Circadian Rhythms in Blood Pressure Regulation and Optimization of Hypertension Treatment With ACE Inhibitor and ARB Medications

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1 nature publishing group STATE OF THE ART Circadian Rhythms in Blood Pressure Regulation and Optimization of Hypertension Treatment With ACE Inhibitor and ARB Medications Ramón C. Hermida 1, Diana E. Ayala 1, José R. Fernández 1, Francesco Portaluppi 2, Fabio Fabbian 2 and Michael H. Smolensky 3 Specific features of the 24 h-blood pressure (BP) pattern are linked to the progressive injury of target tissues and risk of cardiac and cerebrovascular events. Studies have consistently shown an association between blunted asleep BP decline and increased incidence of fatal and nonfatal cardiovascular events. Thus, there is growing interest in how to achieve better BP control during nighttime sleep in addition to during daytime activity, according to the particular requirements of each hypertension patient. One approach takes into consideration the endogenous circadian rhythm-determinants of the 24-h BP pattern, especially, the prominent day night variation of the renin angiotensin aldosterone system, which activates during nighttime sleep. A series of clinical studies have demonstrated a different effect of the angiotensin-converting enzyme (ACE) inhibitors benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, and trandolapril when routinely ingested in the morning vs. the evening. In most cases, the evening schedule exerts a more marked effect on the asleep than awake BP means. Similarly, a once daily The 24-h blood pressure (BP) pattern is the results of both cyclic day night alterations in behavior, e.g., physical activity, mental stress, and posture, and environmental phenomena, e.g., ambient temperature, noise etc. 1,2 plus endogenous circadian (~24 h) rhythms in neural, endocrine, endothelial and hemodynamic variables. The usually higher BP during the daytime of diurnally active normotensive and uncomplicated essential hypertensive persons derives in large part from the dominance of sympathetic tone, 3 5 evidenced by the high plasma norepinephrine and epinephrine 6,7 and urinary catecholamine concentrations 8 in the hours after morning awakening. Moreover, the high-amplitude circadian rhythm in the renin angiotensin aldosterone system (RAAS), 9 14 showing peak plasma concentrations of renin activity, angiotensin- converting enzyme (ACE), angiotensin I 1 Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain; 2 Hypertension Center, University Hospital S. Anna, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy; 3 Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA. Correspondence: Ramón C. Hermida (rhermida@uvigo.es) Received 28 June 2010; first decision 24 July 2010; accepted 4 September American Journal of Hypertension, Ltd. evening, in comparison to morning, ingestion schedule of the angiotensin receptor blockers (ARBs) irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with normalization of the circadian BP profile toward a more dipping pattern, independent of drug terminal half-life. Chronotherapy, the timing of treatment to body rhythms, is a cost-effective means of both individualizing and optimizing the treatment of hypertension through normalization of the 24-h BP level and profile, and it may constitute an effective option to reduce cardiovascular risk. Keywords: blood pressure; chronotherapy; rennin angiotensin aldosterone system; angiotensin receptor blockers; angiotensinconverting enzyme inhibitors; dipper; nondipper; asleep blood pressure; ambulatory blood pressure monitoring; hypertension American Journal of Hypertension, advance online publication 7 October 2010; doi: /ajh and II, and aldosterone just before the usual time of morning awakening, also plays a prominent role in 24-h BP regulation. The comparatively lower BP during nighttime sleep results from withdrawal of sympathetic dominance, predominance of vagal tone, reduced concentration of the constituents of the RAAS, and peak levels of atrial natriuretic peptide and nitric oxide as vasodilators The circadian variation that characterizes the RAAS and its activation during nocturnal sleep also has been hypothesized to explain the findings of stronger BP-lowering effects of bedtime vs. morning schedules of ACE inhibitor (ACEI) 18,19 and angiotensin-ii receptor blocker (ARB) medications. 19 Different circadian rhythms may also significantly affect the pharmacokinetics (PK) and pharmacodynamics, both beneficial and adverse effects, of hypertension medications. Administration-time differences in PK can result from circadian rhythms in gastric ph, gastric emptying, gastrointestinal motility, biliary function, glomerular filtration, liver enzyme activity, and organ blood flow (e.g., duodenum, liver, and kidney) Administration-time differences in pharmacodynamics can result from the time- dependency in PK and/or circadian rhythms in drug-free fraction, AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER april

