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Blood pressure variability and target organ damage

Dr NR Rau MD FICP
Former Prof & Head
Dept. of Medicine
KMC, Manipal.

Dr Shivashankara MD
Professor of Medicine
Dept. of Medicine
KMC,Manipal.

Abstract:

Clinic blood pressure (BP) is recognized as the gold standard for the screening,
diagnosis, and management of hypertension. However, optimal diagnosis and
successful management of hypertension cannot be achieved by a handful of
conventionally acquired BP readings. Popular concepts of BP variability including
“white-coat hypertension” and “masked hypertension”, are well recognized in clinical
practice. Blood pressure variability (BPV) is considered nowadays a novel risk factor
for cardiovascular disease. It is critical to estimate the magnitude of BP variability by
estimating and quantifying each individual patient’s specific BP variations. Short-term
BP variability or exaggerated circadian BP variations that occur within a day are
associated with increased cardiovascular events, mortality and target-organ damage.
A large number of clinical trials confirm that short-term and long-term blood pressure
variability independently contributes to target organ damage, cardiovascular events,
and mortality not only in hypertensive patients but also in subjects with diabetes
mellitus and chronic kidney disease. Therefore, amelioration of BPV has been
suggested as an additional target of the treatment of cardiovascular diseases.
However, antihypertensive therapy as currently practiced does not eliminate all
hazards associated with BP elevation. Calcium channel blockers seem to be more
effective than other blood pressure lowering drugs for the reduction of short-term and
long-term BPV. This review will present some evidence relating to BPV and better

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understanding and recognizing it in day-to-day clinical practice and target organ
damage in hypertension.

Introduction:

The most significant single contributor to the global burden of disease and to global
mortality is hypertension. It is one of the most important preventable causes of death
globally, accounts for more than 12.8% of all deaths annually. The number of people
affected and the prevalence of high blood pressure worldwide are expected to
increase over the next decade. Hypertension is the most common treatable risk factor
for stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic
and peripheral arterial disease, accounting for about 50% of risk. 1 BP fluctuates in
response to various changes in sleep patterns, physical and mental activities and also
responds to autonomic, humoral, mechanical, myogenic and environmental stimuli.
Marked spontaneous oscillations over short and long-term periods is a characteristic
of BP. Owing to this, there may be radical differences in office BP monitoring (OBPM)
or home BP monitoring (HBPM) as compared to his/her average day and night time
BP; which results in a challenge in diagnosing and prescribing treatments to patients.
Although BP regulation aims at reducing incidence of target-organ damage, prevention
of cardiovascular disease and premature death in hypertensive patients; the current
antihypertensive therapy does not ameliorate all hazards associated with
hypertension. While they cause a meaningful change, i.e. reduction by approximately
one-third; the results are suboptimal at best. 2 Usual BP, the theoretical true underlying
level of blood pressure, is widely considered the main determinant of BP-related
vascular risk and of benefit from antihypertensive treatment. Although the diagnosis Commented [AB1]: Haven’t understood this sentence so
don’t know how to change it. Please refer once
of high BP appears to be straightforward, in clinical practice, misdiagnosis is not rare,
and even after many years of research there are still several unresolved issues
regarding optimal BP classification. The American Heart Association guidelines 3 on
measurement BP state that it is generally agreed that conventional clinic readings are
a surrogate marker for a patient’s true BP and are thought to be the most important
component of BP in determining its adverse effects. Like this, clinic BP is used as the

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primary tool for diagnosis and assessment of hypertension and its severity in clinical
practice and in current guidelines.

