(Hypertension. 2000;35:787.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Changes of Nocturnal Blood Pressure Dipping Status in Hypertensives by Nighttime Dosing of 
-Adrenergic Blocker, Doxazosin
Results from the HALT Study
From the Hypertension Center (K.K., J.E.S., T.G.P.), Weill Medical College of Cornell University - The New York Presbyterian Hospital, New York, and the Department of Psychiatry (J.E.S.), SUNY - Stony Brook, NY.
Correspondence to Dr. Kazuomi Kario, MD, PhD, FACC, or Thomas G. Pickering, MD, DPhil, Hypertension Center, Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, NY, 10021. E-mail kak2012@mail.med.cornell.edu or tpicker{at}mail.med.cornell.edu
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Abstract |
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Abstract—Abnormal nocturnal blood pressure (BP) dipping status may be partly determined by nocturnal sympathetic activity. We studied the effect of nighttime dosing of an
1-adrenergic blocker, doxazosin, on the BP dipping
status of 118 hypertensives, all of whom underwent 24-hour ambulatory
BP monitoring before and after treatment. The mean nighttime/daytime
ratio of systolic BP was increased (0.91 after therapy versus
0.89 at baseline, P<0.05). The patients were initially
divided into 4 groups on the basis of their dipping status at the
baseline assessment: 18 (15%) were extreme dippers, with a nighttime
systolic BP fall of at least 20% of daytime BP; 46 (39%) were
dippers (fall between 10% and 20%); 48 (41%) were nondippers (fall
between 0% and 10%); and 6 (5%) were risers (nocturnal increase of
systolic BP). A shift in dipping status toward less nocturnal
BP dipping was observed after doxazosin therapy
(P<0.05). Dipping status was determined by nighttime
more than by daytime BP, and this was not explained by differences in
the number of daytime and nighttime readings. The effects of doxazosin
on the mean nocturnal systolic BP changes were an increase of
4.3 mm Hg in extreme dippers and decreases of 0.7 mm Hg in
dippers, 12 mm Hg in nondippers, and 18 mm Hg in risers;
the reduction was only significant in the latter 2 groups (both
P<0.01). To estimate the effects of regression to the
mean on the changes in dipping status, we also defined dipping status
with the average of the BPs before and after doxazosin and found no
difference in the degree of nighttime BP reduction among each group.
The reduction of daytime BP was now significantly greater in the
subgroups with less dipping: 6.4 mm Hg for extreme dippers and
16 mm Hg for risers (P<0.05). In conclusion,
nighttime dosing with doxazosin markedly affects the nocturnal BP
dipping status of hypertensives, but the apparently greater reduction
in nighttime pressure in nondippers and risers may be, at least partly,
due to the effect of regression to the mean. The most important
determinants of the effect of doxazosin were the absolute BP levels,
both day and night, rather than dipping status per se.