2 STATE OF THE ART Chronotherapy of Hypertension Table 1 Angiotensin-converting enzyme inhibitors: administration-time differences in effects on the circadian BP pattern, i.e., sleep time relative BP decline Medication Dose (mg) Treatment times No. subjects Effect on the sleep-time relative BP decline a Morning Evening Reference Benazepril 10 09:00 vs. 21:00 h 10 = Palatini et al. 37 Captopril + HCTZ b :00 vs. 20:00 h 13 Middeke et al. 38 Enalapril 10 07:00 vs. 19:00 h 8 Witte et al. 39 Enalapril 5 10:00 vs. 22:00 h 12 Sunaga et al. 40 Enalapril 20 Morning vs. evening 10 Pechère-Bertschi et al. 41 Imidapril 10 07:00 vs. 18:00 h 20 = = Kohno et al. 42 Lisinopril 20 08:00 vs. 16:00 h vs. 22:00 h 40 = Macchiarulo et al. 43 Perindopril 4 09:00 vs. 21:00 h 18 = Morgan et al. 44 Quinapril 20 08:00 vs. 22:00 h 18 Palatini et al. 45 Ramipril :00 vs. 20:00 h 33 Myburgh et al. 47 Ramipril 5 08:00 vs. 14:00 h vs. 22:00 h Ramipril 5 Awakening vs. bedtime Spirapril 6 Awakening vs. bedtime Trandolapril 1 Awakening vs. bedtime 30 Zaslavskaia et al Hermida and Ayala Hermida et al Kuroda et al. 49 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, including receptor number/conformation, second messengers, and signaling pathways. 19,25,26 A growing number of studies, all based on ambulatory BP monitoring (ABPM), have consistently revealed an association between blunted asleep BP decline and increased incidence of fatal and nonfatal cardiovascular disease (CVD) events Furthermore, a series of independent prospective studies have shown that the asleep BP mean better predicts CVD risk than either the awake or 24-h BP mean. 28,31,34,35 The nocturnal BP reduction can be quantified in terms of the sleep-time relative BP decline, i.e., percent decline in mean BP during the hours of nocturnal sleep relative to the mean BP during the hours of diurnal activity, calculated as ((awake BP mean asleep BP mean)/awake BP mean) 100. Using this variable, people can be arbitrarily classified based on ABPM data either as dippers, when the sleep-time relative BP decline is >10%, or nondippers otherwise. 36 The aims of this article are to: (i) review the findings of prospective trials involving ACEI and ARB medications that have been investigated for morning-evening, treatment-time differences in efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern, and (ii) discuss the implications of such differences as the basis for the cost-effective chronotherapy of these classes of medications to improve the management of hypertension and reduce CVD risk. In particular, we specifically emphasize the administrationtime-dependent effects of ACEI and ARB medications on the sleep-time relative BP decline and nighttime BP regulation. Chronotherapy with Aceis A substantial number of small sample-size clinical studies have demonstrated administration-time differences in BP effects by benazepril, 37 captopril, 38 enalapril, imidapril, 42 lisinopril, 43 perindopril, 44 quinapril, 45,46 ramipril, 47,48 and trandolapril. 49 Most of these studies indicate that ACEIs exert a more marked effect on the asleep than awake BP means plus significant modification of the circadian BP rhythm toward normal, i.e., a more dipping pattern, when scheduled in the evening than morning (Table 1). Benazepril Palatini et al. 37 conducted a single-blinded crossover study of 10 hypertensive subjects assessed by continuous intra-arterial 384 april 2011 VOLUME 24 NUMBER 4 AMERICAN JOURNAL OF HYPERTENSION

3 Chronotherapy of Hypertension STATE OF THE ART BP monitoring to investigate the acute effects on BP of a single 10 mg dose of benazepril when administered at 09:00 h or at 21:00 h. Morning administration had a more sustained antihypertensive effect than evening administration. This study, however, was too small and underpowered to assess treatmenttime differences in 24 h, daytime or nighttime mean BP reductions. Moreover, the potential administration-time-dependent effects of benazepril treatment for spans longer than just a single day are still to be elucidated. Captopril Middeke et al. 38 reported the captopril (25 mg)-hydrochlorothiazide (12.5 mg) combination medication administered to 13 hypertensive men for 3 weeks was slightly more effective in reducing nighttime BP when ingested in the