For example, the phenomena of isolated office hypertension (that is, high BP when at
the doctor’s office despite a normal BP out of the office) and masked hypertension
(that is, normal BP in the doctor’s office and high BP out of the office) lead to frequent
over- and under-diagnosis of BP-associated CV risk. One of the main causes of the
misdiagnosis of hypertension is the variability of BP.4 over the past few decades there
has been mounting evidence to the effect that in addition to the absolute BP values,
high BPV is associated with the development, progression, and severity of cardiac,
renal, and vascular damage along with increased risk of CV mortality.5-7 Indeed, when
subject at a high CV risk are compared to those at low-moderate risk, increased values
of BPV seems to have a greater prognostic value. 8 Commented [AB2]: Meaning unclear

Also, there is a prevalent assumption among physicians treating hypertension that as

long as the diastolic pressure is adequate for maintaining coronary perfusion, the lower
the BP the better. There is poor understanding of the component of BP causing said
vascular events. Mean BP (average of several readings of either systolic or diastolic
BP) is clearly important, but other factors, such as variability (variation in BP with time)
or instability of BP (transient fluctuations in BP) might also play a part when most
vascular events occur. According to the current paradigm, however, an effective
pharmacological regimen is one that provides continuous, indiscriminate BP reduction
throughout 24 hours. The results of the Ambulatory Blood Pressure Monitoring for
Prediction of Cardiovascular Events study challenge conventional understanding, and
have the potential to effect important changes in the management of hypertension.9

Circadian rhythm and variation of blood pressure in normal and hypertensive

patients

Sleep usually involves calmness and detachment from the external environment, and
hence generally causes a reduction in BP at night. This decrease does not occur under
conditions of total sleep deprivation. The circadian rhythm of BP was ultimately
established by Millar-Craig et al.10 using continuous intra-arterial monitoring. In
persons with normal BP or uncomplicated hypertension, BP declines to lowest levels
during night time sleep (nocturnal dip), rises abruptly with morning awakening
(morning surge), and attains near peak or peak values during the first hours of diurnal

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activity. In the normal dippers, the sleep-time BP mean is lower by 10% to 20%
compared to the daytime mean. The timing and amplitude of the natural rhythm of BP
is influenced by intrinsic factors (neuro humoral regulation) and the extrinsic factors
(physical activity, sleep deprivation or quality, and dietary sodium). Furthermore,
behavioral factors (mental activity and emotional status) and lifestyle factors (alcohol
drinking and smoking) can also affect the natural rhythm of BP.11 Sleep disturbances,
including sleep restriction, sleep apnea, insomnia, and shift work, have also been
found to induce stress on the cardiovascular system and play a role in the development
of cardiovascular disorders.

When hypertension first develops, the normal circadian BP rhythm is preserved. Later,
as target-organ damage compromises the regulation of systemic BP, the circadian
rhythm becomes distorted, with a tendency towards greater variability and excessive
morning BP surge. Finally, sleep-time BP may increase to produce a non-dipper
pattern.10 Diabetes, post-stroke, congestive heart failure, sleep apnea syndrome,
orthostatic hypotension, or medicated hypertension are frequently associated
conditions in non-dipper or riser pattern. Otherwise, smoking, alcohol drinking, over
60 years of age, cold weather, increased arterial stiffness, impaired baroreflex, or
orthostatic hypertension is associated with a morning BP surge pattern. 12

Blood Pressure Variability

Even though average clinic BP values remain the gold standard for the diagnosis and
treatment of hypertension, recent studies in hypertensive subjects have demonstrated
that the assessment and quantification of BPV in addition to normal BP values, is of
both physio pathological and prognostic importance. For instance, there is strong
evidence to show that increased BPV is independently associated with higher risk of
target-organ damage, cardiovascular events, and mortality. It follows that controlling
BPV in addition to reducing absolute BP levels may contribute to optimal
cardiovascular protection in hypertensive patients. Blood pressure variability in
simplistic terms can be defined as the variations in BP over time. These blood pressure
fluctuations are generated by a complex interplay between several cardiovascular
control mechanisms or during shift between daily life behaviour and triggered by
environmental situations.13

