Abstract
purpose. To compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on intraocular pressure (IOP), blood pressure (BP), and diastolic ocular perfusion pressure (DOPP), calculated as the difference between the diastolic blood pressure (DBP) and IOP.
methods. According to a 4 × 4 Latin squares design for repeated measures, 27 untreated patients and patients with newly diagnosed primary open-angle glaucoma (POAG) were treated with timolol 0.5% at 8 AM and 8 PM; brimonidine 0.2% at 8 AM and 8 PM; dorzolamide 2% at 8 AM, 2 PM, and 8 PM; and latanoprost 0.005% at 8 PM. The duration of each treatment course was 6-weeks, with a 4-week washout between each treatment. IOP and BP were measured at baseline and at the end of each treatment period. IOP was measured every 2 hours throughout a 24-hour period. Sitting IOP was measured from 8 AM to 10 PM by Goldmann applanation tonometry. Supine IOP was assessed from 12 to 6 AM by means of a handheld electronic tonometer (TonoPen XL; Mentor, Norwell, MA). BP monitoring was performed by means of an automated portable device (TM-2430; A & D Co., Saitama, Japan).
results. All the drugs tested decreased the IOP significantly at all time points in comparison with baseline pressure. The mean 24-hour IOP after latanoprost administration (16.62 ± 0.98 mm Hg) was significantly lower than that after timolol, brimonidine, or dorzolamide (P = 0.0001). During the 24-hour period, brimonidine induced a significant decrease in systolic BP (SBP) and DBP at all time points when compared with baseline measurements and with those after administration of the other drugs (P < 0.0001). Timolol caused a significant decrease in DBP and SBP at all the 24-hour time points when compared with the baseline and with the dorzolamide- and latanoprost-induced changes (P < 0.0001). The mean 24-hour DOPPs were 50.7 ± 5.9 mm Hg at baseline, 53 ± 5.5 mm Hg with timolol, 46.2 ± 5.4 mm Hg with brimonidine, 55.9 ± 4.6 mm Hg with dorzolamide, and 56.4 ± 4.9 mm Hg with latanoprost. Brimonidine induced a significant decrease in the mean 24-hour DOPP compared with that at baseline (P < 0.0001), whereas dorzolamide and latanoprost induced a significant increase (P < 0.0001).
conclusions. Latanoprost seemed to induce a uniform reduction in IOP during the 24-hour period, although timolol was as effective as latanoprost during the daytime, and dorzolamide are as effective as latanoprost at night. SBP and DBP were significantly decreased by either timolol or brimonidine. In this study of patients with newly diagnosed POAG, only dorzolamide and latanoprost significantly increased mean 24-hour DOPP.
The role of IOP levels in determining the onset and progression of primary open-angle glaucoma (POAG) has been clearly defined by several randomized clinical trials and population-based epidemiologic studies.
1 2 3 4
In fact, it has been shown that IOP reduction is beneficial in reducing the rate of conversion from ocular hypertension to POAG,
1 2 and in halting or slowing the progression of anatomic and functional damage in POAG.
3 4 At present, reduction of IOP remains the gold standard of glaucoma therapy, even if high IOP is not the only risk factor involved in the disease.
5
Several population-based epidemiologic studies
6 7 8 9 10 have shown that low diastolic blood pressure (DBP) and diastolic ocular perfusion pressure (DOPP; DOPP = DBP − IOP) are major risk factors for the genesis and progression of POAG. As a matter of fact, in all of these studies, low DOPP (<55 mm Hg) was associated with an increased prevalence
6 7 8 9 and incidence
10 of POAG.
It thus seems reasonable that medical therapy for POAG should not only reduce IOP, but should also increase DOPP, to further reduce the rate of progression of this disease.
The goals of the present study were to compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on IOP, blood pressure (BP), and DOPP.
Patients with newly diagnosed, untreated POAG, who had typical optic disc excavation and abnormalities of the visual field and retinal nerve fibers layer, were recruited from January to November 2004 from the Glaucoma Service of the Department of Ophthalmology of the University of Brescia, Italy.