evening and significantly more effective (P < 0.01) in reducing daytime BP when ingested in the morning. Enalapril Witte et al. 39 studied the cardiovascular effects plus inhibition of serum ACE induced by once-daily enalapril (10 mg) therapy in eight hypertensive subjects. Enalapril was ingested either at 07:00 h or 19:00 h in a randomized crossover design. Based on 24 h ABPM, morning treatment significantly reduced BP during the day, but it was less effective at night; evening treatment significantly further decreased nighttime BP followed by a slow increase during the day. Thus, the 24-h BP profiles were significantly influenced by the enalapril dosing time. Serum concentrations of enalaprilat peaked 3.5 h after morning and 5.6 h after evening drug ingestion (P < 0.05), whereas the BP-lowering effect peaked 7.4 h after morning and 12 h after evening drug administration. 39 Thus, the administration-time differences in the pharmacodynamics of enalapril cannot be attributed to administration-time-dependent differences in its PK or the different time courses of ACE inhibition. Dry cough, an adverse reaction to ACEIs, occurs in about 12% of enalapril-treated patients, 18 but may be diminished by change to a nighttime medication schedule. 40,50 Fujimura et al. 50 found the dosing time of enalapril affects plasma bradykinin, which is involved in the mechanism of enalaprilinduced cough; it tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Moreover, BP was still significantly reduced 24 h after enalapril administration at 22:00 h, but not at 10:00 h, indicating the prolonged antihypertensive action of enalapril only with evening administration. In keeping with all these findings, nighttime dosing has been recommended for enalapril. 18,40 Imidapril Kohno et al. 42 found no significant morning-evening, treatment- time differences in the attenuation of the daytime or nighttime BP means by imidapril (10 mg/day for 4 weeks) in a crossover study involving 20 hypertensive subjects. Lisinopril Macchiarulo et al. 43 assessed BP changes in 40 subjects with grade 1 2 essential hypertension according to the treatmenttime of lisinopril (20 mg for 8 weeks) once-daily either at 08:00 h, 16:00 h, or 22:00 h. Systolic blood pressure (SBP) and diastolic BP (DBP) showed significantly greater reduction between 06:00 and 11:00 h with the 22:00 h treatment-time than with either one of the two other treatment-times. Thus, lisinopril administration in the late evening seems to be much more effective in reducing BP, particularly during the nighttime and early morning, when CVD risk is higher. 43 Perindopril Morgan et al. 44 conducted a crossover study on 20 hypertensive subjects randomly assigned to perindopril (4 mg/day for 4 weeks) either in the morning, at 09:00 h, or in the evening, at 21:00 h. Subjects were evaluated by 26 h ABPM before and after treatment. Reduction of the daytime BP mean was greater with morning than evening treatment ( 8.0/ 4.7 vs. 5.2/ 3.9 mm Hg SBP/DBP; P < 0.05 for SBP), whereas reduction of the nighttime SBP mean was greater with evening than morning treatment ( 11.7/ 7.2 vs. 8.2/ 5.2 mm Hg, P < 0.05 for both SBP and DBP). Although not specifically evaluated, the study showed evening compared to morning perindopril resulted in an increased sleep-time relative BP decline and corresponding modification of the circadian BP pattern toward a more dipping profile. Quinapril Palatini et al. 45,46 investigated the antihypertensive effect of morning (08:00 h) vs. evening (22:00 h) treatment of 18 hypertensive subjects with quinapril (20 mg/day for 4 weeks). The evening schedule resulted in a more sustained antihypertensive effect, whereas the morning schedule produced a smaller reduction in nighttime BP. 45 Measurement of ACE activity showed evening quinapril administration caused a less pronounced, yet more sustained, reduction of plasma ACE. 46 Overall, evening quinapril administration seems preferable because it gives rise to more sustained and stable 24 h BP control, presumably through more favorable modulation of tissue ACE inhibition and/or effect on the adrenergic-induced morning BP rise. 45 Trandolapril Kuroda et al. 49 investigated a group of 30 hypertensive subjects for the differential effects of a bedtime vs. morning-time schedule of the long-acting lipophilic ACEI trandolapril (1 mg/ day for 8 weeks). With the morning schedule, the awake, but AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 4 april

