Decrease in Urinary Albumin Excretion Associated With the Normalization of Nocturnal Blood Pressure in Hypertensive Subjects

Valsartan is an orally active, specific, and selective angiotensin II receptor blocker.¹ Morning once-per-day dosing ranging from 80 to 320 mg/d results in smooth blood pressure (BP) reduction throughout the entire 24 hours without alteration of the circadian pattern of BP variation.² Previous results on the potential differing effects of 160 mg/d valsartan as a function of its time of administration indicated a significant BP reduction throughout the entire 24 hours independent of treatment time.³ However, valsartan administration at bedtime as opposed to on wakening resulted in an improved diurnal/nocturnal BP ratio (calculated as the decline in the nocturnal relative to the diurnal mean of BP, an index of BP dipping), a larger efficacy in decreasing nocturnal BP, and a significant increase in the percentage of patients with controlled BP after treatment. These results seem particularly relevant, because 2 independent prospective studies have concluded that nighttime BP is a better predictor of cardiovascular mortality than the diurnal or the 24-hour means of BP.^4,5 It was thus proposed that dosing time with valsartan could be chosen in relation to the dipper status of each patient to improve therapeutic benefit and to reduce cardiovascular risk, which still remains to be proven.

Nondipping (patients with <10% diurnal/nocturnal BP ratio⁶) has been related to an increase in end-organ injury^7,8 and cardiovascular events.^4,6,9,10 Moreover, urinary albumin excretion (UAE) in nondippers has been shown to be significantly greater than in dippers.¹¹ There is growing evidence that reduction of UAE provides renal protection and reduces cardiovascular risk,¹² although information of the potential renal benefit of reverting a nondipper to dipper BP profile has not yet been provided. Previous results have already demonstrated that valsartan significantly reduces microalbuminuria in type 2 diabetic patients, an effect that appears to be independent of its BP-lowering action.¹³ We hypothesized that improving the diurnal/nocturnal ratio of BP could further reduce UAE in hypertensive patients. Accordingly, this prospective study evaluates by 48-hour ambulatory BP monitoring (ABPM) the antihypertensive efficacy and the potential effects on UAE of valsartan monotherapy when dosed either in the morning after awakening from nighttime sleep or at bedtime for a 3-month span in hypertensive patients.

Methods

Subjects

This clinical trial was conducted at the Hypertension and Vascular Risk Unit, Hospital Clínico Universitario, Santiago de Compostela, Spain, between December 2003 and February 2005. Shift-workers, heavy drinkers (alcohol intake >80 g/d), smokers (>20 cigarette/d), and heavy exercisers were excluded, as were individuals with either severe arterial hypertension (grade 3, that is BP≥180/110 mm Hg), diabetes, proteinuria (UAE>300 mg/24 hours), or secondary arterial hypertension and cardiovascular disorders, including angina, heart failure, stroke, nephropathy, and retinopathy, or previous myocardial infarction or coronary revascularization as revealed by thorough clinical evaluation according to the standardized protocol at the Unit. Inclusion criteria required the patients to be previously untreated for hypertension and with diagnosis of grade 1 or 2 essential hypertension according to criteria of the recent European Society of Hypertension–European Society of Cardiology guidelines¹⁴ based on conventional BP measurements (systolic BP [SBP] between 140 and 179 mm Hg or diastolic BP [DBP] between 90 and 109 mm Hg) and corroboration by ABPM at the time of recruitment. In this trial, a positive diagnosis of hypertension based on ABPM required that either the diurnal mean be >135 or 85 mm Hg for SBP or DBP, or the nocturnal mean be >120 or 70 mm Hg.^15,16

During the inclusion period, we screened 252 untreated patients and identified 210 who met these inclusion/exclusion criteria. Among these, 200 subjects (78 men and 122 women), 50.7±13.1 years of age, completed the study and provided all required information for this trial. After providing informed consent to participate in this prospective, randomized, open-label, blinded endpoint (PROBE), parallel group chronotherapy trial, subjects were randomly assigned to receive single daily valsartan monotherapy (160 mg/d; the highest recommended and most widely used dose in Spain) either in the morning on awakening from nighttime sleep or at bedtime. Compliance was evaluated on the basis of tablet count and a personal interview with each volunteer. The use of other medication, apart from the provided dose of valsartan, was not allowed during the 3 months of intervention. The State Ethics Committee of Clinical Research approved the study. The demographic characteristics of the participants who completed the study are described in Table 1.