Key Words: : blood pressure monitoring • adrenergic receptor blocking • circadian rhythm • prospective studies
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Introduction |
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One of the most interesting features revealed by ambulatory blood pressure (BP) monitoring (ABPM) is the diurnal variation of BP.1 Most normotensive and hypertensive individuals show a decrease of BP of
10% during the
night (the so-called dipping pattern), but there are others in whom the
BP decrease may be reduced (nondippers)2 3 4 5 6 or exaggerated
(extreme dippers).7 8 These different patterns are
increasingly thought to be of clinical relevance because there is
evidence from a large prospective study6 that hypertensive
patients who are nondippers are at greater risk of
cardiovascular morbidity than dippers. There is also
evidence that extreme dippers are at increased risk of ischemic
stroke, possibly as a result of the excessive nocturnal BP
fall.9 Another clinically relevant group is patients with
renal failure, in whom nondipping is associated with
microalbuminuria (an early marker of renal
damage).4 One prospective study4 has found
that nondipping is an independent risk factor for progression of renal
disease. Thus, it is reasonable to suppose that deviations from the
normal dipping pattern in either direction can have pathological
significance, although for different reasons. Nondippers experience a
greater "BP load" over 24 hours than dippers with the same daytime
BP and, hence, may be more likely to develop target organ damage. On
the other hand, extreme dippers might be more susceptible to
ischemic episodes that result from low BP, especially in
high-risk hypertensive patients with predisposing arterial
stenosis (eg, elderly hypertensives7 and patients
with carotid artery disease10 or coronary artery
disease8 ) when antihypertensive therapy lowers
nocturnal BP further. The mechanisms of dipping are complex. Although both demographic factors (eg, older age and black race) and medical conditions (renal disease, diabetes, Cushing disease, etc) are associated with nondipping, lifestyle and behavioral factors are also important.11 12 13 Thus, both the level of physical activity during the day and the duration and quality of sleep during the night will influence the observed diurnal BP changes.14 The underlying physiological mechanisms are also likely to be complex. The nocturnal decrease of BP is in part determined by changes in sympathetic nerve activity. Thus both plasma and urine catecholamines are lower during the night than during the day,15 and direct recordings from muscle sympathetic nerves have also shown a decreased level of activity during slow-wave (but not REM) sleep.16 In previous studies that assessed heart rate variability, abnormal dipping status (nondippers and extreme dippers) was also partly determined by the abnormal variation of sympathovagal balance during the sleep and awake periods.17 18
Recently, there have been several papers on the differential effects of
antihypertensive medications on the diurnal variation of ambulatory BP
(ABP) levels in hypertensives with different nocturnal dipping
status.19 20 21 22 23 24 25 Doxazosin, an
1-adrenergic blocker, may suppress the
1-adrenergic-dependent BP level selectively,
suppressing nighttime BP levels only in hypertensive nondippers but not
in hypertensive dippers.19 However, there is no report of
nighttime dosing of doxazosin on nocturnal BP in extreme dippers, and
most previous studies have not evaluated the possible effects of
regression to the mean. In this substudy of the Hypertension and Lipid
Trial (HALT),26 27 we have investigated the effect of
nighttime dosing of doxazosin on the BP dipping status of hypertensive
subgroups with different nocturnal BP dipping.
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Methods |
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Patient Selection
The HALT study was an open-label study of the effects of doxazosin on BP and plasma lipids and included 851 patients at 141 centers throughout the United States. Thirty-nine of these sites were equipped to perform ABPM, and 118 hypertensive patients who were either untreated or off medication for
2 weeks (41 men and 77 women) with
mean±SD age of 54±10 years were included in the substudy of ABPM. The
entry BP criterion was a seated diastolic BP (DBP) between
96 and 110 mm Hg at each of the last 2 weekly visits. To be
included in the study, patients had to be >35 years of age, have a
diagnosis of essential hypertension, and have no history of other
significant medical disorders, including drug or alcohol misuse.
Study Design
Each patient was studied for a maximum of 13 weeks, with a
titration period of 
5 weeks, and 8 weeks of maintenance.
After the baseline evaluation was completed, patients were started on 1
mg doxazosin daily, which was taken at bedtime. The dose was doubled at
weekly intervals until either the average seated DBP was <90
mm Hg and had fallen by 10 mm Hg from the baseline level on
each of 2 consecutive visits, a maximum daily dose of 16 mg doxazosin
had been reached, or side effects precluded a further dose increase.
After the titration phase, there was a maintenance phase of 8
weeks on the same dose of doxazosin. All patients signed an informed
consent statement approved by the local Institutional Review Board.
