Administration Time–Dependent Effects of Valsartan on Ambulatory Blood Pressure in Hypertensive Subjects

Abstract

Abstract-This study investigated the administration time-dependent antihypertensive efficacy of valsartan, an angiotensin II receptor blocker. We studied 90 subjects (30 men and 60 women), 49.0Ϯ14.3 (meanϮSD) years of age with stage 1 to 2 essential hypertension; they were randomly assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per-subject basis. The highly significant blood pressure reduction after 3 months of treatment with valsartan (PϽ0.001) was similar for both treatment times (17.0 and 11.3 mm Hg reduction in the 24-hour mean of systolic and diastolic blood pressure with morning administration and 14.6 and 11.4 mm Hg reduction with bedtime administration; PϾ0.174 for treatment time effect). Valsartan administration at bedtime as opposed to on wakening resulted in a highly significant average increase by 6% (PϽ0.001) in the diurnal-nocturnal ratio of blood pressure; this corresponded to a 73% relative reduction in the number of nondipper patients. The findings confirm that valsartan efficiently reduces blood pressure throughout the entire 24 hours, independent of treatment time. They also suggest that time of treatment can be chosen according to the dipper status of a patient to optimize the effect of antihypertensive therapy, an issue that deserves further investigation. Valsartan is an orally active, specific and selective ARB. 2 After a single oral morning dose, the onset of its BP-lowering action is within 2 hours, with peak effect occurring within 4 to 6 hours. Morning once-a-day dosing ranging from 80 to 320 mg/d results in BP reduction throughout the entire 24 hours. 3,4 The trough-to-peak ratio (T:P; the average BP reduction during the last 2 hours of the dosing interval compared with the average of the maximal reduction in BP over 2 consecutive hours 5 ) has been demonstrated to be Ͼ75%, 4 confirming that a single morning dose of valsartan provides effective BP control throughout the day without alteration of the circadian pattern of BP variation. 3 This circadian variation in BP represents, on the one hand, the influence of internal factors such as ethnicity, gender, autonomic nervous system tone, vasoactive hormones, and hematologic and renal variables. 6 BP is also affected by a variety of external factors, including ambient temperature/ humidity, physical activity, emotional state, alcohol or caffeine consumption, meal composition, and sleep/wake routine. 7,8 Because the main steps in the mechanisms regulating BP are circadian-stage dependent, 7 it is not surprising that antihypertensive medications might display a circadian time dependency in their pharmacokinetics and effects. 6 Despite the great number of publishe...

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

“…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).…”

“…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.…”

“…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.…”

Effect of the Angiotensin-Converting Enzyme Inhibitor Perindopril on 24-Hour Blood Pressure in Patients with Lacunar Infarction: Comparison between Dippers and Non-Dippers

“…In the Heart Outcomes Prevention Evaluation (HOPE) trial (38), an ACE inhibitor (ramipril) was given once daily at bedtime and more pronounced BP lowering during the night was achieved. Administration of valsartan at bedtime also reduced the incidence of non-dippers (39). In the present study, once daily administration of perindopril in the morning produced a similar effect on the diurnal BP pattern in non-dippers.…”

Fixed-combination of amlodipine and diuretic chronotherapy in the treatment of essential hypertension: improved blood pressure control with bedtime dosing—a multicenter, open-label randomized study

“…Uzu and Kimura 27 reported that hydrochlorothiazide restores the diminished nocturnal blood pressure decline, and shifts circadian rhythm of blood pressure from a non-dipper to a dipper profile. Hermida et al 28 reported that valsartan administration at bedtime, as opposed to administration upon awakening, resulted in a highly significant average increase in the diurnal/nocturnal ratio of blood pressure, corresponding to a 73% relative reduction in the number of non-dipper patients. In another study, the bedtime administration of trandolapril also significantly reduced morning blood pressure levels.…”