurements and systolic blood pressure was found in the group of patients with POAG or OHT. This interesting result may suggest a role of blood pressure in influencing the circadian rhythm of supine IOP. Little is known about factors associated with circadian variation of IOP, and a positive correlation between IOP readings and blood pressure measurements has been described.35 This issue, which was not within the scope of this trial, deserves a large amount of basic and clinical research and future investigations are needed to clarify whether blood pressure levels are really associated with the circadian variations of IOP.
Any trial such as ours is naturally exposed to a series of biases that cannot be easily avoided and must be taken into consideration when drawing conclusions. The most important concern the measurement of IOP in a clinical setting: hospitalization, exposure to light during the measurements made at night, disturbed sleep, and sudden awakenings can all potentially affect the evaluation of IOP. We tried to protect the study results against these biases as much as possible, most of all with the masked, crossover design of the study, which assured an even distribution of biases to all treatments.
As far as the effect of ocular hypotensive drugs is concerned, the literature usually refers to the articles showing that the effect of latanoprost is constant during the circadian cycle,2 36 whereas timolol has no effect on aqueous flow and therefore does not decrease IOP during the night.17 To our knowledge, there is no previously published direct comparison in a clinical setting. Our results can therefore be considered of value, in that they show that the current therapeutic strategies used in the treatment of glaucoma, which are primarily based on ß-blockers, may mean that the majority of patients are less well protected during the critical nighttime period. Over the years, a large number of studies on the medical treatment of glaucoma have been undertaken in which differences of just a few millimeters of mercury were considered to be a significant result worthy of influencing clinical practice. It is therefore surprising that similar differences occurring during the night, not only between different treatments, but also with the same treatment, are routinely ignored. The results of this study underline the fact that ophthalmologists treating patients with POAG should not continue to ignore, for practical reasons, the nocturnal part of the circadian IOP curve. As Odberg37 has recently, and very appropriately, pointed out, "Glaucoma is after all a 24-hour disease."
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Footnotes |
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Commercial relationships policy: N.
Corresponding author: Nicola Orzalesi, University of Milan, Institute of Biomedical Sciences, San Paolo Hospital, Via di Rudinì 8, 20142 Milano, Italy. orzalesi{at}mailserver.unimi.it
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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),
healthy subjects. Medians of both acrophases and amplitudes were
significantly different when the two groups were compared.