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Extents of these variations differ from person to person and are high in patients with
defunct cardiovascular control mechanisms.14 Typical examples of these routine
fluctuations are rise in BP after physical activity or psychological stress and drop in BP
levels during relaxation or sleep.13 Studies on high CV risk populations have shown
high BPV values in individual subjects as strong predictors of CV mortality and
morbidity, even to a greater extent than average BP values. Depending on the
temporal measurements assessed, BPV can be classified into 5 different types: very
short term, short term, mid-term, long term and very long term.15 Very short term BPV
can be defined as beat to beat variability whereas variability over 24 hours is called as
short term BPV. Day to day variability is identified as mid-term BPV. Long term and
very long term BPV are visit to visit variabilities (VVV) in BP measurements that are
less than and greater than five years respectively. A strong relationship exists between
BPV and BP levels; higher the BP levels, higher the BPV. Different indices have been
in practice to measure various types of BPV; they are reviewed extensively by Parati
et al.15 BPV is usually expressed as standard deviation (SD) of 24 h mean BP. 16 The
SD and coefficient of variation are used to measure all five different types of BPV.
These two indices are specifically important to measure long term BPV. Alternative
indices are proposed or in practice to measure short term BPV. Beat to beat variability
can be estimated from the spectral analysis of frequency domain. 15 Average real
variability (ARV) has been proposed recently for short term BPV. 17 It calculates the
average of the absolute differences between the consecutive BP measurements over
24 hours. As it focuses on the sequence of BP readings, it reflects short term with-in
subject variability.15 Several different intrinsic and extrinsic factors are known to
influence different types of BPV. In a population based study on adult Chinese subjects
with different ethnicities, Wei Li et al has demonstrated that BPV is influenced by
various demographic, clinical and biochemical factors.18 Furthermore, the authors
have also identified that average of night time systolic BP, average of day time diastolic
BP, triglycerides, fasting blood glucose, and apolipoprotein A were significantly and
independently associated with BPV.

Very short-term BPV

Very short-term BPV refers to beat-to-beat fluctuations in BP due to the interplay of

different cardiovascular control systems, such as the baroreceptor reflex, the renin–
angiotensin system, the vascular myogenic response, and the release of nitric oxide

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from the endothelium, as well as changes in behavioral and emotional mechanisms. 19,
20, 21 It is usually assessed in a laboratory via intra-arterial recording or under
ambulatory conditions by non-invasive finger cuffs that continuously track finger-BP
levels through infrared photoplethysmography.19,22 Standard deviations of BP values
or fluctuations in BP obtained from spectral analyses at various frequency bands are
often used as the main indices for assessing very short-term BPV.19

Even though its usefulness and reliability in practical usage is questionable, very short-
term BPV has been used as a tool in diagnosing and treating patients with
cardiovascular disease, as well as to study the mechanism of action of
antihypertensive drugs.19,21,23 Detecting changes in beat-to-beat BPV can also help in
rationally selecting antihypertensive drugs.20 For instance, hypertensive patients with
elevated low-frequency BPV may present with enhanced sympathetic modulation of
vascular tone, and hence may respond well to sympatholytic antihypertensive drugs. 21

Short-Term-BPV

Studies recording the intra-arterial BPV over a day were the first to attempt to relate
short-term BPV to increased cardiovascular mortality and a target organ damage. 5, 24
Ambulatory blood pressure monitoring (ABPM) is the most common method of
analysis of BPV behaviour over a 24-h period. This method is able to determine
whether the loss of the expected BP circadian rhythm is associated with CV morbidity
and mortality in subpopulations of hypertensive patients 25, 26 , as well as in the general
population.27,28 In this sense, the kidney is particularly susceptible to pressure
variations, and so are vascular territories (macro and microcirculation) and the
myocardium .27,29 Multiple BPV phenotypes are detected by ABPM: standard deviation
(SD) of average systolic, diastolic, and mean BP during all period or during
wakefulness and sleep time sub periods; percentage of decrease in BP between night
and day (sleep time /wakefulness); increase in BP on waking in the morning (morning
surge); average of daytime and night time BP-SD each weighted for the duration of
day and night periods, among others .30,31 There is not a universal consensus as to
which of these parameters better reflect the increase in CV risk and the need of
performing further mathematical sub-analysis of the 24-h BP recording in order to
establish a parameter for predicting CV events .31 Both absolute elevated night time
BP and non-dipping profile have been dealt with in several studies. Several