Blood samples were obtained in the clinic from the antecubital vein after nocturnal fasting between 8:00 am and 9:00 am on the same days when 48-hour ABPM was initiated, both immediately before and 3 months after timed treatment. The patients collected their urine during the first 24 hours of ABPM for determination of UAE and creatinine clearance in 24-hour urine. Blood and urine were analyzed for the variables described in Table 1 using routine automatic techniques at the hospital laboratory. Clinic BP measurements (6 per study visit after being seated for at least 5 minutes, on the same day just before starting ABPM) were always obtained by the same investigator with a validated automatic oscillometric device (HEM-737; Omron Health Care Inc, Vernon Hills, Ill).¹⁷

ABPM Assessment

The SBP, DBP, and heart rate (HR) of each participant were automatically measured every 20 minutes from 7:00 am to 11:00 pm and every 30 minutes during the night for 48 consecutive hours with a properly calibrated SpaceLabs 90207 device (SpaceLabs Inc, Issaquah, Wash). Subjects were studied by ABPM under baseline conditions, and again after 3 months of timed therapy. Participants were instructed to perform their usual activities with minimal restrictions but to follow a similar schedule during the 2 days of ABPM and to avoid daytime napping. ABPM always began between 10:00 am and noon. BP series were not considered valid for analysis if >30% of the measurements were lacking, if data were missing for >2-hour spans, if data were collected from subjects while experiencing an irregular rest–activity schedule, or if the nighttime sleep span was <6 hours or >12 hours during monitoring. Protocol-correct data series were collected from 200 subjects. Baseline BP profiles of 10 additional subjects (4 originally assigned to morning treatment and 6 to bedtime treatment) were eliminated because the patients either failed to return for the second ABPM at the end of the treatment period (6 patients) or discontinued treatment because of side effects (2 patients with dizziness in morning treatment and 1 patient with dizziness and 1 patient with diarrhea in bedtime treatment) and were not further evaluated.

Actigraphy

During 48-hour ABPM each participant wore a Mini-Motion-Logger actigraph (Ambulatory Monitoring Inc, Ardsley, NY) on the dominant wrist to monitor physical activity at 1-minute intervals. This compact (approximately half the size of a wrist watch) device functions as an accelerometer. The internal clocks of the actigraph and the ABPM devices were synchronized through their respective interfaces by the same computer. The actigraphy data were used to determine the onset and offset times of diurnal activity and nocturnal sleep to make possible the accurate calculation of the diurnal and nocturnal BP means of each subject.¹⁸

Statistical Methods

Data from 200 randomized patients (Table 1) who provided all required information were used for analyses. Each individual’s clock-hour BP and HR values were first referenced to hours after awakening from nocturnal sleep, according to the information obtained from wrist actigraphy. This transformation avoided the introduction of bias caused by differences among subjects in their sleep/activity routine.¹⁸ Moreover, for comparison purposes, BP data are thus synchronized with drug intake (either on awakening or at bedtime). BP and HR time series were then edited according to conventional criteria to remove measurement errors and outliers.¹⁹ The change in the 24-hour, diurnal (daytime activity), and nocturnal (nighttime rest) means of BP after treatment was compared between groups by repeated measures ANOVA. The demographic and clinical characteristics in Table 1 were compared between groups by ANOVA (quantitative variables) or nonparametric χ² test.

Results

Demographic and Analytical Characteristics

The baseline physical characteristics of the 2 groups of subjects (Table 1) were similar, and they remained unchanged after treatment. The comparison of cardiovascular risk factors indicate the lack of differences among groups in the prevalence of dyslipidemia, current smoking (≤20 cigarette/d), obesity (body mass index [BMI]≥30 kg/m²), and sedentary lifestyle (no regular physical activity at least 30 min/d for at least 2 d/wk). Clinic BP measurements, including pulse pressure (PP) (difference between SBP and DBP), were statistically reduced from baseline ones (P<0.001) after 3 months of once-per-day valsartan monotherapy, independent of dosing time (Table 1). The reduction in SBP and PP was slightly larger after bedtime treatment. The serum values of glucose, creatinine, cholesterol, triglycerides (Table 1), and other laboratory chemistry variables of the 2 treatment groups were comparable at baseline and were unchanged after treatment. Plasma fibrinogen and UAE were significantly reduced when valsartan was administered at bedtime (Table 1).