ABPM and Patient Classification
ABPM was performed twice with a Spacelabs model 90202
recorder, at the end of the drug-free baseline period and at the
end of the maintenance period, as described
previously.26 27 The monitor was programmed to take
readings every 15 minutes during typical waking hours (6 AM
to 10 PM) and every 30 minutes during the night (10
PM to 6 AM). At least 6 readings were required
for an acceptable nighttime recording, and 30 readings were
required for an acceptable daytime recording. For the
present analyses, nighttime parameters (BP and
pulse rate) were defined by the averages from midnight to 6
AM, and daytime parameters were defined by the
averages from 8 AM to 8 PM. The night/day
ratios of each parameter were calculated. Nocturnal BP fall
was calculated as 1-the night/day ratio of systolic BP (SBP)
and expressed as a percentage. Patients were subclassified into the
following 4 dipping groups on the basis of the baseline nocturnal BP
fall: extreme dippers, with a nocturnal BP fall of 20% or more;
dippers, with a fall between 10% and 20%; non-dippers, with a fall
between 0% and 10%; and risers, with a nocturnal increase of SBP. To
estimate the effects of regression to the mean on the changes in
dipping status, we also defined dipping status using the average of
baseline BP and BP after doxazosin.
Statistical Analysis
Changes in BP or pulse rate from the baseline values were
analyzed statistically with paired t tests for each
of the 4 subgroups. The between-subgroup comparisons were tested
statistically with Tukey’s honestly significant difference test after
1-way ANOVA. The linear contrast among the 4 subgroups (from extreme
dippers to risers) was also tested. The change in dipping status after
doxazosin therapy was tested with the McNemar test, and Pearson’s
correlation coefficients were calculated. The criterion for determining
statistical significance was P<0.05. The results are given
as the mean (SD).
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Results |
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The mean night/day SBP ratio was highly correlated between assessments (r=0.497, P<0.001). However, this ratio increased after treatment with doxazosin (from 0.89 at baseline to 0.91 after therapy, P<0.05). At the baseline BP assessment (Table 1), there were 18 (15%) extreme dippers, 46 (39%) dippers, 48 (41%) nondippers, and 6 (5%) risers. There were no significant differences in the daytime BP levels among groups, but the mean nighttime SBP levels varied substantially; from 118 mm Hg in the extreme dippers to 153 mm Hg in the risers, with marked differences between each group (P<0.01, except for the difference between nondippers and risers). Thus, dipping status appeared to be determined much more by the nighttime than by the daytime BP. After doxazosin therapy, the mean nocturnal SBP increased by 4.3 mm Hg in the extreme dippers but decreased in the other groups (by 0.7 mm Hg in the dippers, 12 mm Hg in the non-dippers, and 18 mm Hg in the risers). These changes were statistically significant only in the latter 2 groups (P<0.05). In contrast, there was a substantial drop in daytime SBP after doxazosin therapy that did not vary by group. The lack of significance for the change of daytime SBP (-11 mm Hg) in the risers can be attributed to the small number of patients in this group. The pattern of change in DBP in each group was similar to that of SBP. There were no group differences in baseline pulse rates nor were there any significant changes after doxazosin therapy.
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Table 2 shows the changes in dipping status after doxazosin therapy. Fifty-six percent (n=10) of the 18 extreme dippers changed to dippers (n=4), nondippers (n=5), or risers (n=1) after therapy. The overall numbers of dippers and nondippers were not significantly different after therapy, whereas the number of risers increased (from 6 to 16). Thus, there was an overall shift toward less nocturnal BP dipping after doxazosin therapy (P<0.05, by McNemar’s test).
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Figure 1 shows the relationship between
the baseline daytime and nighttime BP levels and the changes after
doxazosin therapy for the whole group. Almost the same regression lines
were obtained for daytime and nighttime SBP (Figure 1). Figure 1
also indicates that doxazosin has only a BP lowering effect when the
baseline BP exceeds 125 mm Hg, regardless of whether this is
during the daytime or nighttime. Analysis of covariance
revealed that the relationship between daytime BP at baseline and the
change in daytime BP did not vary (neither the slopes nor the
intercepts) significantly across the 4 dipping status groups. The same
was true for nighttime BP. Figure 2 shows
the same data plotted according to the average levels and changes in
each of the 4 subgroups. It demonstrates a cluster of points
corresponding to the daytime BPs and a strong inverse relationship
between the baseline level and the doxazosin-induced change for the
nighttime BPs, for which the correlation was -0.995. Taken together,
these 2 figures show that the effects of doxazosin on daytime and
nighttime BPs are generally similar and that the apparently different
effects in the subgroups are determined by the fact that the
classification of baseline dipping status is almost exclusively the
result of differences in nighttime BPs.
