The duration and distribution of the blood pressure-lowering effect of different antihypertensive drugs during the dosing interval is quite heterogeneous. Drugs with a long duration of action and a homogeneous (smooth) effect on 24-h blood pressure values during the dosing interval may be associated with a reduced short-term blood pressure variability over the 24-h period .
On the contrary, short-acting drugs, losing their antihypertensive effect very soon after dosing, may increase the amplitude of blood pressure swings between peak and trough times  (maximum effect and minimum effect at the end of the dosing interval).
In a clinical setting, the overall performance of an antihypertensive medication, not only in terms of mean blood pressure reduction, but also in terms of distribution over time of blood pressure reduction throughout the 24 h can be evaluated by applying different quantitative indices .
The first index proposed in this regard was the Trough/Peak Ratio (T/P ratio). This index was adopted in order to summarize both the duration and the distribution of the blood pressure-lowering effect of an antihypertensive medication during the dosing interval [1–4]. It may be calculated from office or home blood pressure measurements, or from the data provided by two 24-h ambulatory blood pressure measurement (ABPM), performed before and during pharmacologic treatment, by dividing the trough blood pressure changes (the blood pressure reductions at the end of the dosing interval), by the peak blood pressure changes (the blood pressure reductions corresponding to the maximum effect of the drug)  (Fig.1).
Although an ideal antihypertensive medication providing a homogeneous blood pressure-lowering effect throughout the dosing interval may have a T/P ratio equal to 1, medications with a T/P ratio greater than 0.5 were commonly approved by the US Food and Drug Administration [1,2]. However, T/P ratio takes into account only on two short time intervals (or just two single blood pressure measurements), thus potentially missing important information relative to the remaining part of the 24-h period, and is affected by variations occurring either spontaneously or as a result of patients’ posture and behaviors , which make the T/P ratio a somewhat imprecise indicator of the overall extent and homogeneity of the blood pressure-lowering effect .
In order to overcome the previously mentioned limitations of the T/P ratio in assessing the distribution of the antihypertensive effect of a given drug, a different index, the smoothness index was proposed in 1997 , and then applied in more than 80 pharmacological studies, with the intent of assessing the homogeneity of blood pressure control through the 24 h.
The smoothness index estimates mean 24 hourly changes in blood pressure from duplicated 24-h ABPM recordings (performed before and during pharmacologic treatment). The average of these 24 hourly changes, along with its standard deviation, is then assessed. The smoothness index is calculated as the ratio between the average of the 24 hourly blood pressure changes induced by a given medication and the standard deviation of hourly reductions [1,5,6]. Thus, the smoothness index not only incorporates information on the average degree of blood pressure reduction by a given drug but also on the distribution of these reductions throughout the 24 h .
In 1998, the smoothness index was directly compared with T/P ratio in the population of antihypertensive patients enrolled in the Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation (SAMPLE study)  from ABPM data. The smoothness index correctly identified the occurrence of a balanced 24-h blood pressure reduction with treatment and was significantly correlated with the favorable effects of treatment on left ventricular hypertrophy better than the T/P ratio . Even reproducibility was far greater for the smoothness index than for the T/P ratio [6,7].
The clinical usefulness of the smoothness index was then confirmed in other studies; in fact the smoothness index, but not the T/P ratio predicted changes in carotid artery wall thickness during antihypertensive treatment . Campo et al. observed that treatment-induced changes in left ventricular mass index induced by lercanidipine in hypertensive patients were not correlated with changes in office or 24-h blood pressure, or with the T/P ratio; on the contrary, a significant correlation was found between left ventricular mass index changes and the smoothness index at 6 months.
Therefore, a greater reduction in mean blood pressure levels and in blood pressure variability throughout the 24 h is associated with a higher smoothness index (usually >1) and with a greater cardiovascular protection [1,6,8,9].
The differential effects of antihypertensive medications on the smoothness index were assessed in a large meta-analysis including randomized, controlled studies in hypertension. The smoothness index was influenced by age, race, sex, behavioural and haemodynamic factors . It was also able to differentiate the 24-h blood pressure effects of antihypertensive drugs, with telmisartan and amlodipine achieving the highest values compared with other angiotensin II receptor blockers or with ramipril, possibly because of their long plasma half-lives . All combination therapies had a higher smoothness index than monotherapies .
