The Role and Management

of
Morning Blood Pressure
Surge in Hypertension

Dr. Samuel Sudanawidjaja, SpJP

Global deaths from cardiovascular disease and stroke are increasing due
to aging and increasing populations
20.000.000
1990 2013
18.000.000
40.8%
Increase of 40.8% since 1990
16.000.000 Driven by:
• Population growth: 25.1%
14.000.000 • Population aging: 55.0%
Despite 39.3% decrease in deaths attributed to epidemiologic changes
Number of deaths

12.000.000

10.000.000
41.7%
8.000.000

6.000.000

4.000.000
50.2% 30.7%

2.000.000
74.1%

0
Ischaemic heart disease Ischaemic stroke Haemorrhagic stroke Hypertensive heart disease Total

Roth GA, et al. N Engl J Med 2015;372:1333–1341

INDONESIA

http://www.healthdata.org/indonesia
Hypertension is a major public health concern

Population (in millions) with

hypertension globally3
Globally, 22% of adults had raised
blood pressure in 20141 2000
1.56 billion

1500
Hypertension is responsible for at
972 million
least 45% of deaths due to heart
disease2 1000

500
… and 51% of deaths due to
stroke2
0
Yr 2000 Yr 2025

1. WHO Global Health Observatory Data 2016;

2. WHO Global Brief on Hypertension 2013;
3. Kearney et al. Lancet 2005;365:217–223
Multiple Risk Factors in Addition to Hypertension Lead to High CVD
Risk

50 BP (mmHg)
5-Year CVD Risk per 100 People

45 110 44%
40 120
35 130 33%
30 140

25 150 24%
160 18%
20
170
15 12%
180
10 6%
3%
5
0
Reference + TC- + Smoker + HDL- + Male + Diabetes + 60 years
7 mmol/L 1 mmol/L

Jackson R et al. Lancet. 2005;365:434-41.

*Reference=nondiabetic, nonsmoker woman, aged 50 years with total cholesterol (TC)=4.0 mmol/L and HDL-C=1.6 mmol/L. 5
 Stroke and IHD mortality linked to BP levels

Systolic blood pressure Systolic blood pressure

Age at risk: Age at risk:
256 80–89 years 80–89 years
256
(Floating Absolute Risk and 95% CI)

(Floating Absolute Risk and 95% CI)

128 70–79 years 128 70–79 years
64 64
60–69 years 60–69 years
Stroke Mortality

32 32

IHD Mortality
50–59 years 50–59 years
16 16
40–49 years
8 8

4 4

2 2

1 1

0 0
120 140 160 180 120 140 160 180
Usual systolic BP (mmHg) Usual systolic BP (mmHg)
Prospective Studies Collaboration. Lancet 2002;360:1903–1913
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
Mayo Clinic. High blood pressure (hypertension). 2016.
World Health Organization. A global brief on hypertension. 2013, Geneva, Switzerland.
Image sources: © Jiripravda/Shutterstock.com…
8
 There are many causes of uncontrolled BP

Diverse pathogenesis and etiology

• RAAS
• Salt-sensitive, volume of body fluid
• Sympathetic nerve activity
• Sleep apnea syndrome
• Secondary forms

Poor adherence with AHTs BP types

Excessive BP variability
• Reduced self-CV perception • Non-dipper/reversed dipper
• Forget Uncontrolled BP (nighttime) hypertension
• Adverse drug reactions • Morning surge
• Poor therapeutic effects

• Low renin activity

• Lifestyle (sodium intake)
• Interfering substances (eg, NSAIDs)
• Fail to adjust drug species or dosage timely

Improper therapeutic regimens

Mancia.G J Hypertens 2013;31:1281-1357

White. J Manag Care Pharm 2007;13(suppl S-b):S34-S39
9
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

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

10
Definition of morning surge in BP

n Morning BP surge is an
element of BP variability
n Morning BP surge refers to
the increase or spike in BP
that normally occurs after the
night-time dip when a person
wakes up
n Morning BP surge increases
with aging and higher BP
Factors Associated with blood pressure variability and Morning
Blood Pressure Surge

Factor Association
Aging
Hypertension
Risk factors
Glucose abnormality
Metabolic syndrome
Alcohol drinking
Behaviors Smoking (Tobacco intake)
Emotional state
Salt intake
Diet Psychological stress
Excessive physical activity in the morning
Sleep Poor sleep quality
conditions Nocturnal hypoxia
Monday
Clocks Winter season
Central and peripheral clock genes
Sogunuru. J Clin Hypertens. 2019;21:324
Pathophysiology
of morning BP
surge

Bio G. Integrated Blood Pressure Control 2018:11 4

Risk factors and target organ damage associated with morning surge in BP
Reproducibility of morning surge in BP and cardiovascular risk.

