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nature publishing group STATE OF THE ART
Circadian Rhythms in Blood Pressure Regulation
and Optimization of Hypertension Treatment
With ACE Inhibitor and ARB Medications
1 1 1 2 2
Ramón C. Hermida , Diana E. Ayala , José R. Fernández , Francesco Portaluppi , Fabio Fabbian
3
and Michael H. Smolensky
Specific features of the 24 h-blood pressure (Bp) pattern are evening, in comparison to morning, ingestion schedule of the
linked to the progressive injury of target tissues and risk of angiotensin receptor blockers (a RBs) irbesartan, olmesartan,
cardiac and cerebrovascular events. Studies have consistently telmisartan, and valsartan exerts greater therapeutic effect on asleep
shown an association between blunted asleep Bp decline and Bp, plus significant increase in the sleep-time relative Bp decline,
increased incidence of fatal and nonfatal cardiovascular events. with normalization of the circadian Bp profile toward a more dipping
Thus, there is growing interest in how to achieve better Bp control pattern, independent of drug terminal half-life. Chronotherapy, the
during nighttime sleep in addition to during daytime activity, timing of treatment to body rhythms, is a cost-effective means of
according to the particular requirements of each hypertension both individualizing and optimizing the treatment of hypertension
patient. One approach takes into consideration the endogenous through normalization of the 24-h Bp level and profile, and it may
circadian rhythm-determinants of the 24-h Bp pattern, especially, constitute an effective option to reduce cardiovascular risk.
the prominent day–night variation of the renin–angiotensin–
aldosterone system, which activates during nighttime sleep. Keywords: blood pressure; chronotherapy; rennin–angiotensin–
a series of clinical studies have demonstrated a different effect of aldosterone system; angiotensin receptor blockers; angiotensin-
the angiotensin-converting enzyme (a CE) inhibitors benazepril, converting enzyme inhibitors; dipper; nondipper; asleep blood pressure;
captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, ambulatory blood pressure monitoring; hypertension
and trandolapril when routinely ingested in the morning vs. the
American Journal of Hypertension, advance online publication 7 October 2010;
evening. in most cases, the evening schedule exerts a more marked
doi:10.1038/ajh.2010.217
effect on the asleep than awake Bp means. Similarly, a once-daily
The 24-h blood pressure (BP) pattern is the results of both and II, and aldosterone just before the usual time of morning
cyclic day–night alterations in behavior, e.g., physical activity, awakening, also plays a prominent role in 24-h BP regulation.
mental stress, and posture, and environmental phenomena, The comparatively lower BP during nighttime sleep results
1,2
e.g., ambient temperature, noise etc. plus endogenous cir- from withdrawal of sympathetic dominance, predominance
cadian (~24 h) rhythms in neural, endocrine, endothelial of vagal tone, reduced concentration of the constituents of the
and hemodynamic variables. The usually higher BP during RAAS, and peak levels of atrial natriuretic peptide and nitric
15–17
the daytime of diurnally active normotensive and uncom- oxide as vasodilators. The circadian variation that char-
plicated essential hypertensive persons derives in large part acterizes the RAAS and its activation during nocturnal sleep
3–5
from the dominance of sympathetic tone, evidenced by also has been hypothesized to explain the findings of stronger
6,7
the high plasma norepinephrine and epinephrine and BP-lowering effects of bedtime vs. morning schedules of ACE
8 18,19
urinary catecholamine concentrations in the hours after inhibitor (ACEI) and angiotensin-II receptor blocker
19
morning awakening. Moreover, the high-amplitude circa- (ARB) medications.
dian rhythm in the renin–angiotensin–aldosterone system Different circadian rhythms may also significantly affect
9–14
(RAAS), showing peak plasma concentrations of renin the pharmacokinetics (PK) and pharmacodynamics, both
activity, angiotensin- converting enzyme (ACE), angiotensin I beneficial and adverse effects, of hypertension medications.
Administration-time differences in PK can result from cir-
1
cadian rhythms in gastric pH, gastric emptying, gastroin-
Bioengineering and Chronobiology Laboratories, University of Vigo, Campus
2
Universitario, Vigo, Spain; Hypertension Center, University Hospital S. a nna,
testinal motility, biliary function, glomerular filtration, liver
Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara,
enzyme activity, and organ blood flow (e.g., duodenum,
3
italy; Department of Biomedical Engineering, The University of Texas at a ustin,
20–24
liver, and kidney). Administration-time differences in
a ustin, Texas, USa . Correspondence: Ramón C. Hermida (rhermida@uvigo.es)
pharmacodynamics can result from the time-d ependency
Received 28 June 2010; first decision 24 July 2010; accepted 4 September 2010.
in PK and/or circadian rhythms in drug-free fraction,
? 2011 American Journal of Hypertension, Ltd.