Efficacy With Valsartan on Awakening

Valsartan administration on awakening resulted in a statistically significant reduction in BP from baseline after 3 months of treatment (13.0 and 9.1 mm Hg reduction in the 24-hour mean of SBP and DBP, respectively; P<0.001) (Table 2 and Figure 1). There was also a significant reduction (P<0.001) of 4.0 mm Hg in the 24-hour mean of PP when valsartan was administered on awakening. After treatment, 57.8% of the patients had a controlled diurnal BP (<135/85 mm Hg), but only 45.1% had a controlled nocturnal BP (<120/70 mm Hg). Results further indicate that the mean BP reduction at each clock time during the 24-hour dosing interval was statistically significant (P<0.001 always after correcting for multiple testing). Despite the significant reduction in BP, there was no effect of valsartan on HR (increase in the 24-hour mean of 0.4 bpm, P=0.672, compared with baseline). Average duration of nocturnal rest was similar for the profiles obtained before and after 3 months of morning treatment (P=0.640) (Table 2).

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Efficacy With Valsartan at Bedtime

Figure 1 shows the significant reduction compared with baseline of 15.6 and 10.8 mm Hg in the 24-hour mean of SBP and DBP, respectively (P<0.001), after 3 months of 160 mg/d valsartan taken before bedtime. The 24-hour mean of PP was also significantly reduced from baseline by 4.7 mm Hg (P<0.001). After treatment, 74.5% of the patients had a controlled diurnal BP, and 61.2% had a controlled nocturnal BP. The BP reduction was statistically significant (P<0.001 always after correcting for multiple testing) at each of the 24-hour clock times, indicating BP-lowering effect throughout the entire 24-hour dosing interval when valsartan is administered at bedtime. HR remained unchanged after 3 months of treatment (increase in the 24-hour mean of 1.0 bpm; P=0.379). Average duration of nocturnal rest was equivalent for the profiles obtained before and after bedtime treatment (P=0.602) (Table 2).

Comparison in Efficacy Between Groups

The comparison of results shown in Table 2 reveals lack of statistically significant differences in diurnal, nocturnal, and 24-hour ambulatory BP at baseline among the 2 treatment groups. After 3 months of timed treatment, the 24-hour mean BP was also similar for both groups, although the treatment efficacy of valsartan on the 24-hour BP was slightly larger with bedtime dosing (Figure 1). The effect of medication on the nocturnal mean of BP was significantly greater when valsartan was administered at bedtime, both in absolute and in relative changes from baseline (Table 2). Results further indicate that treatment efficacy was greater for the first 8 hours after dosing when valsartan was administered at bedtime. Results in Figure 1 illustrate the larger treatment efficacy on nocturnal BP with bedtime as compared with morning treatment, corroborating a change in the effects of valsartan as a function of time of administration.

When valsartan was taken on awakening, the mean reduction in the diurnal and nocturnal BP means was similar (Table 2). However, when valsartan was taken at bedtime, the mean reduction in nocturnal BP was significantly greater than the mean reduction in diurnal BP. Accordingly, there was a statistically significant average increase (P<0.001) (Table 2) of 4.6 in the diurnal/nocturnal ratio of SBP only when valsartan was taken at bedtime. The diurnal/nocturnal SBP ratio was, however, slightly decreased after morning therapy. Table 2 further indicates a significant relative decrease by 73% in the prevalence of nondipper subjects after bedtime valsartan administration.

Effects on UAE

For all subjects irrespectively of treatment time, the individualized percent decrease in UAE was not correlated with the decrease in either the 24-hour or the diurnal mean of BP (correlation coefficient r=−0.070, P=0.334 and r=−0.032, P=0.663, respectively). Results, however, indicate that the decrease in UAE is positively correlated with the decrease in nocturnal mean of SBP (r=0.308, P<0.001), and with the increase in diurnal/nocturnal SBP ratio (r=0.314, P<0.001 for both SBP and DBP). Taking into account the differing effects of morning versus night dosing of valsartan on these 2 variables, we analyzed each subgroup of patients separately.

