Module 1

PP-NOR-APA-0053
Clinical Implications of Blood
Pressure Variability
Important Notice

• This presentation on Blood Pressure Variability and related

matters is provided for the purpose of scientific knowledge
sharing and clinical practice discussion. Certain clinical
constructs and related references or citations may allude to
therapeutic options that may not be registered for use in this
country.
• Full prescribing information and primary references should be
accessed for complete safety and efficacy information relating to
the approved use of any medicine.
• Physicians have the professional responsibility to ensure that
pharmaceutical products are prescribed and used appropriately,
based on their own judgment and accepted standards of care.

3
Contents

• Why is management of hypertension important?

• Global burden of hypertension
• Blood Pressure Variability
• Morning BP surge
• Management of Blood Pressure Variability
• Summary
• Patient case discussion

4
Why is management of hypertension important?
Uncontrolled hypertension can lead to
organ damage1

A person is diagnosed with hypertension when their

BP rises to ≥140/90 mmHg2*

Eyes1 Arteries1
• Retinopathy • Damaged and narrowed arteries
• Choroidopathy • Aneurysm
• Optic nerve damage

Brain1
Kidneys1 Heart1 • Transient ischemic attack
• Kidney failure • Coronary artery disease • Stroke
• Kidney scarring • Left ventricular hypertrophy • Dementia
• Kidney artery aneurysm • Heart failure • Cognitive impairment
*ACC/AHA guidelines define hypertension as a BP ≥130/80 mmHg3
1. Mayo Clinic. High blood pressure dangers: Hypertension's effects on your body. 2016. http://www.mayoclinic.org/diseases-
conditions/high-blood-pressure/in-depth/high-blood-pressure/art-20045868. Last accessed 1 December 2017
2. World Health Organization. A global brief on hypertension. 2013, Geneva, Switzerland.
3. Whelton PK, et al. Hypertension. 2017 Nov 13. [Epub ahead of print]
Image source: 1) ©Krzysztof Remlinger/Shutterstock.com 2) ©Alex Mit/Shutterstock.com 3) ©Tefi/Shutterstock.com 4) ©decade3d-
anatomy online/Shutterstock.com 5) ©Jibon/Shutterstock.com 6) ©Tefi/Shutterstock.com
6
Hypertension is one of the main risk factors for
cardiovascular disease1

Reduced blood pressure Reduced risk of cardiovascular events2

10 mmHg  Stroke  Heart attack

in systolic BP
Heart
Stroke attack
or mortality
mortality
5 mmHg (41%) (22%)
in diastolic BP

Lowering blood pressure reduces the risk of

adverse cardiovascular outcomes2
1. World Health Organization. Global Atlas on Cardiovascular Disease Prevention and Control. Mendis
S, Puska P, Norrving B, eds. Geneva, 2011.
2. Law MR, et al. BMJ. 2009;338:b1665.
Image source: 1) ©Krzysztof Remlinger/Shutterstock.com 2) & 3) ©Tittima Ongkantong/Shutterstock.com
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Hypertension in the cardiovascular continuum

• Hypertension and other cardiovascular risk factors have a

combined effect1
• The risk of cardiovascular events increases with the number and
severity of cardiovascular risk factors2
Probability of a Coronary Heart Disease According to
42 the Presence of Risk Factors 40
in Men Aged 45 Years2
36
30
10-Year Probability of Heart
Event (%) 24 21 damage
+
Smoking
18 14 Smoking +
+ Diabetes
12 10 Diabetes
Diabetes +
+ + Abnormal
Abnormal Abnormal Abnormal cholesterol
6 4 cholesterol cholesterol cholesterol
+
+ + +
Hypertension Hypertension Hypertension Hypertension
Hypertension
0 Adapted from Kannel 2000.

1. Mancia G, et al. Eur Heart J. 2013;34:2159-2219.

2. Kannel WB. Am J Hypertens. 2000;13:3S-10S.
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Early intervention to reduce cardiovascular risk
factors is key1

• Treatment at any point along the cardiovascular continuum may

help control disease progression1
BUT, early intervention = best long-term cardiovascular outcomes1

Cardiovascular disease continuum

RISK OF CARDIOVASCULAR
Antihypertensive
medication

RISK FACTORS1

EVENTS
Hypertension Heart attack
Diabetes Stroke
High cholesterol Earlier intervention =
Smoking greater reduction in
Obesity cardiovascular risk1

EARLY TIME OF INTERVENTION LATE

Adapted from Chrysant 2010.

