Optimal timing for antihypertensive dosing: focus on valsartan

Abstract

Some specific features of the 24 h blood pressure (BP) pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events. In particular, many studies show the extent of the nocturnal BP decline relative to the diurnal BP mean (the diurnal/nocturnal ratio, an index of BP dipping) is deterministic of cardiovascular injury and risk. Normalization of the circadian BP pattern is considered to be an important clinical goal of pharmacotherapy because it may slow the advance of renal injury and avert end-stage renal failure. The chronotherapy of hypertension takes into account the epidemiology of the BP pattern, plus potential administration-time determinants of the pharmacokinetics and dynamics of antihypertensive medications, as a means of enhancing beneficial outcomes and/or attenuating or averting adverse effects. Thus, bedtime dosing with nifedipine gastrointestinal therapeutic system (GITS) is more effective than morning dosing, while also reducing significantly secondary effects. The dose-response curve, therapeutic coverage, and efficacy of doxazosin GITS are all markedly dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime as opposed to upon wakening results in improved diurnal/nocturnal ratio, a significant increase in the percentage of patients with controlled BP after treatment, and significant reductions in urinary albumin excretion and plasma fibrinogen. Chronotherapy provides a means of individualizing treatment of hypertension according to the circadian BP profile of each patient, and constitutes a new option to optimize BP control and reduce risk.

Figure 1

Circadian pattern of systolic blood pressure (SBP) before and after valsartan (160 mg/day) administered on awakening (left) or at bedtime (right) in nondipper patients (n=100) with grade 1 or 2 essential hypertension studied by 48 h ambulatory monitoring. Each graph shows hourly means and standard errors (SEs) of data collected before (continuous line) and after (dashed line) 3 months of treatment. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the patients. Nonsinusoidal-shaped curves represented around means and SEs correspond to the best-fitted waveform model determined by population multiple-component analysis. Arrows descending from upper horizontal axis point to the circadian orthophase (rhythm crest time).

Figure 2

Circadian pattern of dystolic blood pressure (DBP) before and after valsartan (160 mg/day) administered on awakening (left) or at bedtime (right) in nondipper patients (n=100) with grade 1 or 2 essential hypertension studied by 48 h ambulatory monitoring. Each graph shows hourly means and standard errors (SEs) of data collected before (continuous line) and after (dashed line) 3 months of treatment. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the patients. Nonsinusoidal-shaped curves represented around means and SEs correspond to the best-fitted waveform model determined by population multiple-component analysis. Arrows descending from upper horizontal axis point to the circadian orthophase (rhythm crest time).

Figure 3

Effects on the diurnal, nocturnal, and 24 h mean of systolic blood pressure (SBP) (top) and dystolic blood pressure (DBP) (bottom) of valsartan (160 mg/day) administered on awakening or at bedtime in nondipper patients with grade 1 or 2 essential hypertension studied by 48 h ambulatory monitoring before and after 3 months of treatment. Probability values are shown for comparison of effects between the 2 groups of subjects by ANOVA.

Figure 4

Effects on the relative nocturnal BP decline with respect to the diurnal mean (diurnal/nocturnal ratio) of valsartan (160 mg/day) administered on awakening or at bedtime in nondipper patients with grade 1 or 2 essential hypertension studied by 48 h ambulatory monitoring before and after 3 months of treatment. P values on top are shown for comparison of effects among the 2 groups of patients by ANOVA. P values on the bottom are shown for the change in diurnal/nocturnal ratio after treatment for every group and variable by paired t-test.