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 4 | 383-391 | ap RiL 2011 383Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on January 19, 2015
STATE OF THE ART Chronotherapy of Hypertension
t able 1 | a ngiotensin-converting enzyme inhibitors: administration-time differences in effects on the circadian Bp pattern,
i.e., sleep-time relative Bp decline
Effect on the sleep-time
a
relative BP decline
Medication Dose (mg) Treatment times No. subjects Morning Evening Reference
37
Benazepril 10 09:00 vs. 21:00 h 10 = ↑ palatini et al.
b 38
Captopril + HCTZ 25 + 12.5 08:00 vs. 20:00 h 13 ↓ ↑ Middeke et al.
39
Enalapril 10 07:00 vs. 19:00 h 8 ↓ ↑ Witte et al.
40
Enalapril 5 10:00 vs. 22:00 h 12 ↓ ↑ Sunaga et al.
41
Enalapril 20 Morning vs. evening 10 ↓ ↑ pechère-Bertschi et al.
42
imidapril 10 07:00 vs. 18:00 h 20 = = Kohno et al.
43
Lisinopril 20 08:00 vs. 16:00 h vs. 40 = ↑ Macchiarulo et al.
22:00 h
44
perindopril 4 09:00 vs. 21:00 h 18 = ↑ Morgan et al.
45
Quinapril 20 08:00 vs. 22:00 h 18 ↓ ↑ palatini et al.
47
Ramipril 2.5 08:00 vs. 20:00 h 33 ↓ ↑ Myburgh et al.
48
Ramipril 5 08:00 vs. 14:00 h vs. 30 ↓ ↑ Zaslavskaia et al.
22:00 h
51
Ramipril 5 a wakening vs. 115 ↓ ↑ Hermida and a yala
bedtime
52
Spirapril 6 a wakening vs. 165 ↓ ↑ Hermida et al.
bedtime
49
Trandolapril 1 a wakening vs. 30 ↓ ↑ Kuroda et al.
bedtime
BP, blood pressure; HCTZ, hydrochlorothiazide.
a
The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline in mean BP during the hours of nocturnal sleep relative to the mean BP during the hours of
diurnal activity, and calculated as: ((awake BP mean – asleep BP mean)/awake BP mean) × 100.
metabolic/clearance processes, and drug-targeted sites, effects on the circadian BP pattern, and (ii) discuss the impli-
including receptor number/conformation, second messengers, cations of such differences as the basis for the cost-effective
19,25,26
and signaling pathways. chronotherapy of these classes of medications to improve
A growing number of studies, all based on ambulatory BP the management of hypertension and reduce CVD risk. In
monitoring (ABPM), have consistently revealed an association particular, we specifically emphasize the administration-
between blunted asleep BP decline and increased incidence of time-dependent effects of ACEI and ARB medications on the
27–34
fatal and nonfatal cardiovascular disease (CVD) events. sleep-time relative BP decline and nighttime BP regulation.
Furthermore, a series of independent prospective studies have
shown that the asleep BP mean better predicts CVD risk than Chronotherapy with aC eis
28,31,34,35
either the awake or 24-h BP mean. The nocturnal BP A substantial number of small sample-size clinical studies
reduction can be quantified in terms of the sleep-time relative have demonstrated administration-time differences in BP
37 38 39–41 42
BP decline, i.e., percent decline in mean BP during the hours effects by benazepril, captopril, enalapril, imidapril,
43 44 45,46 47,48
of nocturnal sleep relative to the mean BP during the hours lisinopril, perindopril, quinapril, ramipril, and
49
of diurnal activity, calculated as ((awake BP mean ? asleep BP trandolapril. Most of these studies indicate that ACEIs exert
mean)/awake BP mean) × 100. Using this variable, people can a more marked effect on the asleep than awake BP means plus
be arbitrarily classified based on ABPM data either as dippers, significant modification of the circadian BP rhythm toward
when the sleep-time relative BP decline is >10%, or nondippers normal, i.e., a more dipping pattern, when scheduled in the
36
otherwise. evening than morning (Table 1).