Eligibility criteria were age ≥ 45 years; no previous ocular surgery; open-angle by gonioscopy: grades III and IV according to Shaffer’s grading system; untreated IOP ≥ 23 and ≤ 32 mm Hg (average of the two highest values recorded during daytime, with measurements taken every 2 hours from 8 AM to 6 PM by Goldmann applanation tonometry); no previous laser trabeculoplasty; visual acuity of 20/40 or better; mean defect >6 dB, according to the Humphrey 24-2 program (Humphrey Visual Field Analyzer model 745 perimeter, Carl Zeiss Meditec, Inc., Dublin, CA); no history of allergy to the ingredients of any of the study medications (eye drops); no cardiovascular disease (e.g., hypertension, cardiac insufficiency, arrhythmia), and no concomitant systemic treatment (e.g., β-blockers, angiotensin-converting enzyme inhibitors) that could modify IOP or blood pressure. Women were enrolled in the study only if they were postmenopausal or were using contraceptives.
Informed consent was obtained from all the participants after the nature and possible consequences of the study were explained. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board (IRB of Clinica Oculistica, The University of Brescia).
The study was a 4 × 4 Latin squares, observer-masked, clinical trial. All patients were evaluated at baseline and then randomized to one of the four treatment sequences.
The experimental eye drop treatments were timolol 0.5% (instilled at 8 AM and 8 PM), brimonidine 0.2% (8 AM and 8 PM), dorzolamide 2% (8 AM, 2 PM, and 8 PM), and latanoprost 0.005% (8 PM).
Patients were instructed to instill a single drop. The duration of each treatment was 6 weeks, followed by a 4-week washout period. IOP and BP were measured at baseline and at the end of each treatment period. At the time of 24-hour IOP and BP assessment patients were hospitalized, and the drugs were administered by study personnel according to the protocol.
DOPP was calculated as the difference between diastolic blood pressure (DBP) and the intraocular pressure (IOP).
All patients underwent 12 measurements of IOP (every 2 hours over a 24-hour period) by Goldmann applanation tonometry and with a handheld tonometer (TonoPen XL; Mentor), and 24-hour blood pressure monitoring by means of an automated portable blood pressure device (TM-2430; A & D Co.).
IOP was measured by Goldmann applanation tonometry (mean of three consecutive readings) with the patient in a sitting position at the slit lamp from 8 AM to 10 PM. From 12 AM to 6 AM, with the patient supine in bed, measurements were made by means of the handheld electronic tonometer (mean of three consecutive readings).
Dynamic blood pressure monitoring was performed by means of the automated portable device (TM-2430; A & D Co.). This instrument measures blood pressure automatically, on the same principle as the conventional mercury sphygmomanometer, with a cuff and a microphone. The interval between measurements can be preselected, and BP readings are recorded on a data processor. Blood pressure measurements were taken automatically every 15 minutes from 8 AM to 10 PM and every 30 minutes from 10 PM to 8 AM. If a reading were considered faulty by the device, it was programmed to reinflate, which helped to avoid missing a measurement. All the values were later recovered from the recording chip on a personal computer. BP and IOP readings were taken in the hospital on two different days, so that BP readings would not be altered by the procedures necessary for IOP measurement or by waking the patient during the night for IOP evaluation. IOP measurements were performed by three well-trained, masked operators who were unaware of the treatment assignments. Their agreement was tested on 15 independent patients before this study, resulting in an intraclass correlation coefficient of 0.97 and 0.99 for TonoPen and Goldmann tonometry, respectively.
Complete ocular and systemic examinations were performed at baseline and at the conclusion of each phase of the trial, and any ocular or systemic adverse events were noted.
Descriptive statistics (mean and SD) were calculated for the variables. Statistical analyses were performed by analysis of variance (ANOVA) for a Latin squares design, followed by multiple comparisons with the Bonferroni correction of the significance level. The sample size of 27 patients provided a power of approximately 0.80, for demonstrating an effect size of 0.65 between the investigated drugs, at a significance level of 0.01 (two-tailed: multiple pair-wise comparisons). Considering the mean 24-hour variation in IOP to be 1.5 mm Hg, an effect size of 0.65 gives a difference of ∼1 mm Hg in pair-wise comparisons. If both eyes were eligible, data of one eye, chosen at random, were used for statistical analysis. The statistical analysis was performed on computer (SPSS ver. 12.0; SPSS Inc., Chicago, IL).
