Modulation of 24-h blood pressure profiles: a new target for treatment?

Target organ damage and the rate of cardiovascular events are significantly related to 24-h average blood pressure levels and to the degree of 24-h blood pressure variability in hypertensive patients [1–3]. The obvious implication of these findings is that cardiovascular protection in treated hypertensive patients is significantly better if antihypertensive treatment is able to provide full coverage of blood pressure over the entire 24-h period. Such a goal might be achieved by proper scheduling of antihypertensive drug administration, using either a once-a-day or a multiple dosing approach. Indeed, in either case, the time of administration can significantly influence the effect of antihypertensive drugs [4,5]. For example, antihypertensive agents acting on the renin–angiotensin system induce a more sustained and stable 24-h blood pressure control when administered at bedtime compared to the morning [5]. In the case of angiotensin-converting enzyme (ACE)-inhibitors, this has been attributed to the more favourable modulation of tissue ACE inhibition that appears to characterize the evening administration [5]. The different timings of drug administration may also impact on different patterns of blood pressure variability over the day and night, such as the morning rise and the nocturnal fall in blood pressure. In the present issue of the Journal, Hermida et al. [6] provide additional information on this topic, and show that bedtime administration of valsartan can revert 24-h circadian blood pressure fluctuations back to normal in patients with a blunted nocturnal blood pressure fall (non-dippers). When valsartan was administered at bedtime, a normalization of the circadian variability of blood pressure, with a restoration of the physiological blood pressure fall at night, was obtained in 75% of non-dippers compared to only 23.6% when valsartan was taken in the morning. Furthermore, the percentage of patients with controlled nocturnal blood pressure was 59.2% with evening administration and only 34.7% when valsartan was taken in the morning. These results may be of clinical interest because they suggest that modulation of 24-h blood pressure fluctuations with antihypertensive therapy may vary according to both the individual baseline 24-h blood pressure pattern and the timing of drug administration. The possible relevance of this conclusion is also supported by several methodological merits of the present study in which the authors avoided a number of common pitfalls of previous papers focusing on blood pressure changes between day and night with ambulatory blood pressure (ABPM) monitoring. First, actigraphy data were used to identify the onset and the end of daytime and night-time periods, with greater precision. Second, ambulatory blood pressure was recorded for 48 h (a procedure quite impractical and hard to implement in clinical practice), and the participant subjects were instructed to follow a similar schedule during the 2 days of recording, which included avoiding the afternoon nap. Such a care in methods for data collections was neglected by most previous studies on the same issue, and this may be one of the reasons explaining the frequent reporting of a limited reproducibility of nocturnal blood pressure fall in untreated subjects, especially for extreme dipping and non-dipping patterns [1,7,8]. This suggests that parameters describing the features of day–night blood pressure changes, when derived from a single ABPM, might not represent reliable markers of the degree of cardiovascular risk. Non-dipping has indeed been related to poorer outcome in several studies. In patients characterized by this pattern, a significantly greater frequency of left ventricular hypertrophy, microalbuminuria and stroke has been described [9–11]. However, in spite of the established relationship between a reproducibly blunted nocturnal decline in blood pressure and the occurrence of target organ damage or cardiovascular events, the mechanisms underlying such a link have not yet been identified. Non-dipping is thought to be the result of an abnormality of blood pressure regulation at least partly due to autonomic nervous system dysfunction. Some authors have found that non-dipping was associated with a blunting of both the nocturnal rise of parasympathetic cardiac modulation and the concomitant reduction in sympathetic cardiovascular modulation [12,13]. Obstructive sleep apnoea is another important factor affecting circadian blood pressure variations, insofar it may prevent the fall of blood pressure at night, and increasing the degree of nocturnal blood pressure variability [14,15]. Even relatively minor disturbances of sleep, including snoring and mild apnoeas, may cause nocturnal elevations in blood pressure [16]. This has also been attributed to increased sympathetic activity [17]. In addition, nocturnal blood pressure non-dipping has been found associated with elevated levels of molecules related to endothelial dysfunction and atherosclerosis, such as D-dimer, plasminogen activator inhibitor-1, von Willebrand factor and soluble intercellular adhesion molecule-1 [18]. Whether restoring a normal day–night blood pressure pattern improves prognosis in non-dippers, this remains largely unknown. In the HOPE study, in which ramipril was given once daily at bedtime, 24-h blood pressure was significantly reduced because of a more pronounced blood pressure-lowering effect during night-time (−17/−8 mmHg) [19]. The night: day ratio of blood pressure was also significantly lowered by ramipril administration, with a difference of 8% after 1 year of follow-up between the placebo and the ramipril groups (0.89 versus 0.82, respectively). According