The aims of this article are to: (i) review the findings of pro-
spective trials involving ACEI and ARB medications that have Benazepril
37
been investigated for morning-evening, treatment-time dif- Palatini et al. conducted a single-blinded crossover study of
ferences in efficacy, duration of action, safety profile, and/or 10 hypertensive subjects assessed by continuous intra-arterial
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Chronotherapy of Hypertension STATE OF THE ART
BP monitoring to investigate the acute effects on BP of a single nighttime BP means by imidapril (10 mg/day for 4 weeks) in a
10 mg dose of benazepril when administered at 09:00 h or at crossover study involving 20 hypertensive subjects.
21:00 h. Morning administration had a more sustained anti-
hypertensive effect than evening administration. This study, Lisinopril
43
however, was too small and underpowered to assess treatment- Macchiarulo et al. assessed BP changes in 40 subjects with
time differences in 24 h, daytime or nighttime mean BP reduc- grade 1–2 essential hypertension according to the treatment-
tions. Moreover, the potential administration-time-dependent time of lisinopril (20 mg for 8 weeks) once-daily either at
effects of benazepril treatment for spans longer than just a 08:00 h, 16:00 h, or 22:00 h. Systolic blood pressure (SBP) and
s ingle day are still to be elucidated. diastolic BP (DBP) showed significantly greater reduction
between 06:00 and 11:00 h with the 22:00 h treatment-time
Captopril than with either one of the two other treatment-times. Thus,
38
Middeke et al. reported the captopril (25 mg)-hydrochloro- lisinopril administration in the late evening seems to be much
thiazide (12.5 mg) combination medication administered to more effective in reducing BP, particularly during the night-
43
13 hypertensive men for 3 weeks was slightly more effective time and early morning, when CVD risk is higher.
in reducing nighttime BP when ingested in the evening and
significantly more effective (P < 0.01) in reducing daytime BP perindopril
44
when ingested in the morning. Morgan et al. conducted a crossover study on 20 hyperten-
sive subjects randomly assigned to perindopril (4 mg/day for
enalapril 4 weeks) either in the morning, at 09:00 h, or in the evening,
39
Witte et al. studied the cardiovascular effects plus inhibition at 21:00 h. Subjects were evaluated by 26 h ABPM before
of serum ACE induced by once-daily enalapril (10 mg) therapy and after treatment. Reduction of the daytime BP mean was
in eight hypertensive subjects. Enalapril was ingested either at greater with morning than evening treatment (?8.0/?4.7 vs.
07:00 h or 19:00 h in a randomized crossover design. Based on ?5.2/?3.9 mm Hg SBP/DBP; P < 0.05 for SBP), whereas reduc-
24 h ABPM, morning treatment significantly reduced BP dur- tion of the nighttime SBP mean was greater with evening than
ing the day, but it was less effective at night; evening treatment morning treatment (?11.7/?7.2 vs. ?8.2/?5.2 mm Hg, P <
significantly further decreased nighttime BP followed by a 0.05 for both SBP and DBP). Although not specifically evalu-
slow increase during the day. Thus, the 24-h BP profiles were ated, the study showed evening compared to morning perin-
significantly influenced by the enalapril dosing time. Serum dopril resulted in an increased sleep-time relative BP decline
concentrations of enalaprilat peaked 3.5 h after morning and and c orresponding modification of the circadian BP pattern
5.6 h after evening drug ingestion (P < 0.05), whereas the toward a more dipping profile.
BP-lowering effect peaked 7.4 h after morning and 12 h after
39
evening drug administration. Thus, the administration-time Quinapril
45,46
differences in the pharmacodynamics of enalapril cannot be Palatini et al. investigated the antihypertensive effect of
attributed to administration-time-dependent differences in its morning (08:00 h) vs. evening (22:00 h) treatment of 18 hyper-
PK or the different time courses of ACE inhibition. tensive subjects with quinapril (20 mg/day for 4 weeks). The
Dry cough, an adverse reaction to ACEIs, occurs in about evening schedule resulted in a more sustained antihyperten-
18
12% of enalapril-treated patients, but may be diminished sive effect, whereas the morning schedule produced a smaller
40,50 45
by change to a nighttime medication schedule. Fujimura reduction in nighttime BP. Measurement of ACE activity
50
et al. found the dosing time of enalapril affects plasma showed evening quinapril administration caused a less pro-
46
bradykinin, which is involved in the mechanism of enalapril- nounced, yet more sustained, reduction of plasma ACE.
induced cough; it tended to increase following enalapril Overall, evening quinapril administration seems prefer-
administration at 10:00 h, but not at 22:00 h. Moreover, BP was able because it gives rise to more sustained and stable 24 h BP
still significantly reduced 24 h after enalapril administration at control, presumably through more favorable modulation of
22:00 h, but not at 10:00 h, indicating the prolonged antihyper- tissue ACE inhibition and/or effect on the adrenergic-induced
45
tensive action of enalapril only with evening administration. morning BP rise.