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investigations have demonstrated that elevated night time BP is more effective in
predicting CV morbi-mortality when compared to the awake or 24 h BP mean values.
25,29,32,,33,34, Moreover, the detection of a blunted nocturnal decrease in BP non-dippe,
or even an increase in BP values inverted dippers, was found to be associated with a
higher prevalence of vascular damage, increased CV risk, and mortality. 35,36 Morning
BP surge (MBPS) has been associated with target organ damage, including left
ventricular hypertrophy (LVH), albuminuria, increased carotid intima-media thickness,
arterial stiffness, reduced coronary flow reserve, and silent cerebrovascular disease.
37,38 However, discrepancies in the findings pointing MBPS as a risk factor for CV
disease have been found in clinical trials. Some 36, 39, but not all studies 40,41 , found a
positive association between MBPS regardless of the 24-h BP levels with CV
outcomes in both hypertensive and the general community. Despite these several
studies, the threshold at which an MBPS becomes pathological remains unclear and
may account for the heterogeneity of the results from clinical studies.37 Therefore, new
measures of MBPS which may more effectively predict CV risk have been
investigated. However, there are still no consensus about the real prognostic
significance of MBPS, and also whether targeting MBPS is more beneficial than
targeting clinic BP. 42 In spite of this, morning BP seems to be an important target of
antihypertensive treatment in current clinical practice for the management of
hypertension .37

Mid-term, long-term and very long term BPV

Long-term BPV refers to day-to-day, visit-to-visit, and season to-season BP

changes.7,22 Factors contributing to long-term BPV remain relatively unclear. Long-
term BPV could be a consequence of poor BP control in treated patients, such as
inadequate treatment by the physician, poor patient adherence, or improper BP-
measurement methods.7,22 It may also be influenced by behavioral changes in an
individual, as well as environmental factors, such as outdoor temperature and day
light-hour differences between different seasons.743,22 For instance, BPV was found to
be greater during winter than in summer, possibly due to increased sodium retention
and vascular resistance caused by augmented sympathetic activity. 43 Some studies
have also suggested that increased arterial stiffness contributes to the pathogenesis
of long-term BPV. Day-to-day BPV can be assessed by ABPM over 48 hours or HBPM
data collected over several days, weeks, or months, while visit-to-visit BPV is usually

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assessed by ABPM or OBPM that is usually spaced by visits over weeks, months, and
years.7,22 However, the reliability of using OBPM to assess long-term BPV has been
questioned, as it does not take into account the patient’s normal activities and requires
frequent visits to the physician for BP measurements.7,22 A recent single-centre cross-
sectional study showed significant differences between single OBPM and means of
consecutive BP measurements.44 In-office measurements are also sometimes
inaccurate, mainly because of the white-coat effect, inadequate or un calibrated
devices, and suboptimal measurement techniques (e.g. incorrect cuff size, no rest
before measurement).45,46 Although a large number of recommendations on correct
OBPM techniques have been published ,these guidelines are generally not translated
into primary-care practice.46,47 There is strong evidence to suggest that increased long
term BPV is associated with higher risk of stroke, cardiovascular events, and mortality,
including all-cause mortality.48,49 Therefore, measuring long-term BPV might be
clinically important, as it can provide useful insights into the long-term control of the
patient’s BP and effectiveness of the patient’s current antihypertensive therapy.7