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, the daytime SBP;
ED, extreme dippers; D, dippers; ND, nondippers; and R, risers.It is possible that the reason the dipping status was determined more by the nighttime than by the daytime BPs is that the smaller number of nighttime readings make each individual’s average nighttime level less reliable than his/her average daytime level. To test the effect of the number of BP measurements on dipping status, we randomly selected 10 readings from the daytime BP measurements (thus giving the same number of readings as during the night) and computed the correlations between dipping status and daytime SBP calculated with (a) all of the readings and (b) the 10 daytime readings (Table 3). Dipping calculated with all of the daytime readings was significantly related to the nighttime SBP (r=-0.689, P<0.001) but not to the daytime SBP (r=0.112, not significant) in the baseline data, the data after doxazosin therapy, and the changes after doxazosin therapy. The effect of using only 10 daytime readings was to reduce the differences between the daytime and nighttime correlations but not to eliminate them. Thus for the baseline data, the correlation with the nighttime SBP was reduced from -0.689 to -0.645 (P<0.00l), whereas the correlation with daytime SBP increased slightly (from 0.122 to 0.191, P<0.05). The effects on the posttreatment data and on the changes after doxazosin were more marked. Nonetheless, the differential effect of the daytime and nighttime readings on dipping status cannot simply be ascribed to the larger number of readings taken during the day; in this sample, nighttime BP is a stronger predictor of dipping than daytime BP.
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To explore the possible effects of regression to the mean on the estimated changes in daytime and nighttime BPs after treatment, we also defined dipping status using the average of the baseline BP and the BP after doxazosin. With this definition, there were no differences in the degree of nighttime BP reduction among groups (Table 4). However, the reduction of daytime SBP was now significantly greater in those subgroups with less dipping: 6.4 mm Hg in the extreme dippers and 16 mm Hg in the risers (P<0.05 for the linear contrast).
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Discussion |
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Nighttime dosing with doxazosin therapy reduces both daytime and nighttime SBP and DBP in hypertensives and appears to also affect their nocturnal dipping status. The overall effect was an increase of the night/day ratio, and a shift in dipping status toward less nocturnal BP dipping. This, of course, confirms our earlier analysis of the same data in which we reported that doxazosin lowers daytime BP more than nighttime BP.26 The effects of doxazosin in hypertensives who differ according to their dipping status are of interest because there is increasing evidence that the nighttime BP may have pathological and prognostic significance that is independent of the daytime BP.6 At one extreme, it might be beneficial to selectively lower the nighttime BP in nondipping patients with albuminuria and renal disease, whereas at the other extreme, further reduction of nighttime pressure in extreme dippers might exacerbate the development of cerebral ischemic lesions.
A weakness of this study is that we did not have placebo controls. A
potential problem that must be addressed in an analysis of the
effects of antihypertensive drugs according to dipper status without
placebo controls is the reproducibility of the dipping status, which
might be affected by regression to the mean. When subjects are
initially classified according to whether the difference between
daytime and nighttime BP is either large or small, they are likely to
show less extreme differences on repeat testing. Thus, a proportion of
both extreme dippers and nondippers are expected to be classified as
dippers on repeat testing. If the second evaluation is made after
administering a drug, the apparent effect of the drug will be to
produce a greater fall of nocturnal BP in the nondippers than in the
dippers (as we observed). The best way to exclude this effect is to
administer placebo pills to a control group,23 24 but this
may be difficult to perform in the clinical practice setting. Recently,
after the recognition of the potential clinical significance of
differences in dipping patterns, there have been several studies of the
effects of antihypertensive drugs in hypertensive subjects who differ
in their nocturnal BP dipping status. With 2
exceptions,23 24 these previous
studies19 20 21 22 25 did not have a placebo control condition.