4 STATE OF THE ART Chronotherapy of Hypertension Table 2 Angiotensin-II receptor blockers: administration-time differences in effects on the circadian BP pattern, i.e., sleep-time relative BP decline Medication Dose (mg) Treatment times No. subjects Effect on the sleep-time relative BP decline a Morning Evening Reference Irbesartan 100 Morning vs. evening 10 Pechère-Bertschi et al. 41 Olmesartan :00 vs. 20:00 h 18 = = Smolensky et al. 68 Olmesartan 20 Awakening vs. bedtime 133 = Hermida et al. 60 Olmesartan 40 Awakening vs. bedtime 40 = Tofé and García 61 Telmisartan :00 vs. 18:00 h 42 = = Niegowska et al. 69 Telmisartan 80 Awakening vs. bedtime 215 = Hermida et al. 70 Valsartan 160 Awakening vs. bedtime 90 = Hermida et al. 54 Valsartan 160 Awakening vs. bedtime 100 b = Hermida et al. 55 Valsartan 160 Awakening vs. bedtime 200 c = Hermida et al. 59 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 diurnal activity, and calculated as: ((awake BP mean asleep BP mean)/awake BP mean) 100. b Elderly subjects. c Nondipper subjects. not asleep, BP was significantly reduced. With the bedtime schedule, both the awake and asleep BP means were effectively controlled without induction of nocturnal hypotension. 49 Ramipril Two different small studies revealed that ramipril when administered in the morning more effectively reduces daytime BP and when administered in the evening more effectively reduces nighttime BP. 47,48 A larger clinical study by Hermida and Ayala 51 involving 115 previously untreated subjects with grade 1 2 essential hypertension randomized to either upon wakening or bedtime ramipril monotherapy (5 mg/day for 6 weeks), and evaluated by 48 h ABPM both before and after treatment, found greater reduction of the 48 h SBP/DBP means with the bedtime than upon-awakening schedule ( 11.2/ 9.5 vs. 8.5/ 6.2 mm Hg SBP/DBP; P = between groups). Although there was no treatment-time-dependent difference in the effect upon the awake BP mean, the bedtime, compared to the upon-awakening schedule, was significantly more effective in reducing the asleep BP mean ( 13.5/ 11.5 vs. 4.5/ 4.1 mm Hg, P < between groups). The sleep-time relative BP decline was decreased when treatment was ingested upon awakening but significantly increased toward a more dipping pattern when taken at bedtime (Table 1); moreover, the proportion of patients with controlled ambulatory BP was increased from 43 to 65% (P = 0.019). Overall, asleep BP regulation was significantly enhanced with ramipril administration at bedtime and without any loss in efficacy during the diurnal activity span. Spirapril Hermida et al. 52 explored the treatment-time-dependent efficacy of the long-terminal plasma half-life (~40 h) spirapril (6 mg/day for 3 months) in a study of 165 grade 1 2 essential hypertensive subjects randomized to therapy either uponawakening or at bedtime. Reduction of the 48 h SBP/DBP means was comparable with the morning and bedtime regimens ( 8.7/ 7.0 mm Hg vs. 9.8/ 6.6 mm Hg SBP/DBP; P > between groups), and the extent of BP reduction during diurnal activity was also independent of treatment time (P = 0.292). However, the bedtime, compared to the uponawakening, schedule was much more effective in diminishing the asleep SBP/DBP means ( 12.8/ 8.6 mm Hg vs. 5.7/ 4.6 mm Hg; P < 0.001). Thus, the sleep-time relative BP decline was significantly increased toward a more dipping pattern only with bedtime spirapril ingestion (P < 0.001), and the proportion of patients with controlled ambulatory BP was increased from 23 to 59% (P < 0.001). 52 Chronotherapy with Arbs ARB medications are highly effective and very well tolerated. They specifically antagonize the potent vasoconstrictor action of angiotensin II, and are a popular means today of managing hypertension. 53 Valsartan Hermida et al. 54 applied 48 h ABPM to assess the efficacy of valsartan (160 mg/day for 3 months) when ingested as a monotherapy either upon morning awakening or at bedtime by 90 grade 1 2 essential hypertensive subjects. The amount of the highly significant reduction of the 48 h SBP/DBP means was comparable when the medication was taken upon- awakening or at bedtime ( 17.0/ 11.2 vs. 14.6/ 11.4 mm Hg; P > 0.174). When valsartan was ingested upon awakening, the mean reduction in the awake and asleep BP means was similar 386 april 2011 VOLUME 24 NUMBER 4 AMERICAN JOURNAL OF HYPERTENSION