to the authors, such a reduction in the night: day ratio was likely to account for the reduction of cardiovascular events observed in the HOPE study [19]. However, it should be emphasized that the HOPE ABPM substudy only included a limited number of patients. Moreover, whether an improvement in outcome was selectively achieved in non-dipper subjects who showed a subsequent normalization of the diurnal blood pressure rhythm, this was not examined. Finally, should the worsened prognosis in non-dippers be related to the associated abnormalities of the autonomic nervous system or to humoral abnormalities, in such a case reverting the day–night blood pressure rhythm to normal in these subjects would be of little use, because this correction would not eliminate the cause of the higher risk of cardiovascular events. Therefore, long-term longitudinal studies are needed to demonstrate whether restoring a normal diurnal blood pressure pattern in non-dippers improves prognosis. In addition to these considerations, the results of investigations focusing on the prognostic value of ABPM data appear to challenge the hypothesis that restoring the physiological blood pressure fall at night should be the main goal of antihypertensive therapy. Indeed, solid evidence is available to support the concept that, in hypertensive patients, the greatest prognostic value is carried by the average 24-h, daytime or night-time blood pressure levels, respectively, as a function of specific experimental or clinical conditions [1–3,20]. A further improvement in predicting the probability of cardiovascular complications has been obtained by considering estimates of overall blood pressure variability over the day and night [2,21–27], with the day–night blood pressure changes representing only one component of 24-h blood pressure fluctuations. These considerations suggest that caution is warranted in the clinical interpretation of the results provided by Hermida et al. [6]. This is also related to two apparent inconsistencies in the data reported in this paper. First, although Hermida et al. [6] conclude that the control of 24-h blood pressure was similar with morning and with evening administration of valsartan, they also report that control of daytime and night-time blood pressure was obtained in a higher percentage of patients receiving an evening dose of the drug. These statements may not be easy to reconcile on the basis of the apparent similarity in the reduction of daytime blood pressure by the two dosing schedules reported in Figures 1 and 2 of this paper. Second, the suggested advantage of valsartan bedtime administration [6] was accompanied by smaller mean T: P ratio (57/55% for SBP/DBP) and smoothness index values (1.55/1.37) compared to its morning administration (94/84% and 1.92/1.65, respectively). According to a number of studies [28–31], the main goal of antihypertensive therapy should be to obtain smooth antihypertensive control throughout the 24-h period, which is reflected by T: P ratio values close to unity and by an elevated smoothness indexes. This goal was not achieved by evening valsartan administration in the study by Hermida et al. [6]. Indeed, challenging the general belief on what the desirable effect of treatment should be on 24-h ambulatory blood pressure values, the data by Hermida et al. [6] suggest that a T: P ratio of less than 1.0 (and probably around 0.5) and a higher hourly SD (which implies a smaller smoothness index) may represent appropriate goals of therapy, at least in ‘non-dipper’ subjects. If a greater antihypertensive effect is obtained during the night-time than during the daytime hours, then an increase in 24-h hourly SD should be expected, which might carry the risk of excessive dipping and cerebral complications [32]. This issue needs therefore to be explored further before such a concept can be proposed as a guide to treatment in clinical practice. A final issue which deserves to be addressed is how the daytime blood pressure dip during the afternoon nap should be dealt with. Although the authors advised their patients to avoid a nap, a profound blood pressure dip, paralleled by a decrease in activity, was present during the early afternoon. It is difficult to conclude whether this was due to some subjects taking a nap or simply to a general decline in physical activity accompanying the digestion phase. However, if this period is removed from the calculation of daytime blood pressure levels, then several ‘borderline’ non-dippers would probably become dippers. This further emphasizes the methodological pitfalls inherent in the assessment of the day–night blood pressure difference, which, by definition, depends on the daytime blood pressure level as well as on the blood pressure level achieved during night-time sleep. Indeed, analysis of 24-h blood pressure profiles incorporating the nap into mean daytime blood pressure might lead to an underestimation of the nocturnal blood pressure drop and thus to an overestimation of the proportion of non-dippers. This may also be the case in those individuals who fail to report in their logbook having taken a nap [33]. In conclusion, Hermida et al. [6] offer stimulating data on the need to more frequently and more carefully consider the time of drug administration, when trying to control the features of 24-h blood pressure profiles by treatment. However, the clinical relevance of this issue does not yet appear to have been completely resolved. In particular, more evidence is needed on the actual protecting effect of specific treatment-induced modifications of a formerly ‘non-dipping’ pattern compared to a more homogeneous reduction in blood pressure induced by antihypertensive treatment over the entire 24-h period.