However, the results obtained from these studies have been
consistent, indicating that nocturnal BP is decreased by a
greater extent in nondipper hypertensives than in dipper hypertensives
after treatment with a wide variety of antihypertensive agents (calcium
antagonists, angiotensin-converting enzyme
inhibitors, and 1-adrenergic
blockers).19 20 21 22 23 24
Because dipping status is determined by both sleep and awake BPs, it might be expected that the 2 determinants would have equal weight. However, in our data, there were no differences among groups in the awake BP levels such that differences in dipping status were determined almost exclusively by differences in nocturnal BP level. Exactly the same thing was shown by White et al21 in their analysis of the effects of extended-release verapamil: the awake BP of the dippers and nondippers were 156/97 and 157/99 mm Hg, respectively, while the corresponding sleep BPs were 133/78 and 152/94 mm Hg, respectively. A probable explanation for this is statistical rather than biological. The duration of the sleep period is less than the duration of the waking period, thus the reliability of the estimate of the average sleep BP level will also be less. This will be particularly true of studies such as ours in which the frequency of readings was less during the night than during the day (in the White et al study it was the same throughout). The comparative unreliability of the sleep readings would also explain the reason White et al found that the administration of a placebo apparently lowered the nighttime SBP/DBP of nondippers by 5/3 mm Hg and raised it in dippers by 3/3 mm Hg, without any effect on the daytime BPs of either group. However, when we reanalyzed the data with the same number of awake and sleep readings, we found that this only partially removed the greater influence of nighttime versus daytime readings on dipping status. Another explanation may be selection bias that resulted from the recruitment criteria of drug treatment studies in hypertensive patients. In this study, as in others, patients were selected according to their clinic BP, which is more closely related to the daytime than to the nighttime BP. Thus, the range of daytime BP will tend to be narrow, whereas the nighttime BP will range more widely. This is precisely what was observed in this HALT study (daytime SD=13.0 mm Hg; nighttime SD=15.8 mm Hg).
To exclude the effect of regression to the mean, we also classified patients into the 4 dipping status groups with the average of their BP values before and after doxazosin therapy. With this classification, we found no differences in the degree of nighttime SBP reduction among groups. The reduction of daytime SBP was now significantly greater in the subgroups with less dipping: 6 mm Hg for extreme dippers and 16 mm Hg for risers. The reduction of nighttime BPs also tended to be greater in the subgroups with less dipping. Thus, the apparently greater reduction in nighttime BP in nondippers and risers may be largely because of the effect of regression to the mean. However, if we subtract the estimated effect of regression to the mean derived from the White et al study (3/3 mm Hg in nondippers and risers, and -5/-3 mm Hg in dippers and extreme dippers), there appears still to be a differential effect of doxazosin on nocturnal BP according to dipper status. Thus, we observed a differential effect of doxazosin between these 2 aggregate groups of 13.4 mm Hg on SBP. If we subtract 8 mm Hg from this (to allow for regression to the mean), there is still a difference of 5.4 mm Hg.
The similarity of the effects of treatment on daytime and nighttime BP
as a function of the baseline level shown in Figure 1 suggests
that the most important determinant of the effect is the level of BP
rather than the dipping status per se. Thus in extreme dippers with
marked nighttime BP fall, the dipping was less after doxazosin therapy,
while at the other extreme, in risers and nondippers, it was increased.