Twenty-seven patients with newly diagnosed POAG were enrolled in this study. All patients completed all phases of the study. No significant adverse event was recorded for any of the studied drugs.
Table 1shows the general features of the patients included. No significant differences in IOP or BP were noted between baseline values and those obtained after each washout period.
Figure 1shows the results of the 24-hour IOP assessment at baseline and after timolol, brimonidine, dorzolamide, and latanoprost treatments. Each of the drugs significantly decreased the IOP at all time points in comparison with untreated baseline IOP.
The mean 24-hour IOP was 22.69 ± 2.58 mm Hg at baseline, 17.63 ± 1.38 mm Hg with timolol, 18.32 ± 1.50 mm Hg with brimonidine, 17.37 ± 1.47 mm Hg with dorzolamide, and 16.62 ± 0.98 mm Hg with latanoprost. The mean 24-hour IOP level after latanoprost administration was significantly lower than that after timolol, brimonidine, or dorzolamide (P = 0.0001). No significant differences were noted between the other drugs.
With regard to single time points, latanoprost had a greater effect on IOP than did timolol at 10 PM (P = 0.001), 12 AM (P = 0.001), 2 AM (P = 0.002), 4 AM (P = 0.002), and 6 AM (P = 0.0001). No significant differences in IOP were found from 8 AM to 8 PM between timolol and latanoprost.
Dorzolamide was as effective as latanoprost on IOP from 10 PM to 6 AM, but less effective than timolol or latanoprost from 6 AM to 8 PM (6 AM: P = 0.0001; 8 AM: P = 0.04; 10 AM: P = 0.0001; 12 to 4 PM: P = 0.01; 6 PM: P = 0.005; and 8 PM: P = 0.002). Dorzolamide was also more effective than brimonidine from 10 PM to 6 AM (10 PM: P = 0.0001; 12 AM: P = 0.003; 2 AM: P = 0.0001; 4 AM: P = 0.003; 6 AM: P = 0.0001), but no significant differences in IOP were found from 6 AM to 8 PM.
The effect on IOP induced by brimonidine was significantly less than that induced by timolol from 8 AM to 4 PM (8 AM: P = 0.02; 10 AM: P = 0.0001; 12 PM: P = 0.004; 2 PM: P = 0.01; 4 PM: P = 0.007), and at 8 PM (P = 0.006); less than that of dorzolamide from 10 PM to 6 AM, and less than that of latanoprost at all time points (P < 0.001).
Table 2shows the mean 24-hour SBP and DBP for the drugs studied. The mean 24-hour SBP and DBP were significantly reduced by brimonidine (SBP and DBP:
P < 0.0001) and by timolol (SPB:
P = 0.009; DBP:
P = 0.01), when compared with the baseline measurements and with those after latanoprost or dorzolamide instillation.
During the 24-hour period, brimonidine induced a significant decrease in SBP and DBP at all time points when compared with baseline and with the other drugs (
P < 0.0001). The greatest decreases in SBP were observed from 6 PM to 9 PM and from 12 to 7 AM. The greatest DBP reduction induced by brimonidine was seen from 11 PM to 7 AM
(Figs. 2 3) .
Timolol induced a fairly uniform and significant decrease in both DBP and SBP at all time points when compared with baseline, dorzolamide, and latanoprost (
P < 0.0001;
Figs. 2 3 ). SBP and DBP were not modified significantly from baseline at any of the 24-hour time points by dorzolamide or latanoprost.
The mean 24-hour DOPP (DOPP = DBP − IOP) was 50.7 ± 5.9 mm Hg at baseline, 53.0 ± 5.5 mm Hg with timolol, 46.2 ± 5.4 mm Hg with brimonidine, 55.9 ± 4.6 mm Hg with dorzolamide, and 56.4 ± 4.9 mm Hg with latanoprost
(Table 3) . There was no significant difference in mean 24-hour DOPP was between timolol and baseline. Brimonidine induced a significant decrease in mean 24-hour DOPP when compared with the baseline value (
P < 0.0001), whereas dorzolamide and latanoprost induced a significant increase in the mean 24-hour DOPP when compared with baseline (
P < 0.0001). No significant difference in mean 24-hour DOPP was evident between these latter two drugs.
