Conventional blood pressure (BP) measurement in an outpatient clinic is still used as the gold standard for screening, diagnosing, and treating hypertension. However, BP is not static and changes from heartbeat to heartbeat, depends on the circadian rhythm, and is influenced by various conditions including nocturnal breathing disorders. A single BP reading is thus not sufficient to adequately assess the risk of cardiovascular morbidity and mortality related to high BP. It is also important to measure BP variability. Blood pressure variability, including greater circadian variation in BP, has been associated with an increased frequency of cardiovascular events, death, and target organ damage. While so-called white coat hypertension and the opposite phenomenon of masked hypertension are widely known, short-term BP variability, including nocturnal hypertension, morning BP surge, and morning hypertension, have been given less attention. (1)

Since target organ damage in hypertension is significantly related to both 24-hour average BP and the variability of blood BP, treatment has to be directed not only towards reducing the 24-hour average BP but also towards normalizing the variability of BP during the day and at night. Therefore, assessing the efficacy of hypertension medications has been increasingly based on ambulatory blood pressure monitoring.

Recent studies in hypertensive patients have shown that assessment and quantification of BP variability are important prognostic indicators. (2, 3) A greater variability in BP is independently associated to an increase in risk of target organ damage and cardiovascular morbidity and mortality. (4, 5) The latest European guidelines for the management of arterial hypertension propose that more attention should be directed towards the consistency of BP control. In addition to an adequate average BP reduction, control of BP variability contributes to optimal cardiovascular protection in patients with hypertension. (6) Blood pressure variability is assessed and calculated based on a 24-hour blood pressure reading.

Blood pressure self-monitoring readings and outpatient measurements performed at longer intervals are used for assessing long-term BP variability. (7) Some studies have shown that BP variability directly correlates with BP and that it is, consequently, generally greater in hypertensive than in normotensive persons. It has also been found that reduction in the average BP leads to a proportional reduction in its variability, which is why the use of long-acting medications may be of benefit in controlling it. (8, 9)

Ambulatory blood pressure monitoring offers several advantages, such as providing information on the maximum effect and duration of effect of hypertension medication and enabling calculation of the smoothness index.

The effect of a hypertension medication is measured by calculating the ratio between the BP reduction immediately before the next dose (trough) and the BP when the effect of the medicine is the greatest, which is usually 2-8 hours after intake (peak). However, the trough-peak ratio is not regarded the optimal indicator because there is a number of factors that can influence the result, such as abnormal distribution of measured BP values, high dispersion of results, meaninglessly high or low BP values, or limited reproducibility. The trough-peak ratio considers two short segments of the 24-hour BP profile. It is therefore very likely to reflect spontaneous BP fluctuations rather than the actual treatment effect. The above can be mostly avoided if the smoothness index is used (Figure 1). The index considers standard deviations of the average hourly BP and the average 24-hour BP. A higher index represents a more stable antihypertensive effect.

A meta-analysis of studies investigating the effect of medications on the smoothness index, published as early as in 2010, clearly demonstrated differences between the effects of some hypertension medications. (10) The meta-analysis included 5188 study participants of which 65% were male. There were 2033 patients (39%) who received monotherapy with telmisartan 80 mg, 712 received ramipril 10 mg, 206 amlodipine 5 mg, 50 losartan 50 mg, 197 valsartan 80 mg and 430 valsartan 160 mg, 140 telmisartan 40 mg, and 1260 patients received combinations of losartan or telmisartan or valsartan with hydrochlorothiazide. The placebo group consisted of 160 participants. The smoothness index has been shown to be higher for systolic BP as compared with diastolic BP. The meta-analysis showed that telmisartan and amlodipine have similar smoothness indices, which are higher than those of losartan, valsartan, and ramipril. Among monotherapies, losartan had the lowest smoothness index. It was followed by ramipril, valsartan, telmisartan 80 mg and amlodipine 5 mg, of which the last two showed comparable smoothness indices that were the highest among other antihypertensive medications (Figure 2). (10)

The smoothness index was higher for combined medications containing hydrochlorothiazide as compared with monotherapy and placebo.

A randomized, controlled, 4 x 4 factorial design study published in 2014 investigating the effect of a combination of telmisartan and amlodipine on the smoothness index included 1461 study participants which received telmisartan (20, 40, or 80 mg) in combination with amlodipine (2.5, 5, or 10 mg). The study demonstrated for the first time the dose-dependency of the smoothness index and the magnitude of the effect that can be expected from treatment with a combination of two long-acting agents. Improvements of the smoothness index were significantly greater with combinations than with either monotherapy. The smoothness index achieved with the highest-dose combination (telmisartan 80 mg/amlodipine 10 mg) was about twice that achieved with amlodipine monotherapy. This correlated with the effects on 24-hour average ambulatory BP in the study. (11)

The smoothness index is clinically relevant. It correlates with regression of left ventricular hypertrophy during hypertension therapy and is an independent indicator of changes in carotid artery wall thickness during therapy. Medications with a higher smoothness index have been shown to be superior in providing cardiovascular protection and preventing target organ damage.