The percent decrease in UAE from baseline was not correlated with either the 24-hour or the diurnal mean of SBP or DBP independently of the time of day of treatment (top graphs in Figures 2 and 3, for changes in SBP after valsartan administered on awakening or at bedtime, respectively). When valsartan was administered on awakening, results (bottom graphs in Figure 2) indicate a significant correlation of an increasing reduction in UAE with a higher therapeutic effect on the nocturnal mean of BP (P=0.047 and 0.020 for SBP and DBP) as well as with a higher increase in the diurnal/nocturnal BP ratio to more of a dipper profile (P=0.033 for both SBP and DBP).

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The bottom graphs in Figure 3 indicate that when valsartan was administered at bedtime, there was a highly significant correlation between the decrease in UAE and the reduction in nocturnal mean of BP (P<0.001 for both SBP and DBP). Moreover, the decrease in UAE was also highly correlated with the increase in the diurnal/nocturnal ratio (P<0.001 for both SBP and DBP). These correlations are significantly larger than those found after morning administration of valsartan because of the increased effect of bedtime dosing on both the nocturnal mean of BP and the diurnal/nocturnal BP ratio. Multivariate analysis further indicates that the best predictor of the reduction in UAE is the increase in the diurnal/nocturnal ratio of SBP, independently of dosing time with valsartan.

Discussion

The results from this trial on the potential benefits on UAE of chronotherapy in the treatment of hypertensive patients indicate, first, that 160 mg/d valsartan provide 24-hour coverage when taken once daily either on awakening or at bedtime. Valsartan, no matter the treatment time, also significantly reduced PP, a marker of cardiovascular risk, during the 24 hours. In keeping with earlier findings,³ results from this new prospective study indicate that a single daily dose of 160 mg/d valsartan on awakening reduces BP smoothly over the 24 hours. The same dose of valsartan taken at bedtime provides comparable BP reduction during the 24 hours while highly improving the diurnal/nocturnal ratio of BP and thus significantly reducing the prevalence of nondipping (Table 1). Results thus corroborate a potential change in the effects of valsartan depending on the time of its administration,³ an observation that supports similar findings on a circadian phase dependency in the dose–response relationship of doxazosin, nifedipine, enalapril, and propranolol, among other antihypertensive drugs.^20,21

Appreciable ingestion time differences in the kinetics of BP-lowering and cardiac medications are well known.²⁰ They result from circadian rhythms in gastric pH and emptying, gastrointestinal motility, biliary function and circulation, liver enzyme activity, and blood flow to the duodenum, kidney, and other organs, among other factors.²² Clinically relevant dosing time differences in the beneficial and adverse effects of BP-lowering medications are also known. They result from the chronokinetics of the medications as well as circadian rhythms in drug-free fraction, rate-limiting steps of key metabolic pathways, receptor number, and conformation, and/or second messenger dynamics.²³ Differences in efficacy depending on the time of day of drug administration lead to differences in effects on the circadian pattern of BP.²¹

This circadian variation is markedly influenced, among many other factors, by the autonomic nervous system tone, vasoactive hormones, and hematologic and renal variables.²⁴ A prominent circadian variation has been demonstrated for plasma renin activity, angiotensin-converting enzyme (ACE), angiotensin II, aldosterone, atrial natriuretic peptide, and catecholamines,²⁵ all reflecting the marked circadian structure of the renin-angiotensin-aldosterone system. Possibly related to the circadian variation that characterizes the renin-angiotensin-aldosterone system, clinical studies demonstrated different effects of the ACE inhibitors benazepril, enalapril, imidapril, perindopril, quinapril, and ramipril when dosed in the morning versus the evening. The potential administration time–dependent effects of other angiotensin II receptor blockers, apart from valsartan, should be prospectively investigated.

Inhibition of the renin-angiotensin-aldosterone system, either by ACE inhibitors or angiotensin II receptor blockers, prevents the development or reduces the level of proteinuria.¹³ Results in Figures 2 and 3 indicate that the decrease in UAE after treatment is independent of the reduction in 24-hour and diurnal means of BP. Previous studies with valsartan,¹³ losartan,²⁶ and irbesartan²⁷ have also found a lack of relation between changes in UAE and the effects of medication of clinic BP measurements, more closely correlated to the diurnal than to the nocturnal mean of BP determined by ABPM. However, results from the present trial document a significant correlation between the decrease in UAE and the effect of treatment on reducing the nocturnal mean of BP and thus increasing the diurnal/nocturnal BP ratio, mainly obtained here with bedtime administration of valsartan. Results indicate that for any given 24-hour BP reduction, the impact on UAE is significantly larger for a higher reduction of nocturnal mean of BP and a higher increase in the diurnal/nocturnal ratio, with a tendency to more of a dipper BP pattern (Table 1). Another independent trial of patients with resistant hypertension has recently shown the potential of reverting the nondipper into dipper BP pattern by taking into account the time of day of antihypertensive treatment.²⁸ In this independent study with combination therapy, the increase in diurnal/nocturnal BP ratio was also markedly correlated to a significant decrease in UAE.

