Abstract
purpose. To compare the around-the-clock intraocular pressure (IOP) reduction
induced by timolol 0.5%, latanoprost 0.005%, and dorzolamide in
patients with primary open-angle glaucoma (POAG) or ocular hypertension
(OHT).
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.
High intraocular pressure (IOP) is considered to be the most
important risk factor for development of primary open-angle glaucoma
(POAG), and its reduction continues to be the only reasonable way of
treating the disease.
1 Surprisingly enough, the vigorous
efforts dedicated to finding new drugs for ocular hypotension (OHT)
have rarely been accompanied by a careful examination of their
circadian effects. With very few exceptions,
2 3 4 reports
on the efficacy of ocular hypotensive drugs are limited to the diurnal
curve of IOP, usually from 9 AM to 5 PM. However, it is clear that such
an evaluation is not sufficient to indicate the real value of an ocular
hypotensive treatment for at least three reasons. First, both IOP and
the rate of aqueous humor flow have a circadian rhythm,
5 and higher IOP may be recorded during the night.
5 6 7 8 9 10 11 12 13 Second, nighttime may be considered a critical period for the control
of glaucoma (particularly low-tension glaucoma) because the nocturnal
decrease in systemic blood pressure may make the nocturnal IOP even
more critical.
14 15 16 Finally, the effect of ocular
hypotensive drugs may not be the same during the night and day. Some
investigators have suggested that β-blockers do not decrease the
production of aqueous humor during sleep,
17 18 19 whereas
both acetazolamide and apraclonidine also have been found to suppress
the rate of aqueous flow in the sleeping eye.
17 Moreover,
administered once a day, the recently introduced latanoprost leads to a
reduction in IOP throughout the night that is comparable to its daytime
effect.
2 3 4
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.
The trial involved 20 patients with diagnosed POAG or OHT.
Glaucoma was defined as IOP higher than 21 mm Hg without medication (in
at least one eye and measured on two consecutive occasions separated by
an interval of at least 2 hours but not more than 12 weeks),
glaucomatous field or optic disc changes, or retinal nerve fiber layer
defects. OHT was defined as IOP higher than 21 mm Hg without medication
(measured as in POAG), and a normal visual field, optic disc, and
retinal nerve fiber layer.
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 (κ =
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 α = 0.05,
1-β = 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).
Twenty patients were enrolled in the trial (10 with POAG and 10
with OHT) Their main characteristics are shown in
Table 1 . Corneal pachymetry was within normal ranges for all subjects.
All patients completed the three crossover phases, and no important
adverse event was recorded.
Figure 1 shows the Goldmann tonometer readings of baseline, timolol,
latanoprost, and dorzolamide circadian curves. All the drugs
significantly reduced IOP in comparison with baseline at all time
points, except for timolol at 3 AM. The mean IOPs were 22.7 ± 1.8
mm Hg at baseline, 18.7 ± 0.9 mm Hg with timolol, 16.3 ±
0.6 with latanoprost, and 19.3 ± 1.7 with dorzolamide. The
differences in mean IOP were statistically significant when latanoprost
was compared with timolol (
P = 0.001) and dorzolamide
(
P = 0.001). There was no statistically significant
difference in the mean IOP between timolol and dorzolamide.
Latanoprost was more effective in lowering IOP than timolol at 3, 6,
and 9 AM, at noon, at 9 PM, and at midnight. It was also more effective
than dorzolamide at 9 AM, at noon, and at 3 and 6 PM. Timolol
significantly reduced IOP in comparison with dorzolamide at 3 PM,
whereas dorzolamide performed better than timolol at midnight and 3 AM.
In comparison with baseline, the mean diurnal (9 AM to 9 PM) versus
nocturnal (midnight to 6 AM) reductions in IOP were, respectively,−
4.1 ± 1.2 mm Hg versus −1.9 ± 0.5 mm Hg
(P = 0.04) for timolol, −6.8 ± 1.3 mm Hg versus−
4.9 ± 1.0 mm Hg (P = 0.1) for latanoprost, and−
3.5 ± 1.2 mm Hg versus −3.4 ± 1.0 mm Hg
(P = 0.8) for dorzolamide.
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.
Figures 4 and 5 show the circadian curves and acrophases of baseline IOP in the
patients with POAG or OHT compared with those observed in the group of
young healthy volunteers. The median acrophases in the two groups were
compared: the amplitude of the circadian rhythm in the POAG-OHT group
was significantly higher than in the control subjects
(
P = 0.02, Mann–Whitney test). The mean acrophase in
the POAG-OHT group was at 8:55 AM as opposed to 5:20 AM in the control
group. This difference was also statistically significant
(
P = 0.04).
The blood pressure measurements in the patients with POAG or OHT and
the corresponding supine IOP at baseline are shown in
Figure 6 . A significant correlation was found between supine IOP and systolic
blood pressure at baseline (
r = 0.61,
P = 0.02).
Responses to the questionnaire indicated that although some patients
experienced some difficulty in going to sleep, in general all judged
the quality of days and nights spent at the hospital for the assessment
of the circadian IOP curves to be normal.
The results of this trial clearly show that the effects of the
three studied drugs differed markedly in the various phases of the
circadian IOP curve.
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 β-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 Odberg
37 has recently, and very appropriately,
pointed out, “Glaucoma is after all a 24-hour disease.”
Submitted for publication November 8, 1999; revised March 6, 2000; accepted March 17, 2000.
Commercial relationships policy: N.
Corresponding author: Nicola Orzalesi, University of Milan, Institute of Biomedical Sciences, San Paolo Hospital, Via di Rudinı̀ 8, 20142 Milano, Italy.
[email protected]
Table 1. Patients’ Main Characteristics
Table 1. Patients’ Main Characteristics
| n | 20 |
| POAG (n) | 10 |
| OHT (n) | 10 |
| Age (mean± SD) | 67± 11.5 |
| Sex | 13 F, 7 M |
| IOP (mean at enrollment) | 23.9± 4.7 mmHg |
| Corneal thickness | 550± 20 mm |
| Prestudy therapy (n) | |
| None | 6 |
| β-Blockers | 8 |
| Dorzolamide | 1 |
| Association* | 5 |
| Systemic hypertension (n) | 13 |
| Treated with β-blockers (n) | 7 |
| Other treatments (n) | 6 |
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