1. Chrysant SG, et al. Curr Clin Pharmacol. 2010;5:89-95.

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Global burden of hypertension
Hypertension is the leading risk factor for
death and disability1

deaths worldwide due to

7.8 million complications of hypertension2
1 in 5
Hypertension is responsible for:2
874 million adults have hypertension2,3
of deaths
40% due to heart
disease
of deaths
40% due to Healthy life
Hypertension or
associated disability
Expected
life years
stroke Early death
Disability-adjusted = years lived + years of
of deaths life years with disability life lost

45% due to kidney disability-adjusted life years

disease 143 million due to hypertension2
1. GBD 2015 Risk Factors Collaborators. Lancet. 2016;388(10053):1659-1724.
2. Forouzanfar MH, et al. JAMA. 2017;317:165-182.
3. World Health Organization. Global status report on noncommunicable diseases. 2014, Geneva, Switzerland.
Image source: 1) ©TotemArt/Shutterstock.com 2) ©AVIcon/Shutterstock.com 3) ©MD. Delwar
hossain/Shutterstock,com 4) ©MD. Delwar hossain/Shutterstock,com 5) ©TotemArt/Shuttertstocl.com 6)
©Leremy/Sutterstock.com 7) ©Piter Kidanchuk/Shutterstock.com 11
 Hypertension-related death and disability rates
vary across countries in Asia1,2
Hypertension-related deaths in countries across Asia in 20151
China 1791.8
India 1012.3
Indonesia 324.1
Pakistan 180.5
Japan 172
Vietnam 110.3
Bangladesh 88.9
Philippines 62.5
Thailand 52.1
Myanmar 50
North Korea 33.1
Malaysia 27.4
South Korea 20.8
Sri Lanka 19.8
Taiwan 13.9
Cambodia 7.3
Laos 5.2
Singapore 4.0
0 50 100 150 0
200
200 300 600 900 1200 1500 1800
Estimated number of deaths related to hypertension in 2015 (in thousands)
Hypertension is the leading risk factor for death and disability
in all regions of Asia2

1. Forouzanfar MH, et al. JAMA. 2017;317:165-182.

2. GBD 2015 Risk Factors Collaborators. Lancet. 2016;388(10053):1659-1724.
12
Awareness and control of hypertension

Only 1 in 2 adults with hypertension are aware of their condition1

are treated with BUT have their BP
37% antihypertensive ONLY 14% under control1
medication1…

Global disparities between high-income countries vs low- and

middle-income countries:1

Awareness 2× Treatment 2× Control 4×

Japan
Korea Awareness, treatment and
Malaysia control of hypertension is
Pakistan unacceptably low in Asia2
Taiwan
0 20 40 60 80 100
Rates of controlled hypertension (%)3
Combined Women Men
1. Mills KT, et al. Circulation. 2016;134:441-450.
2. Park JB, et al. Hypertension Res. 2015;38:227-236.
3. Chia YC, et al. J Clin Hypertens. 2017;1-10
Image source: 1) ©TotemArt/Shuttertstock.com 2) ©Oleksandr Yuhlchek/Shuttertstock.com 3) ©Paul
Stringer/Shuttertstock.com 13
Blood Pressure Variability
Circadian changes in BP

Morning Plateau with activity

Nocturnal dip surge peaks

During the course of the day BP can fluctuate from

minute-to-minute and hour-to-hour1

1. Parati G, et al. Curr Hypertens Rep. 2015;17:537.

Image source: 1) ©Leremy/Shuttertstock.com 2) ©Pensiri/Shutterstock.com 3) ©Pfizer
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Blood Pressure Variability (BPV)

BPV = variation in blood pressure with time1

Example of low BPV Example of high BPV
220 220
200 200
Blood pressure(mmHg)

Blood pressure (mmHg)

180 180 SBP
160 160
Higher
140 140
mean BP
120 120
overall
100 100 DBP
80 80
60 60
40 40
1 2 3 1 2 3
Weeks Weeks

Increases in BPV are associated with an increased risk of

cardiovascular events2

DBP, diastolic blood pressure; SBP, systolic blood pressure

1. Rothwell PM. Lancet. 2010;375:938-948.
2. Parati G, et al. Curr Hypertens Rep. 2015;17:537.
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How to monitor elements of BPV

Very short term Short term Medium term Long term

Beat-to-beat Minute-to- Hour-to-hour Day-to-day Visit-to-visit

BPV minute BPV BPV BPV BPV
Computer analysis of BP tracing 24-hour ABPM HBPM Office BP
measurements

Less commonly Less commonly Less commonly

through home through 24-hour through 24-hour
and clinic BP ABPM or clinic ABPM and
measurements measurements HPBM
measurements

ABPM, ambulatory blood pressure monitoring; HPBM, home blood pressure monitoring
1. Parati G, et al. Curr Hypertens Rep. 2015;17:537.
Image source: ©Angel_AMX/Shuttertstock.com
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Multiple factors are involved in BPV

Humoral Vasomotor
factors ? Mechanical
factors ? factors
Behavioral
factors Arterial
stiffness ?
BPV

Rhythmic
influences
Baroreflexes

Environmental Other
stimuli Genetic reflexes ?
factors ?

