Early morning BP surge

Morning surge in blood pressure in
hypertension- clinical
relevance, prognostic significance
and therapeutic approach
Dr. Mohammed Sadiq Azam M.D.
Assistant Professor of Medicine
Department of Medicine
Deccan College of Medical Sciences, Hyderabad

Definition
• Dippers : Subjects experiencing physiological nocturnal BP drop during sleep. BP

drop achieved is more than 10% of the BP values obtained during the awake
period.
• Extreme Dippers: Subjects experiencing exaggerated nocturnal BP drop i.e., more
than 20% of the BP values obtained during the awake period.
• Non Dippers: Subjects with a blunted nocturnal drop, i.e., less than 10% drop.
• Risers : Subjects who register higher BP values during the night than the daytime.
• MBPS: Rise in systolic BP (≥ 50mmHg) and/ or diastolic BP (≥ 22mmHg) during the
early morning (06:00 –10:00) compared with the mean BP during the night [ Def.
based on study by Gosse et al.](Gosse P . Lasserre R, Minifie C et al –2004. J Hypertens 22:1113--1118

)

Factors Influencing Dipping
Status
• Physical activity during day
• Sleep duration and quality
• Ethnicity
• Sympathetic nervous system
• Glucocorticoids
• Sodium/volume factors
• Renal disease
• Diabetes

Evidence based support
Sl.
no

Name of study / study group

Duration

Subjects involved

1

Jichi Medical University School of Medicine—
ambulatory blood pressure monitoring
(JMS-ABPM)(2003)

6 mnths—1 year

519

2

Gosse et al.( 2004)

1 year

507

3

Ohasama study (2006)

10 year

1430

4

Dublin out come study (2008)

5year 3 months

11,291

5

Amici A, cicconetti P. Sagrafoli C et al (2009)

5years

42

6

LI et al.—( International Database on Ambulatory
Blood Pressure in Relation to Cardiovascular
Outcome-- IDACO) (2010)

unknown

5645

7

Iqbal P, Stevenson L (2011)

1—2 years

1187

8

Israel S et al (2011)

unknown

2627

Figure 1. Definition of morning surge in BP.

Kario K. Hypertension 2010;56:765-773

Copyright © American Heart Association

Figure 2. Risk factors and target organ damage associated with morning surge in BP. The
corresponding reference numbers are shown as superscripts.



Figure 3. Reproducibility of morning surge in BP and cardiovascular risk.



Figure 4. Definition of morning BP surge reactivity.



MORNING vs EVENING BP
Morning bp predicts CV outcomes better than others

Issues
1.
2.
3.
4.

Diurnal rhythm of blood pressure
Diurnal rhythm of CV events
Duration of action of drugs
Effects of drugs on diurnal rhythm of blood
pressure
5. Effects of timing of administration of drugs

Issues
1.
2.
3.
4.

Diurnal rhythm of blood pressure
Diurnal rhythm of CV events
Duration of action of drugs
Effects of drugs on diurnal rhythm of
blood pressure
5. Effects of timing of administration of
drugs

What is the True Blood Pressure?
Daytime BP?

Dipping Pattern?Nighttime
BP?
Morning
Surge?

24 Hr
Average
BP?

Clinic BP?

Variability of
BP?
Home BP?

Ambulatory BP Differences for
Normotensives, and Mild and
Established HTN Patients
120110-

Diastolic 10090Blood
Pressure 80-

(mm Hg)

Mild hypertensives

70-

Normotensives

60-

0Clinic

Work

Home

Sleep

Clinical situations in which the normal
diurnal rhythm of BP may be
lost
Autonomic Dysfunction Syndromes
Diabetes Mellitus
Renal Failure
Secondary forms of hypertension e.g. Cushing’s disease
Drugs, e.g. cyclosporine
African-American ethnicity

Nocturnal BP Changes and CV
Mortality: Ohasama study
(Ohkubo et al; AJH 1997; 10: 1201)
4

3.69

3.5
3
Risk of CV
Mortality

2.56

2.5
2
1.5
1

0.96

1

0.5
0

Extreme
dippers

Dippers

Nondippers

Risers

Circadian Rhythm of Ischemic &
Hemorrhagic Strokes
Gallerani et al, Acta Neurol Scand 1993; 87: 482)
45
40
35
% of
strokes

Ischemic
Hemorrhagic

30
25
20
15
10
5
0

1-6

6 -12

12-18

18-24

Hour of day

Analysis of The Influence of the Morning
Surge of BP on Stroke Incidence
(Kario,
Pickering et al, Circ 2003; 107:1401))