Dorzolamide and latanoprost induced a significant increase at all 24-hour DOPP time points when compared with the baseline values. No significant differences were evident between these two drugs, except at 10 AM (P = 0.001) and 2 PM (P = 0.01). At these two time points, the DOPP obtained with dorzolamide were significantly lower than those with latanoprost and were not significantly different from those after timolol.
Timolol induced a significant increase in DOPP from 8 AM to 4 PM (8 AM, 10 AM, 12 PM, 2 PM: P < 0.0001; 4 PM: P = 0.05), and at 4 AM (P = 0.02) and 6 AM (P = 0.03) when compared with baseline. No significant differences from baseline were evident from 6 PM to 2 AM.
Brimonidine induced no significant difference in DOPP from baseline at 8 AM, 10 AM, 2 PM, or 6 AM. At all the remaining time points, DOPP was reduced significantly by brimonidine (
P < 0.0001). The greatest reduction in DOPP induced by brimonidine was evident from 12 to 4 AM
(Fig. 4) .
The results of our study provide evidence that the four treatments studied influence the circadian IOP curve and BP profile in patients with POAG in different ways.
All the investigated drugs were able to induce a significant decrease in IOP when compared with the baseline measurement. Latanoprost, administered once a day in the evening, induced a constant IOP reduction for 24 hours, although the hypotensive effect was greatest during the day and 12 hours after administration. This result is similar to those of studies previously reported on the 24-hour effect of latanoprost on IOP,
11 12 13 14 15 16 17 and the difference in IOP reduction between diurnal and nocturnal periods could be explained partially on the basis of variations in physiologic mechanisms of IOP control during the 24-hour cycle.
17
Timolol induced a greater reduction in IOP during the day (8 AM to 8 PM) and a less, albeit still significant, reduction during the night. This is in accordance with Konstas et al.
18 Moreover, timolol induced an IOP reduction not significantly different from that of latanoprost during the day (from 8 AM to 8 PM), again with a less but still significant ocular hypotensive effect in comparison with baseline during the night (from 10 PM to 6 AM). Similar results, comparing 24-hour IOP profiles of timolol and latanoprost, were obtained by Liu et al.
17 They reported that once-daily administration of timolol in the morning (Timoptic XE; Merck, West Point, PA) was as effective as latanoprost, when administered once a day in the evening, in reducing IOP during the diurnal period, but that only latanoprost reduced IOP during the nocturnal period. Different results in IOP nocturnal readings obtained by Liu et al.,
17 may be mainly referable to their different methodology in the study design and their small sample size (18 patients).
Timolol lowers the IOP by reducing aqueous humor flow, but has no effect on outflow resistance or on episcleral venous pressure.
19 It thus seems reasonable to hypothesize that the decreased activity of timolol during the night is due to either the inability of β-adrenergic antagonists to reduce nocturnal aqueous humor flow or to increased pressure in the episcleral venous system in the supine position.
20 Moreover, it has to be considered that aqueous humor flow is reduced by approximately 45% during sleep, in comparison to that during waking hours,
20 21 22 and so the reduced activity of timolol may be because of the existence of a baseline flow rate that cannot be further suppressed.
11 15 21 22 23
Dorzolamide, induced a more pronounced reduction in IOP during the night (from 10 PM to 6 AM). Moreover, we observed that dorzolamide was able to reduce IOP during the night, when the patient was in a supine position, to the same extent as did latanoprost at all the time points between 10 PM and 6 AM. This observation has also been reported by others,
11 22 23 and it is also consistent with the nighttime decrease in aqueous humor flow observed with dorzolamide by Vanlandingham et al.
24
In contrast to the results of Orzalesi et al.,
11 our data show that dorzolamide had an ocular hypotensive effect during the night cycle equal to that of latanoprost. A possible explanation could be patient selection in the study reported by Orzalesi et al., in which 13 of the 20 patients had hypertension being treated with systemic β-blockers (6 patients) and with other unspecified medications (7 patients). In our study, all patients had POAG but no cardiovascular diseases and were taking no systemic medication that could modify IOP or blood pressure; accordingly, there was no pharmacologic interaction between systemic and topical therapies.