Tools to Measure BPV

Various tools enable to measure BPV. Twenty four hour ABPM is one of them which
helps to determine the BPV precisely. In principle, ABPM allows 24 hour (or even
longer) recording of BP and evaluates various parameters such as mean BP,
variations between daytime and night time, pressure loads, area under the curve, and
pulse pressure variability. Furthermore, a 24 hour ABPM measurement renders the
possibility to evaluate short-term BP variability between measurement intervals not
longer than 15 minutes.50 These various assessments facilitated by ABPM are
valuable for the clinical management of hypertension as they increase the accuracy
for diagnosis and prediction of CV risk.51 Absolute indications for ABPM include
identifying white coat or masked hypertension and 24 hour abnormal BP patterns and
assessing the efficacy of antihypertensive treatment.52 Some of the limitations of
ABPM include discomfort during night time, occasional inability to detect genuine
artefactual measurements, limited availability of the devices, and high cost. Apart from
this repeated measurements with well calibrated automated blood pressure monitoring
device can be acquired at HBPM or OBPM. From these values, BPV can be
determined by calculating the SD or coefficient of variation.

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BPV and Cardiac Hypertrophy

Early available data suggest that mean BP values obtained with 24-h BP monitoring
predict more effectively the presence of LVH than does a single BP measurement. 53
Increase in 24 h BPV over 24 h evaluation 54 or during day time 55 recorded with ABPM
was associated with a higher degree of hypertensive cardiovascular complications,
such as LV systolic dysfunction .56 The studies investigating the association between
BPV and LVH have mostly examined short-term variability. 56,57,58 The non-dipper
pattern of the night time BP and the exaggerate MBPS evaluated with ABPM are
associated with a greater LV mass and CV morbidity in a general population 59 and
with a CV remodelling in hypertensive patients 60 However, a recent meta-analysis
examining the correlation between short-term BPV and LV mass indexes suggests
that there is a weak positive correlation, between BPV and LV mass 61,62 while another
study showed that higher visit-to-visit BPV predicts CV events in hypertensive patients
with LVH.63 In addition, several problems have been detected in the evaluation of the
cardiovascular impact of short term and long-term BPV, including limited
reproducibility of BPV, the lack of normal reference values, and limitations of
conventional devices for ABPM.64 Considering the limitations of the evaluation of the
clinical relevance of BPV, preclinical studies have clearly contributed in the actual
knowledge of the role of BPV in cardiovascular disease. The sinoaortic denervated
(SAD) rat represents an excellent experimental model to investigate the
consequences of BPV on target organs, considering the fact that SAD increases
fluctuation in BP without affecting mean values. Specifically, the ablation of carotid and
aortic baroreceptor afferents in SAD rats induces a chronic increase in short-term BPV
with normal average blood pressure level.65

BPV and Chronic Kidney Disease

People with end stage renal disease are characterized by marked BP variations and
alterations in circadian BP rhythm. However, no short-term BPV study in humans has
found a influence on prognostic role of BPV on mean BP levels in determining the
development or progression of renal dysfunction. Few studies have shown that an
increase in short-term BPV may be positively correlated with impaired renal function
assessed with microalbuminuria or by estimation of glomerular filtration rate. 66,67

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However, longitudinal studies have found that a non-dipper or inverted dippers
patterns of night time BP evaluated over 24 h ABPM are independent predictors of a
poor renal prognosis, as evaluated by many clinical markers of renal function .68,69
HBPM has been found to have a predictive value for impairment of renal function 70,71

but not all studies have founded the same results. Visit-to-visit BPV may be of
significant value in predicting the risk of development and progression of nephropathy
and chronic kidney disease .72,73