Apart from the effect of treatment on UAE, plasma fibrinogen was also significantly reduced after bedtime treatment with valsartan (Table 1). Clinical trials and epidemiological observations have indicated that elevated plasma fibrinogen levels are strongly correlated with an increased frequency of vascular events, thus recognizing fibrinogen as a significant parameter for assessing the potential risk of acute myocardial infarction and stroke.²⁹ Previous results have already established that plasma fibrinogen is significantly elevated in nondipper as compared with dipper hypertensive subjects.³⁰ The reduction in fibrinogen in relation to the normalization of the BP profile from a nondipper to a dipper pattern could provide further evidence of the potential reduction in cardiovascular risk associated to the normalization of the circadian BP pattern in hypertensive patients with altered nocturnal BP, an issue that deserves further investigation.

The mechanisms underlying the loss of the nocturnal decline in BP are unclear.³¹ Nonetheless, the extent of the nocturnal decline in BP in hypertension seems to be of importance clinically. O’Brien et al⁶ reported that nondipper hypertensive subjects are significantly more likely to have a stroke than dippers. Verdecchia et al⁹ also showed that after an average follow-up period of 3.2 years, nondipper hypertensive patients experienced nearly 3-times as many adverse cardiovascular events as dippers. More recently, Staessen et al,⁴ summarizing results from the Syst-Eur trial in which nitrendipine was dosed at bedtime, reported that nondippers experienced a greater incidence of stroke and myocardial infarction than the group of persons who had a normal dipping pattern after treatment. Results from this trial also suggested that nighttime BP was the best predictor of risk. A recent evaluation of the data from the Ohasama study found, after an average follow-up of 9.2 years, that a 5% decrease in the decline of nocturnal SBP in hypertensive patients was associated with a 31% increased risk of cardiovascular mortality.¹⁰ What is even more relevant is that dipper hypertensive subjects had a relative hazard of cardiovascular mortality (2.37) similar to that of nondipper normotensive subjects (2.16).¹⁰

The potential reduction in cardiovascular risk associated with the normalization of the circadian variability of BP (ie, conversion from nondipper to dipper pattern) has not yet been fully established. Apart from the Syst-Eur trial mentioned, results from the HOPE (Heart Outcomes Prevention Evaluation) substudy, in which patients were evaluated by ABPM, indicated a significantly BP reduction mainly during hours of nighttime sleep.³² The authors suggested that the beneficial effects on cardiovascular morbidity and mortality in the HOPE study may be related to the 8% increase in the diurnal/nocturnal ratio of BP seen after the ACE inhibitor ramipril was administered at bedtime. In the present trial, despite a relatively short follow-up (3 months), results indicate a significant UAE reduction significantly correlated to the increase in diurnal/nocturnal BP ratio and the corresponding tendency to a normalized dipping BP pattern. However, international guidelines provide reference thresholds for ABPM, including normal limits for diurnal and nocturnal BP.^15,16 In this trial, the percentage of patients with controlled diurnal and nocturnal SBP and DBP was significantly increased from 35.3% to 55.1% (P=0.004) when valsartan was administered at bedtime. Thus, in addition to the beneficial effects on UAE and fibrinogen, from the point of view of BP control, valsartan seems to be more efficient when dosed at bedtime.

Perspectives

The results of this prospective trial on subjects with grade 1 or 2 essential hypertension randomly assigned to receive the 160 mg daily dose of valsartan either on awakening or at bedtime corroborate a significant change in the effects on ambulatory BP (mainly on nocturnal values) of this antihypertensive medication in relation to the time of day of drug administration. Most important, results provide first evidence to our knowledge that reverting a nondipper to a normal dipper BP pattern provides a significant reduction in UAE and could thus reduce cardiovascular risk. This is a hypothesis that deserves further prospective investigation from follow-up studies.

Footnotes