Kario K. Hypertension. 2010;56:765-773

 Association between CV events and early
morning period

18:00 0:00 6:00 12:00

Time of day
CV, cardiovascular risk; EMBPS, early morning blood pressure surge.

1. Muller JE, et al. N Engl J Med 1985;313:1315–1322. 2. Marler JR, et al. Stroke 1989;20:473–476.
The Association between MBPS and CV Events
Sogunuru. J Clin Hypertens. 2019;21:324
 J Clin Hypertens. 2019;21:324・
34

EVIDENCE FROM ASIA

1. Stroke (especially hemorrhagic stroke) is more common than myocardial infarction

in Asians
2. Asians show a steeper association between BP and cardiovascular disease
3. Asians have higher salt intake than Westerners, leading to higher salt sensitivity
4. There is a high prevalence of obesity and metabolic syndrome in Asia
5. High morning and nocturnal BP readings are more common in Asians
 Sleep-trough
morning SBP
surge in two
groups of
Japanese (gray)
and European
(black) subjects

Bilo G Integrated Blood Pressure Control 2018:11 47–56

 Assessment of MBPS

´ Sleep-trough MBPS :
the difference between the mean systolic BP (SBP) over 2 hours following the awakening and the average
of three BP values centered on the lowest nocturnal BP

´ The calculation of MBPS in individual subjects may create difficulties

´ a universal cutoff for defining elevated MBPS is missing

´ MBPS assessment requires night time BP measurement, which currently can only be obtained
with ambulatory BP monitoring

´ A different approach, achievable also with home BP monitoring, is based on the assessment of
mean morning BP.

Bilo G Integrated Blood Pressure Control 2018:11 47–56

Assessment of morning BP and Hypertension

Ambulatory BP Home BP Clinic BP

Within 2 h of waking up, or 6 Within 1 h of waking up,

Time of day 6 am to 10 am
am to 10 am or 6 am to 10 am

All readings during 2 h after 2 or 3 readings during 1 h 2 or 3 readings from 6 am

BP readings
waking up after waking up to 10 am

Criteria for morning

≥135/85 mm Hg ≥135/85 mm Hg ≥140/90 mm Hg
hypertension

Diagnosis
Clinical usefulness Diagnosis Screening

Abbreviation; BP, blood pressure

J Clin Hypertens. 2018;20:39・4.

Pharmacologic treatment and
MBPS
• Is there any benefit in reducing the morning BP surge
independent of a reduction in 24-h BP?

• Which class of antihypertensives is best for reducing the

morning BP surge and its related CV risk?

The effects of BP-lowering treatment in the morning hours

have two distinct aspects:

• the need for adequate control of BP levels in the morning

• the impact of treatment on the dynamic BP change, that

is, MBPS
J Clin Hypertens. 2018;20:39・4.
 Several factors might be involved in
the determination
of the effects of specific drugs on MBPS

´ Duration of BP-lowering action

´ Relationship between BP level and variability

´ Drug intake timing

´ Pharmacodynamic aspects
Treatment of Morning Hypertension

• Principle, a long-acting antihypertensive drug whose effect lasts for

24 hours is used in appropriate

• Therapy is aimed at reducing the ME average to less than 135 mmHg

(systolic pressure). Typical drugs used in this therapy include long-
acting calcium antagonists and diuretics.

• When the ME difference exceeds 15–20 mmHg after actual

prescription, dosing in both the morning and evening (or at bedtime)
may be more useful.

JMAJ, May 2015 —Vol. 48, No. 5

The importance of long-acting anti-hypertensives

Allow continuity of anti-

hypertensive action1

Improve anti-
hypertensive therapy Greater smooth and
sustained BP control3,5
adherence2
Long-acting
anti-
hypertensives

“…long-acting CCBs may be a

Lower CV risk4
preferable treatment in reducing
BPV measures”6

1. Osterberg, LG et al. Clin Pharmacol Ther. 2010;88:457-9.

2. Grigoryan L, et al. J Clin Hypertens 2013:15;107-11.
3. Mancia G, Parati G. Blood Press 2001:10(Suppl. 3)26-32.
4. Alderman MH et al. Lancet.1997;349:594-8.
5. Parati G et al. J Hypertens. 2014;32:1326-33.
6. Eguchi K. Curr Hypertens Rep. 2016;18:75.
27
Commonly used oral antihypertensive drugs