In keeping with all these findings, nighttime dosing has been
18,40
recommended for enalapril. t randolapril
49
Kuroda et al. investigated a group of 30 hypertensive sub-
imidapril jects for the differential effects of a bedtime vs. morning-time
42
Kohno et al. found no significant morning-evening, schedule of the long-acting lipophilic ACEI trandolapril (1 mg/
treatment- time differences in the attenuation of the daytime or day for 8 weeks). With the morning schedule, the awake, but
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 4 | ap RiL 2011 385Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on January 19, 2015
STATE OF THE ART Chronotherapy of Hypertension
t able 2 | a ngiotensin-ii receptor blockers: administration-time differences in effects on the circadian Bp pattern, i.e., sleep-time
relative Bp decline
Effect on the sleep-time
a
relative BP decline
Medication Dose (mg) Treatment times No. subjects Morning Evening Reference
41
irbesartan 100 Morning vs. evening 10 ↓ ↑ pechère-Bertschi et al.
68
Olmesartan 20–40 08:00 vs. 20:00 h 18 = = Smolensky et al.
60
Olmesartan 20 a wakening vs. bedtime 133 = ↑ Hermida et al.
61
Olmesartan 40 a wakening vs. bedtime 40 = ↑ Tofé and García
69
Telmisartan 40–80 06:00 vs. 18:00 h 42 = = Niegowska et al.
70
Telmisartan 80 a wakening vs. bedtime 215 = ↑ Hermida et al.
54
Valsartan 160 a wakening vs. bedtime 90 = ↑ Hermida et al.
b 55
Valsartan 160 a wakening vs. bedtime 100 = ↑ Hermida et al.
c 59
Valsartan 160 a wakening vs. bedtime 200 = ↑ Hermida et al.
BP, blood pressure.
a
The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline in mean BP during the hours of nocturnal sleep relative to the mean BP during the hours of
b c
diurnal activity, and calculated as: ((awake BP mean – asleep BP mean)/awake BP mean) × 100. Elderly subjects. Nondipper subjects.
not asleep, BP was significantly reduced. With the bedtime (6 mg/day for 3 months) in a study of 165 grade 1–2 essential
schedule, both the awake and asleep BP means were effectively hypertensive subjects randomized to therapy either upon-
49
controlled without induction of nocturnal hypotension. awakening or at bedtime. Reduction of the 48 h SBP/DBP
means was comparable with the morning and bedtime regi-
r amipril mens (?8.7/?7.0 mm Hg vs. ?9.8/?6.6 mm Hg SBP/DBP; P >
Two different small studies revealed that ramipril when admin- 0.287 between groups), and the extent of BP reduction dur-
istered in the morning more effectively reduces daytime BP ing diurnal activity was also independent of treatment time
and when administered in the evening more effectively reduces (P = 0.292). However, the bedtime, compared to the upon-
47,48
nighttime BP. A larger clinical study by Hermida and awakening, schedule was much more effective in dimin-
51
Ayala involving 115 previously untreated subjects with grade ishing the asleep SBP/DBP means (?12.8/?8.6 mm Hg vs.
1–2 essential hypertension randomized to either upon waken- ?5.7/?4.6 mm Hg; P < 0.001). Thus, the sleep-time relative
ing or bedtime ramipril monotherapy (5 mg/day for 6 weeks), BP decline was significantly increased toward a more dipping
and evaluated by 48 h ABPM both before and after treat- pattern only with bedtime spirapril ingestion (P < 0.001), and
ment, found greater reduction of the 48 h SBP/DBP means the proportion of patients with controlled ambulatory BP was
52
with the bedtime than upon-awakening schedule (?11.2/?9.5 increased from 23 to 59% (P < 0.001).
vs. ?8.5/?6.2 mm Hg SBP/DBP; P = 0.004 between groups).