5 Chronotherapy of Hypertension STATE OF THE ART ( 17.0 vs mm Hg in SBP, P = 0.604; 11.1 vs mm Hg in DBP, P = 0.855). However, when valsartan was ingested at bedtime, the mean reduction in asleep BP was significantly greater than the reduction in awake BP ( 17.9 vs mm Hg in SBP, P = 0.009; 13.3 vs. 9.8 mm Hg in DBP, P = 0.015). Accordingly, the bedtime schedule resulted in a highly significant average increase by 6% in the sleep-time relative BP decline, which translated into a 73% reduction from baseline in the number of nondipper patients. 54 These findings document a significant change in the dose-effect curve of valsartan that is highly dependent on its time of administration. These results were corroborated by two subsequent independent prospective clinical trials (Table 2), one conducted on elderly hypertensive patients, 55 characterized by the progressive attenuation of the sleep-time relative BP decline with aging, 56,57 and the second on nondipper hypertensive subjects. 58 The first trial 55 involved 100 elderly (68.2 ± 4.9 (mean ± s.d.) years of age) grade 1 2 essential hypertensive subjects randomized either to upon awakening or bedtime valsartan monotherapy (160 mg/day for 3 months). There was significant reduction in the 48 h SBP/DBP means irrespective of the dosing time; although, this effect was slightly stronger with the bedtime than upon-awakening schedule ( 15.3/ 9.2 vs. 12.3/ 6.3 mm Hg; P = for SBP, P = for DBP). The sleep-time relative BP decline was unchanged from baseline in those ingesting valsartan upon awakening ( 1.0/ 0.3 mm Hg for SBP/DBP; P > 0.195), while it was significantly increased (6.6/5.4 mm Hg for SBP/DBP; P < 0.001) in those ingesting it at bedtime. The reduction of the asleep BP mean was double in patients routinely taking their medication at bedtime compared to those who did so upon awakening (P < 0.001). If one might consider the specific reduction of asleep BP to be a worthy therapeutic goal, based on the strong relationship between elevated asleep BP and CVD risk, 28,31,34,35 results of this valsartan trial involving elderly hypertensive patients, who showed diminished nocturnal BP decline at baseline, indicate bedtime treatment is superior to upon-awakening treatment, because it significantly improves sleep-time BP control and remodels the 24-h BP profile toward a more normal dipping pattern by increasing the sleep-time relative BP decline. The second trial 58 used a similar design to investigate the treatment-time-dependent effects of the same dose of valsartan (160 mg/day for 3 months) in a selected sample of 148 nondipper grade 1 2 essential hypertensive subjects. The significant decrease from baseline in the 48 h SBP/DBP means (P < 0.001) was not treatment-time dependent (upon awakening: 13.1/ 8.5 vs. at bedtime: 14.7/ 10.3 mm Hg SBP/DBP; P > for the treatment-time effect). The sleep-time relative BP decline, however, was significantly increased only when valsartan was ingested at bedtime, which resulted in 75% of the subjects in this group reverting to a 24-h dipper BP pattern, significant increase in the proportion of patients with controlled ambulatory BP, and significant reduction in urinary albumin excretion, a measure of hypertensive renal damage. 58 An extension of this trial, which included 200 nondipper hypertensive subjects, 59 yielded similar more favorable changes in the asleep BP mean plus more desired effects on the BP circadian profile, i.e., increase in sleep-time relative BP decline toward a more dipping BP pattern, after 3 months of bedtime in comparison to upon-awakening valsartan treatment. Olmesartan The findings were similar with olmesartan based on the study of 123 grade 1 2 essential hypertensive subjects randomized to monotherapy (20 mg/day for 3 months) either upon awakening or at bedtime. 60 Comparable modulation of the 48 h SBP/DBP means was achieved when the medication was taken upon awakening or at bedtime ( 13.8/ 11.2 vs. 13.9/ 10.2 mm Hg SBP/DBP; P > between groups). However, the bedtime schedule was significantly more effective than the upon-awakening one in reducing the asleep BP mean ( 15.2/ 11.5 mm Hg vs. 11.2/ 8.7 mm Hg; P < between groups). Furthermore, the sleep-time relative BP decline, which was slightly reduced with treatment upon awakening, was significantly increased with treatment at bedtime (P < 0.001), thereby diminishing the prevalence of BP nondipping by 48% from baseline. Tofé and García 61 used a crossover design to evaluate the ambulatory BP response to olmesartan (40 mg/day for 8 weeks) when taken either upon awakening or at bedtime by 40 type 2 diabetes hypertensive subjects, who are more prone to having a blunted nocturnal BP decline than the general population. 2, Bedtime compared to morning olmesartan ingestion resulted in a significantly greater reduction of nighttime SBP ( 16.2 vs. 11.8; P = 0.007) and significant increase in the sleep-time relative SBP decline (7.4 vs. 2.2%; P < 0.001), while also increasing the percentage of patients with a dipper BP pattern. 61 A previous small crossover study on 18 hypertensive patients, on the other hand, did not detect morning vs. evening-time administration differences in the BP-lowering effects of olmesartan. 