BPV Cerebrovascular Dysfunction and Brain Damage

Hypertension is the most important risk factor for the development of carotid
atherosclerotic lesion and cerebral small vessel disease, which are contributors to
stroke and cognitive decline in the elderly. 74 Therefore, the detection of the early
involvement of these vascular territories, before the clinical manifestations occur,
might have the potential to prevent future brain damage. 75 Increased short- and long-
term BVP have been suggested as an independent risk factor for stroke in elderly
hypertensive patients 76 A disturbed nocturnal decline in BP was associated with
cerebral infarction, whereas a large morning pressor surge and a large nocturnal
decline in BP were both associated with cerebral hemorrhage 77 Regarding to
cognitive dysfunction, BPV is associated with low scores in cognitive tests in elderly 78
and has been claimed as a predictor for cognitive decline high risk in middle age
subjects 79 Moreover, in young subjects, the long-term BPV was related to worse
psychomotor speed and verbal memory in 25 years of follow-up, independently of BP
levels 80 The association of short-term BPV and early stages of carotid artery damage
has been detected more than a decade ago and is confirmed also in recent studies
81,82 Non-dipping pattern and exaggerated MBPS have been associated with increased
values of carotid intima media thickness and a high level of blood inflammatory
markers in elderly with high CV risk 83,84 and middle aged hypertensive subjects.
Moreover, day-by-day BPV is also related not only with carotid artery atherosclerosis
but also to arterial stiffness and endothelial function in normotensive and mild-
moderate hypertensive individuals .85,86 It seems that cerebral small vessel disease
(CSVD) may be connected with silent cerebral injury as the link between the
pathophysiologic mechanisms of stroke and cognitive impairment. Recently, short-
term variability has been related to the presence of subclinical CSVD in hypertension
subjects, independently of the BP levels and other clinical covariates. 87

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BPV as a Target for Antihypertensive Treatment: Short and Long-Term Studies

The independent role of BPV in predicting organ damage and CV morbi-mortality

remains controversial in the clinical practice. Notwithstanding, in recent years,
numerous publications have analyzed whether antihypertensive drugs have an effect
in the reduction of BPV, independently of the BP values. Moreover, few studies have
discussed the association between decrease of BPV with pharmacological treatment
and the improvement in target organ damage, and consequently, a reduction in CV
events.

Most of the data comes from post hoc analysis of clinical trials and databases, which
used different classes of antihypertensive drugs and distinguished clusters of target
organ damage and CV outcomes. Also, the studies used different BPV phenotypes.
Some evaluated the effect of antihypertensive drugs on short-term BPV by ABPM,
while others used long-term BPV by HBPM, visit-to-visit, or longer intervals such as
between seasons.

A systematic review to assess the differences between classes of antihypertensive

drugs in the effectiveness in preventing stroke was performed recently. Compared with
other drugs, inter individual variation in SBP was reduced the most by calcium channel
blockers (CCB) and non-loop diuretic drugs and increased by angiotensin conversion
enzyme inhibitor (ACEi), angiotensin receptor blocker(ARB), and β-adrenergic
receptor blocker (βB). 88 A post hoc analysis of two large clinical trials compared both
the within-visit and the ABPM variability between groups receiving amlodipine-and
atenolol-based treatment, and the within BPV variability between placebo and atenolol
and diuretic-based treatment groups. As a result, amlodipine decreased BPV over time
and reduced the risk of stroke, while atenolol had opposite effects. 89 A meta-analysis
of an ABMP database evidenced that subjects treated with telmisartan or amlodipine
had a higher smoothness index compared with others treated with losartan, valsartan,
or Ramipril.90 The same ABPM data base was further evaluated and BP variability was
inferred through the smoothness index and of the treatment-on-variability index. As
compared with various monotherapies, telmisartan/amlodipine combination was
associated with a smoother 24-h BP reduction profile as well as significantly lower and
smoother BP levels over 24 hr, reflecting its effectiveness in lowering BP and its longer
duration.91

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A randomized, double blind placebo-controlled study with four parallel treatment arms
(placebo, candesartan, indapamide, and amlodipine) analyzed short-term BVP with
ABPM data. In summary, amlodipine and indapamide treatment was associated with
a significant reduction in BPV, but the effect of amlodipine on BPV was also associated
with a BP reduction. 92 The effect of two antihypertensive drug combinations
[(olmesartan/CCB) and (olmesartan/diuretic)] on Home blood pressure variability
(HBPV) and on arterial stiffness was investigated. The study demonstrated that the
ARB/CCB combination improved HBPV in addition to home BP reduction. Moreover,
the reduction in HBPV was partially attributable to the arterial stiffness reduction by
this combination.93 A randomized, open-label, blinded-endpoint trial studied the
administration time-dependent BP-lowering efficacy of valsartan/ hydrochlorothiazide
combination therapy on BPV measured with ABPM. The results demonstrated that the
proportion of subjects with properly controlled ambulatory BP after combination
therapy was significantly greater with bedtime than upon-awakening treatment. 94