Although there was no treatment-time-dependent difference in Chronotherapy with a rB s
the effect upon the awake BP mean, the bedtime, compared to ARB medications are highly effective and very well tolerated.
the upon-awakening schedule, was significantly more effective in They specifically antagonize the potent vasoconstrictor action
reducing the asleep BP mean (?13.5/?11.5 vs. ?4.5/?4.1 mm Hg, of angiotensin II, and are a popular means today of managing
53
P < 0.001 between groups). The sleep-time relative BP decline hypertension.
was decreased when treatment was ingested upon awakening
but significantly increased toward a more dipping pattern when Valsartan
54
taken at bedtime (Ta b l e 1); moreover, the proportion of patients Hermida et al. applied 48 h ABPM to assess the efficacy of
with controlled ambulatory BP was increased from 43 to 65% valsartan (160 mg/day for 3 months) when ingested as a mono-
(P = 0.019). Overall, asleep BP regulation was significantly therapy either upon morning awakening or at bedtime by 90
enhanced with ramipril administration at bedtime and without grade 1?2 essential hypertensive subjects. The amount of the
any loss in efficacy during the diurnal activity span. highly significant reduction of the 48 h SBP/DBP means was
comparable when the medication was taken upon-a wakening
s pirapril or at bedtime (?17.0/?11.2 vs. ?14.6/?11.4 mm Hg; P > 0.174).
52
Hermida et al. explored the treatment-time-dependent effi- When valsartan was ingested upon awakening, the mean
cacy of the long-terminal plasma half-life (~40 h) spirapril reduction in the awake and asleep BP means was similar
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Chronotherapy of Hypertension STATE OF THE ART
(?17.0 vs. ?15.9 mm Hg in SBP, P = 0.604; ?11.1 vs. ?10.8 mm Hg significant increase in the proportion of patients with controlled
in DBP, P = 0.855). However, when valsartan was ingested at ambulatory BP, and significant reduction in urinary albumin
58
bedtime, the mean reduction in asleep BP was significantly excretion, a measure of hypertensive renal damage. An exten-
greater than the reduction in awake BP (?17.9 vs. –12.0 mm Hg sion of this trial, which included 200 nondipper hypertensive
59
in SBP, P = 0.009; ?13.3 vs. –9.8 mm Hg in DBP, P = 0.015). subjects, yielded similar more favorable changes in the asleep
Accordingly, the bedtime schedule resulted in a highly sig- BP mean plus more desired effects on the BP circadian profile,
nificant average increase by 6% in the sleep-time relative BP i.e., increase in sleep-time relative BP decline toward a more
decline, which translated into a 73% reduction from baseline in dipping BP pattern, after 3 months of bedtime in comparison
54
the number of nondipper patients. These findings document to upon-awakening valsartan treatment.
a significant change in the dose-effect curve of va lsartan that is
highly dependent on its time of administration. o lmesartan
These results were corroborated by two subsequent inde- The findings were similar with olmesartan based on the
pendent prospective clinical trials (Table 2), one conducted study of 123 grade 1–2 essential hypertensive subjects ran-
55
on elderly hypertensive patients, characterized by the pro- domized to monotherapy (20 mg/day for 3 months) either
60
gressive attenuation of the sleep-time relative BP decline upon awakening or at bedtime. Comparable modulation
56,57
with aging, and the second on nondipper hypertensive of the 48 h SBP/DBP means was achieved when the medica-
58 55
s ubjects. The first trial involved 100 elderly (68.2 ± 4.9 tion was taken upon awakening or at bedtime (?13.8/?11.2
(mean ± s.d.) years of age) grade 1?2 essential hypertensive vs. ?13.9/?10.2 mm Hg SBP/DBP; P > 0.348 between groups).
subjects randomized either to upon awakening or bedtime val- However, the bedtime schedule was significantly more effective
sartan monotherapy (160 mg/day for 3 months). There was sig- than the upon-awakening one in reducing the asleep BP mean
nificant reduction in the 48 h SBP/DBP means irrespective of (?15.2/?11.5 mm Hg vs. ?11.2/?8.7 mm Hg; P < 0.023 between
the dosing time; although, this effect was slightly stronger with groups). Furthermore, the sleep-time relative BP decline,
the bedtime than upon-awakening schedule (?15.3/?9.2 vs. which was slightly reduced with treatment upon awakening,
?12.3/?6.3 mm Hg; P = 0.094 for SBP, P = 0.007 for DBP). The was significantly increased with treatment at bedtime (P <
sleep-time relative BP decline was unchanged from baseline in 0.001), thereby diminishing the prevalence of BP nondipping
those ingesting valsartan upon awakening (?1.0/?0.3 mm Hg by 48% from baseline.
