Advantages of Ambulatory Blood Pressure Monitoring in Assessing the Efficacy of Antihypertensive Therapy

The cumulative evidence in the past three decades situates ambulatory blood pressure monitoring (ABPM) as a central element in diagnosing and predicting the prognosis of subjects with hypertension. However, for various reasons, this diagnostic and prognostic importance has not been translated in equal measure into making decisions or guiding antihypertensive treatment. Mean 24-h, daytime, and night-time blood pressure estimates, the occurrence of divergent phenotypes between clinic measurements, and ABPM, as well as the main elements that determine blood pressure variability over 24 h, especially night-time dipping, are all elements that in addition to providing evidence for patient prognosis, can be used to guide antihypertensive treatment follow-up enabling greater precision in defining the effect of the drugs. In recent years, specific indices have been developed using 24-h monitoring, evaluate the duration of treatment action, the homogeneity of the effect over the monitoring period, and its possible effects on variability. In future controlled clinical trials on antihypertensive therapies it is necessary to evaluate the effects of those treatments on hard endpoints based on therapy guided by ABPM. Electronic supplementary material The online version of this article (doi:10.1007/s40119-015-0043-1) contains supplementary material, which is available to authorized users.

individual's organ damage and cardiovascular prognosis [1][2][3][4]. Moreover, regarding diagnostic aspects, ABPM has enabled two new phenotypes to be defined, white-coat hypertension (HTN) and masked HTN, both of great clinical interest [5,6]. Applying ABPM to therapeutic assessment has had less of an impact, both on the part of the investigators as well as on the part of the  [14].
Night-time BP measurements have been progressively acquiring more importance. Of all the indicators obtained during ABPM, it is the one that is best correlated with the prognosis [1][2][3][4]. Its main advantage is that it can be considered the baseline BP (the one that is specified for tissue perfusion in a state of rest). In addition, the fact that it is generally measured at rest gives it higher reproducibility and less variability, which makes it easier to correlate it with organ damage and prognosis. The data from the Spanish ABPM Registry [4], as well as the various prospective cohort databases [15], indicate that of all the BP indicators (clinic, daytime, night-time, and 24-h) it is the one that is best independently correlated with the prognosis (Fig. 1). The main disadvantages are that it requires an exact definition of the rest period, it may be affected by the presence of a daytime rest (nap) [16], and it is equally affected by the quality of sleep [17], especially in patients who repeatedly wake up during the night or who have sleep apnea. Similarly, its association with organ damage has been described as similar to that of normotensive individuals in some studies, or with a higher prevalence of cardiac or renal damage in others. In many cases, it is hard to reach a conclusion since, even with the whitecoat HTN diagnosis, these individuals have higher ABPM figures than normotensive individuals and, in addition, a very high percentage go on to develop sustained HTN in its progression [22]. and early detection of the appearance of sustained HTN seems to be the best option [27].

DIPPING PATTERNS
The decrease in BP caused by rest and sleep, usually at night, has a favorable impact on reducing the pressure burden related to the organ damage. Almost 40 years ago, it was described that some patients in whom this night-time dip was less pronounced (the threshold has been established at 10% versus the daytime values) had a worse risk profile and a higher probability of developing cardiovascular events and death [28]. In general, four dipping patterns have been described based on this night-time decrease. The most common pattern in the healthy population is known as the ''dipper'' pattern and it represents between a 10% and 20% decrease from daytime values. The extreme ''dipper'' pattern exceeds this 20% and, even though it has been described as associated with a risk of cerebrovascular accident in the Asian population, a clearly deleterious effect has not been demonstrated on the prognosis in Westerners. Conversely, a decrease below 10%, known as a ''non-dipper'' pattern (recently the term ''reduced dipper'' has been proposed), or an increase in BP during rest, known as a ''riser'' pattern, have both been associated with a worse prognosis and related with organ damage [28,29].
The data from the Spanish ABPM Registry have allowed us to determine that the prevalence of these ''deleterious'' patterns is very high, approaching 50% of untreated patients and exceeding this figure in those on treatment (Fig. 4). Old age, the female sex, obesity, diabetes, and a history of previous cardiovascular disease are associated with an inadequate decrease in both treated and untreated patients. In treated patients, increasing the number of drugs also results in a higher probability of presenting a non-dipper or riser pattern [30,31].
The main problem in assessing the dipping pattern is its association with night-time BP levels.