Visit-to-visit intra individual variations of both clinical and 24-h mean BP of clinic BP
were compared between patients treated with atenolol and lacidipine. In conclusion,
visit-to-visit BPV does not differ substantially between βB and CCB treatment.95
Indices of short-term BP variability were studied in a cohort of patients treated by either
CCB, diuretics, ACEi, ARBs, or βB alone or in combination. Patients treated with CCB
and diuretics alone or in addition to other drugs had lower BPV compare with those
not treated with these classes. 96 Antihypertensive drug class effect on day-to-day HBP
variability after a recent minor cerebrovascular event has been investigated. Variability
in SBP was reduced in patients treated with CCB/diuretics compared to both and
ACEi.97 The association of visit-to-visit BP variability with target organ damage and
cardiovascular outcomes in patients with left ventricular hypertrophy randomized to
losartan- and atenolol-based treatment was recently analyzed. As a result, higher in-
treatment BP variability, independently of mean BP, was associated with later stroke
and composite CV events, but not myocardial infarction or target organ damage. 98
However, the association between of visit-to-visit BP variability and cognitive
impairment in a post hoc study of elderly patients was not associated with BP mediated
lowering medication.99 A study compared visit-to-visit BP variability between old and
very old subjects and between two treatment combinations, that is, ARB/CCB and
ARB/diuretic. Long-term variability was smaller in the ARB/CCB group than in the

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other group, especially in the very old and also in the isolated systolic hypertensive
patients. 100 A prospective, randomized trial analyzed visit-to-visit and seasonal
variations in BP in elderly patients that received combination of ARB/CCB or
ARB/diuretics. Visit to-visit BPV was significantly lower in the ARB/CCB group than in
the ARB/diuretic group. As for seasonal variability, no significant between-group
differences were found. 101 Another study compared a combination of a CCB/ACEi to
the corresponding monotherapies and placebo for their effects on HBPV. The study
showed that CCB/ACEi lowers HBPV more effectively than in other treatments. 102

Recently, the effects of three CCB-based treatments (CCB/ARB, CCB/βB,

CCB/diuretic) on intra-individual visit-to-visit BPV were studied, corroborating the
previous observations. The maximum BPs did not differ among groups. However, BPV
was lower in the CCB/diuretic group compared to CCB/βB group. The simultaneously
evaluation of the effectiveness of a fixed-dose combination of perindopril/amlodipine
in the doctor’s office at each visit, daily at home, and by ABPM was evaluated in
another study. It was possible to show a significant reduction in BP levels and a
beneficial effect on improving BVP detected on various parameters related to BVP 103

Together, this data suggests that CCB as monotherapy or in addition to diuretics may
be more effective in reducing BPV and some CV outcomes compared to other
antihypertensive drugs alone or in combination.

Conclusion:

To Summarize, the concept of BP variability though has been evaluated for several
decades, its clinical implication is still far from clear. Despite the availability of clinical
evidence demonstrating that BPV could cause target organ damage, it did not attain
desired significance in routine clinical practice. Reasons for this could be due to the
lack of high quality trials that evaluated a direct relationship between BPV reduction
and lowering of the CV risk and the difficulty in measuring BPV in a busy outpatient
setting. Both short-term and long-term BPVs are independently associated with target
organ damage and cardiovascular events in patients with hypertension, diabetes
mellitus, and chronic kidney disease. Some antihypertensive drugs, either as
monotherapy or in combination, effectively reduce short-term and long-term BPV.
Nevertheless, available data suggest a greater capability of calcium channel blockers
in comparison to other therapeutic classes to attenuate long-term BPV and effective

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BPV management of hypertension, rather than simply controlling average BP levels.
This concept may then be considered clinically meaningful. It is reasonable to include
BPV in the diagnostic armamentarium of hypertension management.

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