61
for SBP/DBP; P > 0.195), while it was significantly increased Tofé and García used a crossover design to evaluate
(6.6/5.4 mm Hg for SBP/DBP; P < 0.001) in those ingesting it the ambulatory BP response to olmesartan (40 mg/day for
at bedtime. The reduction of the asleep BP mean was double 8 weeks) when taken either upon awakening or at bedtime by
in patients routinely taking their medication at bedtime com- 40 type 2 diabetes hypertensive subjects, who are more prone
pared to those who did so upon awakening (P < 0.001). If one to having a blunted nocturnal BP decline than the general
2 62–67
might consider the specific reduction of asleep BP to be a wor- population. , Bedtime compared to morning olmesartan
thy therapeutic goal, based on the strong relationship between ingestion resulted in a significantly greater reduction of night-
28,31,34,35
elevated asleep BP and CVD risk, results of this valsar- time SBP (?16.2 vs. ?11.8; P = 0.007) and significant increase
tan trial involving elderly hypertensive patients, who showed in the sleep-time relative SBP decline (7.4 vs. 2.2%; P < 0.001),
diminished nocturnal BP decline at baseline, indicate bedtime while also increasing the percentage of patients with a dipper
61
treatment is superior to upon-awakening treatment, because BP pattern.
it significantly improves sleep-time BP control and remodels A previous small crossover study on 18 hypertensive patients,
the 24-h BP profile toward a more normal dipping pattern by on the other hand, did not detect morning vs. evening-time
increasing the sleep-time relative BP decline. administration differences in the BP-lowering effects of
58 68
The second trial used a similar design to investigate the o lmesartan. However, methodological differences between
treatment-time-dependent effects of the same dose of v alsartan this and the positive trials may explain the disparate results. The
68
(160 mg/day for 3 months) in a selected sample of 148 non- study by Smolensky et al. relied on a crossover design with all
dipper grade 1–2 essential hypertensive subjects. The signifi- participants first being treated in the morning and then in the
cant decrease from baseline in the 48 h SBP/DBP means (P < evening, thus without randomization of subjects for the order
0.001) was not treatment-time dependent (upon awakening: (morning vs. evening) of the timed therapy. Most relevant, this
?13.1/?8.5 vs. at bedtime: ?14.7/?10.3 mm Hg SBP/DBP; P > trial used fixed clock hours (08:00 h and 20:00 h, rather than the
0.126 for the treatment-time effect). The sleep-time relative BP individually specified upon-awakening and bed times that are
decline, however, was significantly increased only when val- more strongly related to circadian BP regulation) to compare
sartan was ingested at bedtime, which resulted in 75% of the the BP-lowering effects of the two different olmesartan dosing
subjects in this group reverting to a 24-h dipper BP pa ttern, times. Finally, this trial involved only 18 grade 1 u ncomplicated
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 4 | ap RiL 2011 387Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on January 19, 2015
STATE OF THE ART Chronotherapy of Hypertension
essential hypertensive subjects who displayed a normal BP summarized herein confirm their effects can vary, sometimes
60
di pping profile, while the study by Hermida et al. investigated dramatically, as a function of the circadian time of dosing.
a much larger sample of grade 1–2 hypertensive subjects who Several authors, disregarding current available clinical
evidenced a wider range of sleep-time relative BP decline. The information, have proposed the differential administration-
same methodological problems, i.e., lack of dosing-time ran- time-dependent effects on asleep BP regulation of some hyper-
domization, use of fixed clock hours for treatment, and small tension medications and their ability to restore the normal
sample size, also apply to another study of 42 hypertensive men dipping BP pattern may be just a direct consequence of their
showing comparable BP reductions with telmisartan adminis- short terminal half-life and limited (shorter than 24 h) dura-
69
tration either at 06:00 h or 18:00 h. tion of action; thus, they argue that treatment timing might be
72,73
relevant only for short-acting ACEI and ARB medications.