MORNING HTN AND MORNING SURGE
After the sleep-induced night-time BP dip, the morning surge that accompanies waking is a physiological phenomenon. However, some studies have observed that an exaggerated morning BP surge is associated with a higher rate of cardiovascular events [33]. The hormone changes that affect cortisol and catecholamines, the increase in heart rate, and the higher platelet aggregability that happen in these morning hours are a rationale to explain this phenomenon [34].
Another parameter of interest intimately related to the morning surge is known as morning HTN, which consists of high BP figures obtained just after waking. A recent study in patients being treated for HTN demonstrated that the BP figures obtained in the first hour of the morning through selfmeasurement had a greater prognostic impact than clinic BP figures. Values above 145 mmHg were associated with a higher rate of cardiovascular events [35].
The main problems that arise when

BP VARIABILITY
BP is a dynamic parameter that fluctuates based on several circumstances, some intrinsic and other extrinsic [36]. Long-term BP variability may be determined through successive visits. This variability has a prognostic impact, especially in predicting cerebrovascular accidents [37]. ABPM enables short-term fluctuations to be assessed. Some of these, caused by the activity/rest rhythm, have already been mentioned and are part of the night-time dip patterns. However, pressure fluctuations within one of these periods (daytime and especially at night) also have a prognostic impact. They can be evaluated by calculating the standard deviation in one of the periods separately and by using indices that take into account these deviations, and project the calculation over the entire 24-h period [36].
In recent years, there has been a growing interest in assessing the impact of antihypertensive treatment on this short-term variability determined by ABPM. Initial studies have used modifications in the posology of the drugs (administering part or all of the treatment at night) and assessed their impact on the dipping pattern.
Thus, it has been demonstrated that this night-time administration promotes a larger night-time dip and, as such, a proportion of non-dipper or riser patients becomes dippers. In one of these studies, this phenomenon was associated with a better cardiovascular prognosis [38].

THERAPEUTIC INDICES OBTAINED USING ABPM
In addition to all the above-described parameters used to assess the effect of antihypertensive therapy, some mathematical indices have been developed that combined potency, duration of action, and homogeneity of effect. This allows for a better assessment of the effects of antihypertensive treatment.
The first of these indices is the trough-topeak (T/P) ratio. Interest in this ratio appeared nearly two decades ago and consists of calculating the ratio between the decrease in BP obtained in the hours just before the end of the therapeutic window (with drugs administered once a day between 22 and 24 h after administration) and the maximum effect calculated after several hours (between 4 and 6 h after administration). In theory, the closer it is to unity, the greater the homogeneity of effect, suggesting that the residual effect of the drug is close to its maximum effect. However, the T/P ratio has two significant problems. The first is a result of poor reproducibility, caused by the need to extract short periods of monitoring from a 24-h ABPM that may be influenced by external factors. Thus, the peak period or maximum effect may coincide with a postprandial rest (nap), which will magnify it, or with a period of higher physical or mental activity, which will minimize it. For its part, calculating the trough effect may coincide with the last hours of sleep or with waking, both circumstances that may change it. In addition, the T/P ratio does not take into account the magnitude of the antihypertensive effect, so that minimal decreases in BP in the peak will be associated with high T/P indices (placebos usually have a T/P index around 1) [39].
The second index that measures homogeneity of effect is called the smoothness index (SI) [40]. It is calculated based on the hourly reductions in BP, corrected by the standard deviation of those reductions. Thus, the greater the magnitude of the hourly reduction and the smaller the differences between those reductions (less variability), the higher the resulting number will be. The higher the SI value is, the higher the drug potency and the greater the homogeneity of effect. Some