68 However, methodological differences between this and the positive trials may explain the disparate results. The study by Smolensky et al. 68 relied on a crossover design with all participants first being treated in the morning and then in the evening, thus without randomization of subjects for the order (morning vs. evening) of the timed therapy. Most relevant, this trial used fixed clock hours (08:00 h and 20:00 h, rather than the individually specified upon-awakening and bed times that are more strongly related to circadian BP regulation) to compare the BP-lowering effects of the two different olmesartan dosing times. Finally, this trial involved only 18 grade 1 uncomplicated AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 4 april

6 STATE OF THE ART Chronotherapy of Hypertension essential hypertensive subjects who displayed a normal BP dipping profile, while the study by Hermida et al. 60 investigated a much larger sample of grade 1 2 hypertensive subjects who evidenced a wider range of sleep-time relative BP decline. The same methodological problems, i.e., lack of dosing-time randomization, use of fixed clock hours for treatment, and small sample size, also apply to another study of 42 hypertensive men showing comparable BP reductions with telmisartan administration either at 06:00 h or 18:00 h. 69 Irbesartan Pechère-Bertschi et al. 41 studied 10 uncomplicated essential hypertension subjects to explore the differential effects of morning (between 07:00 h and 09:00 h) vs. evening (between 18:00 h and 20:00 h) irbesartan (terminal half-life h) treatment (100 mg for 6 weeks). The amount of the nighttime SBP reduction was almost double with the evening compared to the morning schedule ( 7.4 vs. 4.2 mm Hg). Telmisartan Hermida et al. 70 studied 215 grade 1 2 essential hypertensive subjects randomized to either upon-awakening or bedtime monotherapy with long-terminal half-life ( 24 h) telmisartan (80 mg/day for 12 weeks). Significant and comparable reduction in the 48 h SBP/DBP means from baseline was achieved by the two schedules (upon-awakening: 10.6/ 7.9 vs. at bedtime: 11.7/ 8.3 mm Hg SBP/DBP; P > between groups). The bedtime schedule, however, was significantly more effective in decreasing the asleep SBP/DBP means ( 13.8/ 9.7 vs. 8.3/ 6.4 mm Hg SBP/DBP; P < between groups). Thus, the sleep-time relative BP decline was slightly reduced when telmisartan was taken upon awakening ( 1.6/ 1.0 for SBP/DBP, P = 0.010/P = 0.157), whereas it was significantly enhanced when taken at bedtime (3.1/3.9 for SBP/DBP, P < 0.001), thereby reducing the prevalence of nondipping from baseline by 76% (P < 0.001) and increasing the sleep-time relative BP decline toward a more dipper profile without loss of 24 h efficacy 70 (Table 2). Discussion The pharmacologic characteristics of most hypertension medications have been shown to be highly dependent on treatment-time. 19,71 However, the majority of the once-a-day hypertensive medications have been approved without specification of a preferred ingestion-time. 53 Because the effects of BP-lowering medications are circadian-stage dependent, that is dependent on ingestion time with reference to endogenous 24 h rhythms, the specific administration-time-dependent dose-effect curve of medications must be first determined and taken into consideration when prescribing therapy. Studies on the chronotherapy of hypertension with ACEIs and ARBs summarized herein confirm their effects can vary, sometimes dramatically, as a function of the circadian time of dosing. Several authors, disregarding current available clinical information, have proposed the differential administrationtime-dependent effects on asleep BP regulation of some hypertension medications and their ability to restore the normal dipping BP pattern may be just a direct consequence of their short terminal half-life and limited (shorter than 24 h) duration of action; thus, they argue that treatment timing might be relevant only for short-acting ACEI and ARB medications. 72,73 These unfounded conclusions do not take into account that the PK and pharmacodynamics of hypertension medications may depend markedly on their administration time relative to the rest-activity cycle of patients. Moreover, studies show the marked differences between morning and evening administration apply also to BP-lowering medications with long (beyond 24 h postdosing) and sustained action, e.g., spirapril, 52 telmisartan, 70 and olmesartan. 