The advantage of combination treatments over monotherapies was also confirmed by Omboni et al.. The smoothness index was significantly higher in hypertensive patients treated with olmesartan with a thiazide diuretic or a calcium-channel blocker (dual treatment), as well as in those treated with olmesartan with a thiazide diuretic and a calcium-channel blocker (triple treatment), than in those treated with monotherapies alone . High doses of the different drugs had a smoother effect than low doses . The olmesartan/amlodipine combination, in particular, compared with amlodipine, was associated to a better homogeneity of blood pressure reduction (higher smoothness index)  which was, again, dose-related. Similar results were obtained comparing telmisartan/amlodipine combination versus monotherapies [13,14].
The smoothness index was high in responders to felodipine treatment and low in nonresponders  during the first 2-week treatment period. It increased in nonresponders after an additional 2 weeks of treatment with extended-release felodipine 10 mg/day . The smoothness index of SBP and DBP was comparably high for nifedipine and diuretics, thus demonstrating a similar and well balanced antihypertensive response to both drugs .
On the contrary, among the drug class of the angiotensin receptor blockers, candesartan cilexetil, showed a smoothness index significantly greater than losartan, implying a smoother and sustained antihypertensive effect . When hypertensive patients were randomized to different blood pressure targets, such as in the HOT (Hypertension Optimal Treatment) study, the T/P ratio and the smoothness index were lowest in the highest blood pressure target group and highest in the lowest blood pressure target group .
In this issue of the Journal of Hypertension, Shin et al. evaluated possible associations between the smoothness index of central SBP and changes of ambulatory carotid--femoral pulse wave velocity (PWV) in response to 20-week treatments with losartan with amlodipine versus losartan with hydrochlorothiazide combinations. The study included 142 patients examined with the Mobil-O-Graph device. The authors’ conclusion was that the combination losartan with amlodipine was superior to the combination losartan with hydrochlorothiazide, showing a higher smoothness index or central and peripheral SBP, mainly because of a better reduction of night-time PWV. The results of this study, therefore, confirm the clinical usefulness of the smoothness index of blood pressure control, and the advantage over the T/P ratio.
As mentioned, this may be probably ascribed to the fact that, among the available indices in order to explore 24-h blood pressure coverage by treatment, since the smoothness index, at difference with the T/P ratio, takes into account the whole blood pressure data obtained throughout the 24 h by ABPM performed before and after treatment, and not only by two single time points [1,5,6].
Also another index was developed in order to evaluate circadian blood pressure fluctuations (which may explain a major part of the variability of the smoothness index) as well as the dependence of 24-h blood pressure standard deviation on 24-h mean blood pressure levels . Treatment-on-variability index (TOVI) considers both mean 24-h blood pressure reductions by treatment and a measure of absolute short-term blood pressure variability under treatment . It is computed as the ratio between the average of the 24 hourly blood pressure reductions by treatment and the weighted 24-h blood pressure standard deviation, at difference with smoothness index, which combines the average of the hourly blood pressure reductions and the standard deviation of such an average . In the previously mentioned analysis of a large ABPM database containing data from hypertensive patients treated with telmisartan/amlodipine combination or various monotherapies, TOVI values of telmisartan/amlodipine combination were significantly higher compared with telmisartan 80 mg, amlodipine 10 mg, valsartan 160 mg, ramipril 10 mg and placebo, indicating a smoother 24-h blood pressure BP reduction profile (as suggested by the higher smoothness index) as well as the achievement of significantly lower and smoother blood pressure levels over 24 h (higher TOVI) with the combination treatment [1,13,14]. Therefore, combination treatment was associated with a smoother blood pressure reduction over 24 h and with a more favorable balance between mean 24-h blood pressure reduction and the degree of on-treatment blood pressure variability; in addition, the study demonstrated a substantial agreement between smoothness index and TOVI for the assessment of the homogeneity of the effects of antihypertensive treatments [1,13,14].
In conclusion, maintaining a smooth blood pressure control over the entire 24 h may contribute to the improvement of cardiovascular outcomes, and reductions in blood pressure variability may decrease hypertension-related organ damage and cardiovascular risk . Mathematic indices, such as the smoothness index represent useful measures of the homogeneity of the antihypertensive effect over 24 h; in fact the smoothness index provides a superior measure of the homogeneity of blood pressure control compared with the T/P ratio . However, further studies are still needed to confirm that, in humans, interventions that are associated with higher smoothness index and with a reduced blood pressure variability can also decrease the rate of cardiovascular events [21–24].
Conflicts of interest
There are no conflicts of interest.
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