Brimonidine significantly reduced IOP at all the 24-hour time points when compared with baseline IOP. The IOP profile was quite similar to that of dorzolamide from 8 AM to 8 PM and to that of timolol from 10 PM to 6 AM. The brimonidine-induced reduction in IOP throughout the 24-hour period was significantly and consistently less than that induced by latanoprost. Our results show that the effect of brimonidine on IOP over 24-hours is fairly constant, with no significant differences between day (8 AM–8 PM) and night (10 PM–6 AM) measurements.
Brimonidine is an α
2-agonist that exerts its ocular hypotensive effect primarily by decreasing aqueous humor flow,
25 and it has been shown to have a daytime effect similar to that of timolol.
25 26 27 28 Toris et al.
28 29 further demonstrated that brimonidine reduces IOP by a dual mechanism: decreasing aqueous humor, and increasing uveoscleral flow. On the basis of this evidence, it is possible that the uniform reduction in IOP induced by this drug is due to uveoscleral flow during the night, which would explain the fairly uniform IOP behavior induced by the drug over the 24-hour period.
In regard to the influence of these glaucoma medications on the 24-hour BP profile, the most interesting finding is the marked reduction of systolic and diastolic BP induced by brimonidine.
Based on data in the literature, the effects of brimonidine on arterial BP are controversial. As a matter of fact, data from a short-term randomized clinical trial
30 show that brimonidine 0.2% induces a statistically significant change in mean SBP at 1, 2, 6, and 8 hours after its most recent instillation and 21 days after initiation of treatment (range, 5.7 ± 14.3–7.1 ± 10.2 mm Hg). The mean changes in diurnal DBP ranged from −0.3 ± 9.2 to −4.4 ± 9.9 mm Hg, changes that were significantly different from baseline. In addition, Stewart et al.
31 found a significant reduction in BP after administration of brimonidine alone or in association with timolol. In other randomized clinical trials of brimonidine,
26 28 32 long-term results did not show any significant reduction in systolic or diastolic blood pressures.
In the short-term investigation described herein, brimonidine was able to reduce DBP and SBP significantly over a 24-hour period. To our knowledge, this is the first study to have investigated 24-hour BP and IOP changes induced by brimonidine in patients with POAG.
The differences in our BP results from those of other investigators may well be attributable to the fact that, in the other studies, BP evaluation was limited to only a few measurements, generally made at the same diurnal intervals as tonometry (i.e., five times per day). Furthermore, it has been demonstrated that most subjects show higher BP levels when the measurements are performed by healthcare personnel at a clinic or even at home than when BP is self measured at home with an automated device.
33
The cardiovascular effects of brimonidine appear to be mediated through the central nervous system.
34 Clonidine, a related compound, produces profound hypotension by binding to noradrenergic imidazoline receptors in the vasomotor center of the medulla.
33 As a matter of fact, the cardiovascular effects of brimonidine in monkeys have been inhibited by pharmacologically blocking central imidazoline receptors, but not by blocking either central or peripheral α-2 receptors.
35
In contrast to direct vasoactive antihypertensive drugs, clonidine exerts its blood pressure–lowering effects by central sympathoinhibition, and thereby acts in an opposing direction to the parasympathetic baroreflex control.
36
The present study suggests that brimonidine enhances nocturnal hypotension. The most likely mechanism for this effect may be referable to a further central reduction in sympathetic activity with reduced catecholamines, leading to a reduction in cardiac output and peripheral vascular resistances.
37
In our study, timolol was able to reduce BP over the 24-hour period when compared with the baseline, but this reduction was not statistically significant at all time points. Our results are quite similar to those of other investigators, who have shown that topically applied β-blockers are able to reduce systemic BP slightly.
38 39 40 41 β-blockers may not affect nocturnal blood pressure as greatly, because they act primarily on the sympathetic nervous system, which is most active during the daytime.
42 Although this may imply that β-blockers are less likely to produce nocturnal hypotension, there are several reports of β-blockers lowering nighttime BP levels.
38 39 40 41
However, no large study has investigated systematically the effects of β-blocker eye drops on systemic BP by means of 24-hour blood pressure monitoring. Hayreh et al.