60,61 Thus, the differential treatment-time-dependent effects on SBP and DBP by ACEIs and ARBs summarized in Tables 1 and 2 appear to be a classrelated phenomenon for these two families of BP-lowering medications and independent of drug plasma terminal halflife. The enhanced impact of bedtime therapy with ARBs and ACEIs on asleep BP reduction, increase of sleep-time relative BP decline, and normalization of the circadian BP pattern toward a more dipping pattern, is hypothesized to result from the achievement of peak or near peak drug levels overnight around the time when the RAAS activates, i.e., when plasma renin activity and plasma concentrations of ACE, angiotensin I and II, and aldosterone rise to highest levels. The potential reduction in CVD risk associated with either the specific lowering of asleep BP as a novel therapeutic target and/or the normalization of the circadian BP variability, i.e., increasing the sleep-time relative BP decline, is still a matter of debate. Subjects in the active treatment group of the HOPE (Heart Outcomes Prevention Evaluation) study 74 were treated with the ACEI ramipril at bedtime. A small substudy in which subjects were evaluated by 24 h ABPM evidenced marked BP reduction, particularly during the nighttime sleep span, 75 thus diminishing the prevalence of nondippers in this high-risk CVD patient cohort. It is noteworthy the authors of the HOPE study concluded that the protective effects of ramipril against CVD morbidity and mortality may be related to the resultant increased sleep-time relative BP decline, which constitutes change toward the normalization of the 24 h BP pattern. 75 Another relevant study in which the nondipper BP profile in subjects with chronic renal failure was normalized with evening, but not morning, 4-week isradipine dosing 76 unfortunately did not conduct follow-up to evaluate potential changes in CVD risk, mainly due to the short period of active treatment. On the other hand, recent results have demonstrated that 388 april 2011 VOLUME 24 NUMBER 4 AMERICAN JOURNAL OF HYPERTENSION

7 Chronotherapy of Hypertension STATE OF THE ART urinary albumin excretion is significantly reduced to a larger extent with bedtime than morning valsartan treatment. 77 This reduction was not related to attenuation of the 24 h BP mean, but rather to the decrease in the asleep BP mean and, mainly, with the increase in the sleep-time relative BP decline achieved by bedtime valsartan administration. Moreover, plasma fibrinogen has also been shown to be significantly reduced with bedtime, as compared to morning, valsartan treatment in direct correlation with the increased sleep-time relative BP decline resulting from the conversion of nondippers into dippers. 55,77 The potential differential reduction of CVD morbidity and mortality risk by a bedtime vs. upon-awakening treatment schedule has been evaluated prospectively in the MAPEC study, 78,79 specifically designed to test the hypothesis that bedtime chronotherapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2,156 hypertensive subjects were randomized either to ingest all their prescribed hypertension medications upon awakening or at least one of them at bedtime. Subjects were evaluated by 48 h ABPM at baseline, with identical assessment conducted annually, or more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of nondipping (34 vs. 62%; P < 0.001), and higher prevalence of controlled ambulatory BP (62 vs. 53%, P < 0.001). After a median follow-up of 5.6 years, the group of subjects ingesting at least one BP-lowering medication at bedtime exhibited significantly lower relative risk of total CVD events than the group of subjects ingesting all medications upon awakening (0.39 ( ); P < 0.001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline toward a more normal dipping pattern two new and novel therapeutic targets requiring proper patient evaluation by ABPM were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Results of the prospective MAPEC study thus indicate that bedtime chronotherapy with at least one BP-lowering medication, compared to conventional upon-waking treatment with all medications, more effectively improves BP control, better decreases the prevalence of nondipping and, most importantly, significantly reduces CVD morbidity and mortality. The nondipper BP pattern, characterized by the loss or even reversal of the expected 10% sleep-time relative BP decline, increases one s risk of cardiovascular and cerebrovascular events, nephrosclerosis, and progression to end-stage kidney failure in renal patients. The nondipper BP pattern is more frequent in hypertension secondary to specific medical conditions, such as chronic renal failure, diabetes, and autonomic nervous system dysfunction, than in uncomplicated primary hypertension. 