Biological Daily dose, No. of

Class and drug
half-life, h mg doses per d
Β-Blockers
Atenolol 7 25-100 1
Bisoprolol 12 2.5–100 1
Metoprolol 3-7 50-200 1 or 2
Dihydropyridine calcium channel blocker
Amlodipine 30-55 2.5-10 1
Felodipine ER 11-17 1.5-10 1
Lacidipine 13-19 2-4 1
Lercanidipine 8-10 10-20 1
Nifedipine GITS 2 20-80 1
Nitrendipine 8-24 10-40 1 or 2
Thiazide diuretic
Chlorthalidone 40 25-50 1
Hydrochlorothiazide 5.6-14.8 12.5-50 1 or 2
Indapamide 14-18 1.25-5 1
J Clin Hypertens. 2018;20:39・4.
Commonly used oral antihypertensive drugs

Biological Daily dose, No. of

Class and drug
half-life, h mg doses per d
Angiotensin-converting enzyme inhibitor
Benazepril 11 10–40 1 or 2
Captopril 1.9 50–150 2
Enalapril 11 2.5–40 1 or 2
Lisinopril 12 10 – 40 1
Perindopril 17 2–8 1
Ramipril 4 2.5 – 20 1 or 2
Angiotensin receptor blocker
Candesartan 9 4 – 32 1
Irbesartan 15 75–300 1
Losartan 2 25 – 100 1 or 2
Olmesartan 13 10 – 40 1
Telmisartan 24 20 – 80 1
Valsartan 6 80 - 320 1

J Clin Hypertens. 2018;20:39・4

 Study Year Design Study population Study medication (mg/day) Results
Acelajado 2012 Crossover 42 nondiabetic, Morning vs. evening dosing of No significant reduction in trough MBPS between
et al,70 hypertensive patients nebivolol 5–10 mg morning and evening nebivolol administration
Studies (−7.54±18.23 mmHg for AM nebivolol vs.
−11.08±31.41 mmHg for PM nebivolol, P=0.5)

evaluating the Rosito et al,46 1997 Crossover 12 patients with

mild to moderate
Verapamil 240–480 mg vs. placebo
once-daily morning dose
Significant reduction in MBPS with verapamil
compared to placebo (MBPS 9.5±3.3 mmHg on

effects of Denardo 2015 Parallel group

hypertension
117 patients with Verapamil 180–360 mg (n=63) vs.
treatment vs. 19.7±3.6 mmHg on placebo, P<0.04)
No significant difference in the size of MBPS

pharmacologic et al,71 hypertension and

coronary artery
atenolol 50–100 mg (n=54) between the two treatments

treatment on
disease
Eguchi et al,72 2003 Crossover 61 essential Candesartan (4–12 mg) vs. lisinopril Significantly greater decrease in MBPS with
hypertensive patients (10–20 mg) once-daily morning dose candesartan than with lisinopril (P<0.05) in
MBPS Eguchi et al,66 2004 Parallel group 76 hypertensive Valsartan 40–160 mg (n=38) vs.
subjects with large MBPS at baseline
The reduction in terms of MBPS was significantly
patients amlodipine 2.5–10 mg (n=38) once- greater in amlodipine group than in valsartan
daily dose group (−6.1 vs. + 4.5 mmHg, P<0.02)
Kwon et al,73 2013 Parallel group 77 hypertensive Amlodipine 5–10 mg (n=39) vs. Significant reduction of relative preawake MS
patients with acute losartan 50–100 mg (n=38) once- in amlodipine group vs. losartan group (2.13 vs.
stroke daily dose −3.68, P=0.03)
Mizuno et al,74 2016 Parallel group 105 elderly essential Aliskiren/amlodipine 150–300/5 mg Aliskiren/amlodipine was significantly less effective
hypertensive patients (n=53) vs. high-dose amlodipine 10 in reducing early morning SBP (P=0.002) and
mg (n=52) MBPS (P=0.001) than high-dose amlodipine
Kasiakogias 2015 Crossover 41 patients with Valsartan 160 mg or with a fixed No significant differences in MBPS change with
et al,76 hypertension and combination of amlodipine (5/160 morning or evening dosing (P=0.24)
never treated OSA or 10/160 or 10/320 mg) in a single
morning dose vs. the same regimen
in a single evening dose
Zappe et al,77 2015 Crossover 1093 hypertensive Valsartan 160–320 mg (n=330) AM No significant difference across the three
patients vs. PM vs. lisinopril 20–40 mg AM treatment groups in terms of early morning BP
(n=327) and MBPS
Rakugi et al,78 2014 Parallel group 147 hypertensive Candesartan 8–12 mg (n=71) vs. Significant reduction of sleep-trough surge (−9.3
patients with baseline azilsartan 20–40 mg (n=76) once vs. −4.4 mmHg, P=0.04) and of prewaking surge
MBPS daily (−5.7 vs. +0.1 mmHg, P=0.02) in patients with
large MBPS treated with azilsartan compared with
candesartan
 Amlodipine for Lowering BPV: vs. ARB, Candesartan, or
Thiazide Indapamide (X-CELLENT Study)

Placebo Candesartan Indapamide SR Amlodipine

18
16

Systolic BPV (mmHg)

P = 0.04 P = 0.03
14 P = 0.01
* * * *
12 * P = 0.08
10 *
8
6
4
2
0
Daytime Nighttime Daily average real
variability
BPV after 3-months treatment *P<0.05 vs. placebo

X-CELLENT trial findings

• Amlodipine reduced systolic BPV daytime, night-time, and 24-h variability
• Indapamide reduced systolic BPV daytime and 24-h variability

Zhang Y et al. Hypertension. 2011;58:155-60.