41 found, in a mixed population of POAG, anterior ischemic optic neuropathy, and normal tension glaucoma patients, that betaxolol and timolol enhance nocturnal arterial hypotension. In our study also, short-term topical administration of timolol significantly reduced BP over a 24-hour period.
As would be expected from the BP and IOP profiles after administration of the studied drugs, DOPP was significantly increased by both dorzolamide and latanoprost in comparison with that at baseline, at all time points. Mean 24-hour DOPP was higher after timolol administration than at baseline, but the increase was not statistically significant. Brimonidine, however, induced a significant decrease in mean calculated 24-hour DOPP when compared with that at baseline. Differences in the 24-hour BP and DOPP profiles deserve further investigation, to determine whether some adaptations occur between short- and long-term administration of these drugs.
Based on the results of various population-based epidemiologic studies, it seems to be accepted that low DOPP is associated with an increased prevalence
6 7 8 9 and incidence
10 of POAG. As a matter of fact, according to Bonomi et al.,
8 it can be assumed that there is an increased risk of glaucomatous damage when DOPP is less than 55 mm Hg.
In our study, only dorzolamide and latanoprost increased the mean 24-hour DOPP level to greater than 55 mm Hg in patients with POAG. Nevertheless, the presumed benefit/risk of an increase/decrease in DOPP need to be qualified, based on the persistence of the effect in long-term treatment regimen.
Randomized clinical trials
3 4 have shown the beneficial effects of lowering IOP in reducing or halting the deterioration of visual field defects in early and advanced POAG. The ultimate goal in the management of glaucoma is to protect the retinal ganglion cells and to preserve visual function of the affected patient.
Some patients, despite a significant reduction in IOP, show a progression of anatomic and functional damage, suggesting that factors other than IOP are involved in this disease. For these reasons, DOPP may be more important than IOP alone in determining optic nerve head damage.
In conclusion, our results suggests that some pharmacologic therapies for POAG have an influence on systemic BP, and, despite their favorable action in reducing IOP, they do not induce a significant increase in DOPP. We suggest that more data with long-term studies are needed, before the importance of drug-induced changes in DOPP, in determining optic nerve head damage, is validated.
Submitted for publication September 22, 2005; revised February 16 and March 6, 2006; accepted May 17, 2006.
Disclosure:
L. Quaranta, None;
F. Gandolfo, None;
R. Turano, None;
F. Rovida, None;
T. Pizzolante, None;
A. Musig, None;
E. Gandolfo, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Luciano Quaranta, Clinica Oculistica, Piazzale Spedali Civili 1, 25123 Brescia, Italy;