2 However, the findings of a recent study based on 48 h ABPM indicate a high, i.e., 38%, prevalence of nondipping even among untreated patients with essential hypertension, 80 and of further relevance is the finding that the percentage of nondipper patients significantly increases to 62% while under management with (morning) hypertension therapy. 80 International guidelines recommend the prescription of long-acting, once-daily hypertension medications that have 24 h efficacy; 53 they improve adherence to therapy, minimize BP variability, and provide smoother and more consistent BP control. However, in our opinion, these recommendations might only be valid for those medications when ingested in the morning. The morning ingestion of a hypertension medication with high 24 h homogeneous and sustained efficacy is unlikely to affect the circadian BP profile and from our perspective could eventually qualify only as a potential choice of treatment for dipper hypertensive patients. This therapeutic scheme does not seem appropriate for nondippers, since normalization of the circadian BP rhythm and specific control of asleep BP must be considered to be important clinical goals of their pharmacotherapy; indeed, meeting these novel treatment goals has been found 79 to reduce the heightened CVD risk associated with nondipper hypertension Many studies indicate the asleep BP mean is a better predictor of CVD risk than either the awake (clinic cuff of ABPMdetermined daytime mean) or 24 h BP mean. 28,31,34,35 Thus, for any given conventional clinic or awake BP mean value, subjects with higher asleep BP mean will have increased CVD risk, rendering ABPM a required tool for proper risk stratification. Moreover, reduction of asleep BP has been shown to reduce CVD risk, independent of the effects of treatment on the awake BP mean. 79 Available scientific evidence derived from numerous clinical trials reveals that asleep BP regulation can be better achieved with ACEI and ARB class medications when administered consistently at bedtime than upon awakening in the morning (Tables 1 and 2). The bedtime scheduling of medications of these two classes, regardless of their terminal plasma half-life, very effectively reduces abnormally high sleep-time BP and converts an abnormal nondipping circadian BP profile toward a normal dipper one. In fact, with bedtime treatment, there is greater likelihood of increasing the sleeptime relative BP decline and of properly reducing asleep BP by using medications with a shorter or nonhomogeneous duration of action (Table 1), thereby challenging the current international recommendations discussed above. In hypertensive subjects, pharmacologic therapy should take into account the seldom considered, yet crucial, variable of treatment-time with respect to the rest-activity pattern of the patient. Given that the teaching of medical and pharmaceutical sciences today continues to be based exclusively on the concept AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 4 april

8 STATE OF THE ART Chronotherapy of Hypertension of homeostasis, it is not surprising that most practitioners continue to assume the time of day when medications is taken is of little or no importance. 72,73 This review on the chronotherapy of hypertension medications interacting with the RAAS shows this assumption is not only invalid, at least when awakening vs. bedtime administration times are compared, but that it is possible to significantly improve the clinical management of hypertension without further financial burden to patients that would accrue by an increase in dose or prescription of additional therapeutic agents, simply by selecting the correct time of treatment. Disclosure: The authors declared no conflict of interest. Acknowledgments: Dirección General de Investigación, Ministerio de Ciencia e Innovación (SAF FEDER; SAF FEDER); Consellería de Economía e Industria, Dirección Xeral de Investigación e Desenvolvemento, Xunta de Galicia (09CSA018322PR; INCITE07- PXI ES; INCITE08-E1R ES; INCITE09-E2R ES); and Vicerrectorado de Investigación, University of Vigo. 1. Portaluppi F, Smolensky MH. Circadian rhythm and environmental determinants of blood pressure regulation in normal and hypertensive conditions. In White WB (ed), Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics. Humana Press: Totowa, NJ, 2000, pp Hermida RC, Ayala DE, Portaluppi F. Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Adv Drug Deliv Rev 2007; 59: Furlan R, Guzzetti S, Crivellaro W, Dassi S, Tinelli M, Baselli G, Cerutti S, Lombardi F, Pagani M, Malliani A. 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