irbesartan These unfounded conclusions do not take into account that
41
Pechère-Bertschi et al. studied 10 uncomplicated essen- the PK and pharmacodynamics of hypertension medications
tial hypertension subjects to explore the differential effects of may depend markedly on their administration time relative to
morning (between 07:00 h and 09:00 h) vs. evening (between the rest-activity cycle of patients. Moreover, studies show the
18:00 h and 20:00 h) irbesartan (terminal half-life 11–15 h) marked differences between morning and evening administra-
treatment (100 mg for 6 weeks). The amount of the nighttime tion apply also to BP-lowering medications with long (beyond
52
SBP reduction was almost double with the evening compared 24 h postdosing) and sustained action, e.g., spirapril,
70 60,61
to the morning schedule (?7.4 vs. ?4.2 mm Hg). telmisartan, and olmesartan. Thus, the differential
treatment-time-dependent effects on SBP and DBP by ACEIs
telmisartan and ARBs summarized in Tables 1 and 2 appear to be a class-
70
Hermida et al. studied 215 grade 1–2 essential hypertensive related phenomenon for these two families of BP-lowering
subjects randomized to either upon-awakening or bedtime medications and independent of drug plasma terminal half-
monotherapy with long-terminal half-life (≥24 h) telmisartan life. The enhanced impact of bedtime therapy with ARBs and
(80 mg/day for 12 weeks). Significant and comparable reduc- ACEIs on asleep BP reduction, increase of sleep-time relative
tion in the 48 h SBP/DBP means from baseline was achieved by BP decline, and normalization of the circadian BP pattern
the two schedules (upon-awakening: ?10.6/?7.9 vs. at bedtime: toward a more dipping pattern, is hypothesized to result from
?11.7/?8.3 mm Hg SBP/DBP; P > 0.347 between groups). the achievement of peak or near peak drug levels overnight
The bedtime schedule, however, was significantly more effec- around the time when the RAAS activates, i.e., when plasma
tive in decreasing the asleep SBP/DBP means (?13.8/?9.7 renin activity and plasma concentrations of ACE, angiotensin
vs. ?8.3/?6.4 mm Hg SBP/DBP; P < 0.001 between groups). I and II, and aldosterone rise to highest levels.
Thus, the sleep-time relative BP decline was slightly reduced The potential reduction in CVD risk associated with either
when telmisartan was taken upon awakening (?1.6/?1.0 for the specific lowering of asleep BP as a novel therapeutic target
SBP/DBP, P = 0.010/P = 0.157), whereas it was significantly and/or the normalization of the circadian BP variability, i.e.,
enhanced when taken at bedtime (3.1/3.9 for SBP/DBP, P < increasing the sleep-time relative BP decline, is still a matter
0.001), thereby reducing the prevalence of nondipping from of debate. Subjects in the active treatment group of the HOPE
74
baseline by 76% (P < 0.001) and increasing the sleep-time rela- (Heart Outcomes Prevention Evaluation) study were treated
tive BP decline toward a more dipper profile without loss of with the ACEI ramipril at bedtime. A small substudy in which
70
24 h efficacy (Table 2). subjects were evaluated by 24 h ABPM evidenced marked BP
75
reduction, particularly during the nighttime sleep span, thus
DisC ussion diminishing the prevalence of nondippers in this high-risk
The pharmacologic characteristics of most hypertension CVD patient cohort. It is noteworthy the authors of the HOPE
medications have been shown to be highly dependent on study concluded that the protective effects of ramipril against
19,71
treatment-time. However, the majority of the once-a-day CVD morbidity and mortality may be related to the resultant
hypertensive medications have been approved without speci- increased sleep-time relative BP decline, which constitutes
53 75
fication of a preferred ingestion-time. Because the effects of change toward the normalization of the 24 h BP pattern.
BP-lowering medications are circadian-stage dependent, that Another relevant study in which the nondipper BP profile
is dependent on ingestion time with reference to endogenous in subjects with chronic renal failure was normalized with
76
24 h rhythms, the specific administration-time-dependent evening, but not morning, 4-week isradipine dosing unfortu-
dose-effect curve of medications must be first determined and nately did not conduct follow-up to evaluate potential changes
taken into consideration when prescribing therapy. Studies in CVD risk, mainly due to the short period of active treat-
on the chronotherapy of hypertension with ACEIs and ARBs ment. On the other hand, recent results have demonstrated that
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Chronotherapy of Hypertension STATE OF THE ART
urinary albumin excretion is significantly reduced to a larger nervous system dysfunction, than in uncomplicated p rimary
77 2
extent with bedtime than morning valsartan treatment. This hypertension. However, the findings of a recent study based on
reduction was not related to attenuation of the 24 h BP mean, 48 h ABPM indicate a high, i.e., 38%, prevalence of nondipping
80
but rather to the decrease in the asleep BP mean and, mainly, even among untreated patients with essential hypertension,
with the increase in the sleep-time relative BP decline achieved and of further relevance is the finding that the percentage of
by bedtime valsartan administration. Moreover, plasma fibrin- nondipper patients significantly increases to 62% while under
80
ogen has also been shown to be significantly reduced with bed- management with (morning) hypertension therapy.