quaranta@med.unibs.it.
| Number of patients | 27 |
| Age (mean ± SD) | 58 ± 5.5 years |
| Gender | 15 female 12 male |
| IOP (24-hour mean at enrollment) | 24.2 ± 3.8 mm Hg |
| Systolic BP (mean at enrollment) | 126.2 ± 4.8 mm Hg |
| Diastolic BP (mean at enrollment) | 76.5 ± 5.1 mm Hg |
Table 2. Mean 24-Hour Systolic and Diastolic BP by Antiglaucomal Drugs
Table 2. Mean 24-Hour Systolic and Diastolic BP by Antiglaucomal Drugs
| Baseline | Timolol | Brimonidine | Dorzolamide | Latanoprost |
| Systolic BP | 125.1 ± 4.5 | 121.8 ± 4.4 | 116.8 ± 4.5 | 124.5 ± 4.5 | 124.5 ± 4.2 |
| Diastolic BP | 73.6 ± 4.5 | 70.6 ± 4.3 | 64.5 ± 4.6 | 73.7 ± 4.3 | 73.3 ± 4.5 |
Table 3. Twenty-four Hour Calculated Diastolic Ocular Perfusion Pressure and Mean Change from the Baseline by Antiglaucoma Drugs
Table 3. Twenty-four Hour Calculated Diastolic Ocular Perfusion Pressure and Mean Change from the Baseline by Antiglaucoma Drugs
| Time | Baseline | Timolol | Brimonidine | Dorzolamide | Latanoprost |
| 8 AM | 48.6 ± 3.2 | 53.5 ± 3.6 | 49.6 ± 4.1 | 56.5 ± 2.3 | 57.2 ± 2.3 |
| | (4.9 ± 4.9) | (0.9 ± 5.6) | (7.8 ± 3.8) | (8.5 ± 4.3) |
| 10 AM | 45.5 ± 2.2 | 52.7 ± 3.2 | 46.4 ± 3.6 | 53.6 ± 2.7 | 56.1 ± 2.6 |
| | (7.2 ± 3.9) | (0.8 ± 4.3) | (8.0 ± 2.9) | (10.5 ± 3.5) |
| 12 PM | 53.6 ± 2.3 | 57.4 ± 3.8 | 48.2 ± 3.5 | 58.4 ± 2.4 | 59.5 ± 2.4 |
| | (3.8 ± 4.7) | (−5.4 ± 4.0) | (4.7 ± 3.6) | (5.9 ± 3.4) |
| 2 PM | 51.4 ± 2.8 | 54.8 ± 3.2 | 50.7 ± 3.1 | 55.6 ± 2.9 | 57.6 ± 2.7 |
| | (3.3 ± 3.4) | (−0.6 ± 3.9) | (4.2 ± 3.2) | (6.1 ± 3.1) |
| 4 PM | 56.4 ± 3.4 | 58.3 ± 3.7 | 48.7 ± 3.7 | 60.3 ± 2.3 | 59.8 ± 2.3 |
| | (1.9 ± 4.9) | (−7.7 ± 6.0) | (3.8 ± 4.3) | (3.3 ± 4.3) |
| 6 PM | 56.6 ± 3.6 | 57.8 ± 2.4 | 49.2 ± 2.4 | 59.6 ± 2.6 | 60.5 ± 2.1 |
| | (1.4 ± 4.0) | (−7.1 ± 4.8) | (3.2 ± 4.5) | (4.1 ± 3.8) |
| 8 PM | 56.8 ± 3.2 | 57.4 ± 2.5 | 50.2 ± 2.8 | 60.3 ± 2.7 | 60.6 ± 2.2 |
| | (0.8 ± 3.5) | (−6.3 ± 3.8) | (3.7 ± 4.5) | (4 ± 3.5) |
| 10 PM | 57.9 ± 3.8 | 58.1 ± 2.9 | 52.0 ± 2.3 | 62.1 ± 2.5 | 62.8 ± 2.3 |
| | (0.1 ± 5.1) | (−5.9 ± 3.9) | (4.1 ± 5.0) | (4.8 ± 4.4) |
| 12 AM | 52.5 ± 2.7 | 52.4 ± 2.5 | 44.4 ± 2.5 | 57.0 ± 2.9 | 56.4 ± 2.1 |
| | (−0.1 ± 3.5) | (−8.1 ± 3.3) | (4.4 ± 3.8) | (3.9 ± 3.2) |
| 2 AM | 46.3 ± 2.1 | 46.9 ± 3.1 | 39.9 ± 2.6 | 51.3 ± 2.7 | 50.8 ± 2.3 |
| | (0.6 ± 2.3) | (−6.4 ± 2.8) | (5.0 ± 2.5) | (4.5 ± 2.9) |
| 4 AM | 40.5 ± 2.8 | 42.4 ± 3.2 | 33.6 ± 3.7 | 47.6 ± 2.6 | 47.1 ± 2.4 |
| | (1.9 ± 3.6) | (−6.8 ± 4.5) | (7.0 ± 3.9) | (6.6 ± 3.5) |
| 6 AM | 42.6 ± 2.5 | 44.5 ± 3.7 | 41.5 ± 4.2 | 49.4 ± 2.2 | 49.5 ± 2.5 |
| | (1.8 ± 3.9) | (−1.1 ± 4.3) | (6.8 ± 3.4) | (5.8 ± 2.9) |
| Mean 24-hour | 50.7 ± 5.9 | 53.0 ± 5.5 | 46.2 ± 5.4 | 55.9 ± 4.6 | 56.4 ± 4.9 |
| | (2.3 ± 4.5) | (−4.5 ± 5.4) | (5.2 ± 4.1) | (5.7 ± 4.1) |
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