The effects of doxazosin therapy on dipping status suggest that
-adrenergic action contributes to the diurnal BP variation in
hypertensive patients. Two studies in rats have investigated the
effects of different antihypertensive agents on the diurnal BP
variation. One used captopril, clonidine, hydralazine,
metoprolol, and prazosin,28 and found that
hydralazine and captopril had little effect, whereas clonidine
and metoprolol produced a minor flattening of the BP rhythm. In
contrast, -blockade with prazosin completely eliminated the diurnal
BP changes. The second study29 used metoprolol with
atropine (to produce cardiac autonomic blockade),
hexamethonium, and prazosin. Blockade of the heart had
no effect on BP, whereas both - and ganglionic-blockade eliminated
the diurnal BP changes. These data suggest that -adrenergic tone
plays an important role in the diurnal changes of BP, at least in the
rat. Studies in humans are less clear-cut. In a previous
analysis of the HALT data, in which doxazosin was given at
night to hypertensive patients, we found that the peak BP lowering
effect was during the morning hours, with relatively little effect on
nighttime BP.26 This would not be expected from the
pharmacodynamics of the drug, which would have predicted a greater
effect during the night, but is consistent with other data that
shows that -adrenergic tone is greater in the morning than in the
evening. A second study, by Ebata et al,19 compared the
effects of doxazosin given twice daily in 15 dippers and 12 nondippers
and found that daytime BP was reduced in both groups. However, the
nighttime BP was lowered in nondippers but not in dippers. This can be
explained by assuming that -adrenergic tone falls during the night
in dippers but remains high in nondippers.
The effect of antihypertensive drugs on the diurnal BP variation
depends not only on the mechanism of action of the drugs but also on
the time of administration and the pharmacokinetics and
pharmacodymamics. Thus, when doxazosin is given in the morning, its
limited duration of action may result in its having less effect on the
nocturnal BP. Nighttime dosing of doxazosin suppresses the morning BP
surge (largely dependent on -adrenergic tone).26 Thus,
nighttime dosing might be ideal in hypertensive patients with a
nondipping pattern of nocturnal BP or in those having a marked morning
BP rise.
In our recent Japanese study using brain MRI, silent cerebrovascular
disease was more advanced in hypertensive elderly extreme dippers
compared with dippers.7 This raises the possibility that
excessive BP reduction by antihypertensive therapy might advance
nocturnal hypoperfusion of cerebral circulation and lead to clinically
overt stroke or vascular dementia, especially in high-risk hypertensive
patients. The marked nocturnal decrease in the low-frequency
power/high-frequency power ratio obtained from the power spectral
analysis of heart rate variability (a crude indirect indicator
of sympathetic activity) observed in hypertensive extreme dippers
suggests that nocturnal BP in these patients may be attributed to a
lower level of sympathetic activity compared with other dipping
statuses.17 In addition, the orthostatic BP
increase found in hypertensive extreme dippers30 suggests
enhanced vascular reactivity including -adrenergic dominant
sympathetic activation or postsynaptic vascular reactivity, such that
the exaggerated day/night BP difference may be, at least in part,
caused by the effects of posture rather than of sleep. Thus, we
speculated that doxazosin decreases daytime BP by suppressing this
hyperreactivity, without affecting the (already low) nighttime BP, and
hence improves the excessive nocturnal dipping, as demonstrated in 1
typical hypertensive extreme dipper with orthostatic BP
increase.31 In the present study, 56% of extreme
dippers changed their dipping status to dippers, nondippers, or risers.
This might protect against nocturnal ischemic
cardiovascular events and vascular dementia in extreme
dippers.
The therapeutic significance of the differential effects of antihypertensive treatment according to dipper status remains uncertain. Although, as discussed above, there is evidence that the extreme dipping pattern may lead to nocturnal ischemia, there is also evidence that nondippers are at greater risk for cardiovascular morbidity than dippers, both for cardiovascular events6 and for progression of renal disease.4 Thus, at the present time it is reasonable to suppose that the normal dipping pattern is optimal from a prognostic point of view, and hence that it would be appropriate to use antihypertensive therapy to lower nocturnal BP in nondippers but not in extreme dippers. This is exactly what we observed with doxazosin.
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Footnotes |
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This study was supported, in part, by a grant from Pfizer Pharmaceuticals.
Received August 24, 1999; first decision September 16, 1999; accepted November 4, 1999.
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- Timio M, Venanzi S, Lolli S, Lippi G, Verdura C, Monarca C, Guerrini E. "Non-dipper" hypertensive patients and progressive renal insufficiency: a 3-year longitudinal study. Clin Nephrol. 1995;43:382–387.[Medline] [Order article via Infotrieve]
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Kario K, Eguchi K, Nakagawa Y, Motai K, Shimada K.
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