time, as compared to morning, valsartan treatment in direct International guidelines recommend the prescription of
correlation with the increased sleep-time relative BP decline long-acting, once-daily hypertension medications that have
55,77 53
resulting from the conversion of nondippers into dippers. 24 h efficacy; they improve adherence to therapy, minimize
The potential differential reduction of CVD morbidity and BP variability, and provide smoother and more consistent BP
mortality risk by a bedtime vs. upon-awakening treatment control. However, in our opinion, these recommendations
schedule has been evaluated prospectively in the MAPEC might only be valid for those medications when ingested in
78,79
study, specifically designed to test the hypothesis that bed- the morning. The morning ingestion of a hypertension medi-
time chronotherapy with at least one hypertension medication cation with high 24 h homogeneous and sustained efficacy is
exerts better BP control and CVD risk reduction than conven- unlikely to affect the circadian BP profile and from our per-
tional therapy, i.e., all medications ingested in the morning. spective could eventually qualify only as a potential choice of
A total of 2,156 hypertensive subjects were randomized either treatment for dipper hypertensive patients. This therapeutic
to ingest all their prescribed hypertension medications upon scheme does not seem appropriate for nondippers, since nor-
awakening or at least one of them at bedtime. Subjects were malization of the circadian BP rhythm and specific control of
evaluated by 48 h ABPM at baseline, with identical assessment asleep BP must be considered to be important clinical goals of
conducted annually, or more frequently (quarterly) if treat- their pharmacotherapy; indeed, meeting these novel treatment
79
ment adjustment was required. Despite lack of differences in goals has been found to reduce the heightened CVD risk
27–34
ambulatory BP between groups at baseline, subjects ingesting associated with nondipper hypertension.
medication at bedtime showed at their last available evaluation Many studies indicate the asleep BP mean is a better predic-
significantly lower mean sleep-time BP, higher sleep-time rela- tor of CVD risk than either the awake (clinic cuff of ABPM-
28,31,34,35
tive BP decline, reduced prevalence of nondipping (34 vs. 62%; determined daytime mean) or 24 h BP mean. Thus,
P < 0.001), and higher prevalence of controlled ambulatory BP for any given conventional clinic or awake BP mean value,
(62 vs. 53%, P < 0.001). After a median follow-up of 5.6 years, subjects with higher asleep BP mean will have increased CVD
the group of subjects ingesting at least one BP-lowering medi- risk, rendering ABPM a required tool for proper risk stratifi-
cation at bedtime exhibited significantly lower relative risk of cation. Moreover, reduction of asleep BP has been shown to
total CVD events than the group of subjects ingesting all medi- reduce CVD risk, independent of the effects of treatment on
79
cations upon awakening (0.39 (0.29–0.51); P < 0.001). The pro- the awake BP mean. Available scientific evidence derived
gressive decrease in asleep BP and increase in sleep-time relative from numerous clinical trials reveals that asleep BP regulation
BP decline toward a more normal dipping pattern—two new can be better achieved with ACEI and ARB class medications
and novel therapeutic targets requiring proper patient evalua- when administered consistently at bedtime than upon awaken-
tion by ABPM—were best achieved with bedtime therapy, and ing in the morning (Tables 1 and 2). The bedtime scheduling
they were the most significant predictors of event-free survival. of medications of these two classes, regardless of their termi-
Results of the prospective MAPEC study thus indicate that nal plasma half-life, very effectively reduces abnormally high
bedtime chronotherapy with at least one BP-lowering medica- sleep-time BP and converts an abnormal nondipping circadian
tion, compared to conventional upon-waking treatment with BP profile toward a normal dipper one. In fact, with bedtime
all medications, more effectively improves BP control, b etter treatment, there is greater likelihood of increasing the sleep-
decreases the prevalence of nondipping and, most importantly, time relative BP decline and of properly reducing asleep BP by
significantly reduces CVD morbidity and mortality. using medications with a shorter or nonhomogeneous dura-
The nondipper BP pattern, characterized by the loss or even tion of action (Table 1), thereby challenging the current inter-
reversal of the expected ≥10% sleep-time relative BP decline, national recommendations discussed above.
increases one’s risk of cardiovascular and cerebrovascular In hypertensive subjects, pharmacologic therapy should take
events, nephrosclerosis, and progression to end-stage kidney into account the seldom considered, yet crucial, variable of
failure in renal patients. The nondipper BP pattern is more treatment-time with respect to the rest-activity pattern of the
frequent in hypertension secondary to specific medical condi- patient. Given that the teaching of medical and pharmaceutical
tions, such as chronic renal failure, diabetes, and autonomic sciences today continues to be based exclusively on the concept
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 4 | ap RiL 2011 389Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on January 19, 2015
STATE OF THE ART Chronotherapy of Hypertension
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