1. Mancia G. Hypertension. 2012;60:512-517.

Image source: ©Angel_AMX/Shuttertstock.com
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Predictive value of BPV for adverse outcomes

Very short-term BPV Short-term BPV Mid-term BPV Long-term BPV

(beat-to-beat) (over 24h) (day-to-day) (visit-to-visit)

Subclinical Cardiovascular Renal events All cause Cardiovascular

organ damage events mortality mortality

Increases in short- and long-term BPV may predict cardiac, vascular and
renal organ damage and cardiovascular events and mortality1

1. Parati G, et al. Curr Hypertens Rep. 2015;17:537.

Image source: 1) ©Angel_AMX/Shuttertstock.com 2) ©LynxVector/Shuttertstock.com 3) ©MD. Delwar
hossain/Shuttertstock.com 4) ©AVIcon/Shuttertstock.com 5) ©MD. Delwar hossain 6) ©Piter
Kidanchuk/Shuttertstock.com 7) ©a Sk/Shuttertstock.com
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Morning BP surge
Morning surge of BP

Morning BP
surge
• Morning BP surge is an
element of BP variability1
• Morning BP surge refers to
the increase or spike in BP
that normally occurs after the
night-time dip when a person
wakes up2
• Morning BP surge increases
with aging and higher BP1
• Asian individuals show
greater morning BP surges3

Adapted from Kario 2010.

1. Kario K. Hypertens. 2015;65:1163-1169.

2. Kario K. Hypertens. 2010;56:765-773.
3. Kario K. J Hum Hypertens. 2017;31:231-243.
Image source: ©Pfizer
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Predictive value of morning BP surge for
adverse outcomes

Greater morning BP surge is associated with an increased

incidence of cardiovascular events and mortality1
Morning BP Cardiovascular Cardiovascular
surge events mortality

Prognostic significance of
morning BP surge??

Degree of morning BP surge Degree of night-time BP fall

(potentially risky phenomenon) (potentially protective phenomenon)

1. Parati G, et al. Curr Hypertens Rep. 2015;17:537.

Image source: 1) ©johavel/Shutterstock.com 2) ©LynxVector/Shuttertstock.com 3) ©MD. Delwar
hossain/Shuttertstock.com 4) ©Piter Kidanchuk/Shuttertstock.com 5) ©a Sk/Shuttertstock.com
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Management of
Blood Pressure Variability
 Implications for treatment: need for
long-acting antihypertensive agents

• Long-acting antihypertensive agents may reduce BP variability

and protect against dangerous morning BP surge1,2
Morning BP
surge

* *
* *
*
*

Adapted from Kario 2010.

Short-acting antihypertensive effect2

Long-acting antihypertensive effect persists through morning surge2
* Sample activities for illustration purposes
1. Patel PV, et al. J Clin Hypertens. 2008;10:140-145.
2. Höcht C, et al. Curr Pharmaceut Design. 2015;21:744-755.
3. Kario K. Hypertens. 2010;56:765-773.
Image source: 1) ©Leremy/Shutterstock.com 2) ©Pensiri/Shutterstock.com 3) ©Pretty Vectors/
Shutterstock.com 24
Guideline recommendations

“Hypertension is the most common condition seen in primary care and

leads to myocardial infarction, stroke, renal failure, and death if not
detected early and treated appropriately”1
2014 JNC8

“Systolic BP variability appears to be an important independent

predictor of clinical outcomes. Updated guidance recommends the
best available evidence-based treatment options to suppress BPV
in people with hypertension”2
2011 NICE Guidelines

1. James PA, et al. JAMA. 2014;311:507-520.

2. National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127:
http://www.nice.org.uk/guidance/cg127
25
Guideline recommendations

“Consideration should be given to the evidence that visit-to-visit BPV

may be a determinant of CV risk, independently of the mean BP levels
achieved during long-term treatment, and that, thus, CV protection may
be greater in patients with consistent BP control throughout visits.”1
2013 ESH/ESC Guidelines

“Drugs with 24 h efficacy are preferred. Long-acting drugs also

minimize BPV, which may offer protection against progression of
organ damage and the risk of CV events.”2
2016 ESC Guidelines

1. Mancia G, et al. Eur Heart J. 2013;34:2159-2219

2. Piepoli MF, et al. Eur Heart J. 2016;37:2315-2381.
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Summary
Take-home messages

• Uncontrolled hypertension can lead to progressive tissue

damage and life-threatening cardiovascular events1
• Early intervention to reduce BP and other cardiovascular risk
factors is key2
• Increases in Blood Pressure Variability (BPV) are associated with
an increased risk of cardiovascular events3
• BPV is an important independent predictor of clinical outcomes4
• Morning BP surge is an important element of BPV5
• Long-acting drugs minimize BPV and may offer protection
against CV events6

1. Mayo Clinic. High blood pressure dangers: Hypertension's effects on your body. 2016.
http://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/high-blood-
pressure/art-20045868. Last accessed 1 December 2017
2. Chrysant SG, et al. Curr Clin Pharmacol. 2010;5:89-95.
3. Parati G, et al. Curr Hypertens Rep. 2015;17:537.
4. National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127:
http://www.nice.org.uk/guidance/cg127
5. Kario K. Hypertens. 2015;65:1163-1169.
6. Piepoli MF, et al. Eur Heart J. 2016;37:2315-2381.
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Case example
Thank you