31
Amlodipine versus valsartan: effect on ambulatory
BP and morning surge
Clinic 24-h Morning surge
10 A prospective randomised
+4,5 open-label study comparing
Difference in systolic BP (mmHg) the effects of once-daily
0 morning administration of
amlodipine (long-acting
-7 -6,1 CCB) with valsartan (long-
-10
p=0.02 acting ARB) on ambulatory
-13
-14
BP in 76 Japanese patients
-20
p=0.008 with hypertension

-26 Amlodipine Valsartan

-30 p=0.001 (n=38) (n=38)

Amlodipine had a significantly stronger antihypertensive effect than valsartan on

all BP parameters including 24-h ambulatory BP and morning BP surge

ARB, angiotensin receptor blocker; CCB, calcium channel blocker

1. Eguchi K, et al. Am J Hypertens. 2004;17:112-7. 32
32
Amlodipine vs nifedipine effect on morning BP surge

An open crossover trial to

compare the effects of
amlodipine (5 to 10 mg/day)
and nifedipine [30 to 60
mg/day], in 40 patients with
mild to moderate essential
hypertension

Amlodipine had greater efficacy than nifedipine GITS in reducing morning

BP

GITS, gastrointestinal therapeutic system

1. Ferrucci A et al. Clin. Drug Invest 1997;13(Suppl 1):67-72. 33
33
 Amlodipine reduces the risk of stroke and
myocardial infarction

Reduced stroke risk Reduced myocardial

by 37% infarction risk by 29%
CI, confidence interval; SD, standard deviation.
34
Wang JG, et al. Hypertension 2007;50:181-188.
 Efficacy of an Amlodipine-Based Regimen for Reducing CV
Risk in Older and Younger Patients (ASCOT)

• An amlodipine-based regimen reduced the relative risk of CV events more

effectively than an atenolol-based regimen in both older and younger patients
• However, as the event rates were higher in older patients, the absolute
benefits were greater for older vs. younger patients

Total CV events and procedures CV mortality Fatal and non-fatal strokes

P=0.42
Risk reduction (%)

9%
P<0.01 P<0.01
15%
17% P<0.01 P=0.05
23% 24%

P<0.01

≥65 years old, n=8137 30%

<65 years old, n=11020

P-value: vs. atenolol-based regimen

Collier DJ et al. J Hypertens. 2011;29:583-91. 35

 Titration of amlodipine is not associated with
36 increased incidence of peripheral edema

• Some practitioners in Asia are reluctant to prescribe a higher dose of amlodipine due to concerns about an
increased incidence of peripheral edema1

Study Outcome of amlodipine titration from 5 to Incidence of peripheral edema

10 mg
Kario K, et al, 20131 Significantly decreased both SBP and DBP - 11 out of 174 patients (6.3%)
- No subsequent treatment discontinuations

Uno H, et al, 20082 Achieved greater reduction in morning and - Not observed
evening BP - Total of 37 patients

Chung JW, et al, Comparably to losartan plus - One patient with lower extremity edema
20093 hydrochlorothiazide - Not considered agent-related
- Total of 64 patients

BP, blood pressure; DBP, diastolic BP; SBP, systolic BP.

1. Kario K, et al. Vasc Health Risk Manag 2013;9:695-701. 2. Uno H, et al. Hypertens Res 2008;31:887-896. 3. Chung JW, et al. Korean Circ J 2009;39:151-156.
Take Home Massage

´ For more effective prevention of cardiovascular diseases, the use of a

chronobiological approach that targets morning hypertension and
employs home BP monitoring is recommended in addition to standard
antihypertensive treatment according to current guidelines.
´ Morning Blood Pressure Surge, as part of Blood Pressure Variability, need to
be considered in physician’s decision process in deciding process of
hypertension management
´ The key element in controlling MBPS is the use of long-acting drugs, which
provide effective coverage BP in the morning hours
´ Amlodipine, a calcium channel blocker, is an recommended as first line
therapy for hypertension and has proven efficacy in managing BPV and
MBPS
THANK YOU