Cox regression analysis for clinical stroke events
Covariates
Age (10 yrs)
Male gender
BMI
24 hr SBP
Morning BP surge*
Nocturnal BP fall*
Lowest sleep BP
* per 10 mmHg

RR
1.80 (1.21-2.69)
1.42 (0.76-2.67)
0.98 (0.90-1.07)
1.37 (1.16-1.63
1.29 (1.10-1.51)
0.88 (0.73-1.06)
1.05 (0.65-1.71)

P value
0.004
0.266
0.663
0.003
0.001
0.167
0.837

Efficacy: ARB(telmisartan) vs CCB (amlodipine)
using 24-h ABPM
Placebo (n=58)

Week 12, SBP

Telmisartan (40-120 mg) (n=62)
Amlodipine (5-10 mg) (n=65)

BP (mm Hg)
160

140

120

100

0
0800

1200

1600

2000

Time

2400

0400

0800

Lacourcière Y et al, in press

Do different drug classes have
different effects on Daytime vs.
Night time BP?

Meta-Analysis of Effects of Antihypertensive Drug
Classes on Daytime & Nighttime BP
Weiner, Rieckmann, & Pickering, 2005

• Medline search of trials in which effects of antihypertensive drugs
on daytime, nighttime, and 24 hr BP were described
• 55 trials satisfied criteria, & were grouped into 3 classes:
ACEI, ARBs, Beta blockers (n=10), CCBs & Diuretics (n=35), and
combinations (n=10).
• Across all studies, the absolute change of daytime BP (14/8 mmHg)
was significantly greater than the change of nighttime BP (12.5/4.5
mmHg, p<0.01).
• The magnitude of the difference between the daytime & nighttime
changes did not differ between the groups (p>0.7).

Meta-Analysis of Effects of Antihypertensive Drug
Classes on Daytime & Nighttime BP

ARB+D
ACEI+D
D
ARB

Night
Day

ACEI
CCB-nonDHP
CCB-DHP
0

5

10

15

20

Change of SBP with Treatment mmHg

25

Meta-Analysis of Effects of Antihypertensive Drug Classes
on Daytime & Nighttime BP

ACEI, ARBs
40

CCBs, Diuretics

Day: B=.07 (p=0.53)
Night: B=.04 (p=0.63)

40

35

35

30
BP
Change 25
mmHg 20

30

15

15

10

10

5

Day: B=.55 (p<0.001)
Night: B=.55 (p<0.001)

5

0
100

25
20

120

140

160

180

0
200 100

DAY

120

140

NIGHT

Baseline Systolic BP mmHg

160

180

200

Are there class differences in
thresholds for lowering BP? (Sekino
et al, J Hum Hypertens 1998: 12: 719)

Drug

Amlodipine
Bisoprolol
Lisinopril
Combination1

Average Effect
on BP Level
CBP
ABP
-20
-15
-19
-12
-20
-19
-20
-14

Threshold BP*
Daytime Nighttime
127
106
124
110
97
108
128
106

* Estimated from regression line of baseline BP versus
change
1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648

Diuretics Convert Non-Dippers to
Dippers (Uzu & Kimura Circ 1999; 100:1635)
150

Day
Night

140
Systolic
pressure
mmHg

130
120
110
100

No Rx
Dippers

HCTZ

No Rx

HCTZ

Non-Dippers

Regression of Carotid Atherosclerosis by
Controlling Morning BP
(Marfella et al, Am J Hypertens 2005: 18: 308)
Clinic

Day

Night

Morning

0

Carotid IMT
0

SBP -5
mm
Hg -10

0

IMT
mm-0.01
NS

-15

-0.02
0.02

NS
-20

-0.03

-25
-30

NS

Metoprolol
Carvedilol

<0.02
<0.001

-0.04
-0.04

Effects of Alpha-Blockade on the Morning
Surge of Blood Pressure
(Kario,
Pickering, et al Am J Hypertens 2004;17; 668)

No Rx

Doxazosin

Effects of graded
release Diltiazem vs.
Enalapril on Morning
BP
(White et al, Am Heart J
2004: 148: 628)

Ramipril
Diltiazem ER

Effects of Time of Administration of
ARB(Valsartan )on Diurnal Changes of BP
(Hermida et al Hypertens 2003: 42:283)

0
-2
Change
of SBP -4

mmHg

Day

Night

24 hour

-6
-8
-10
-12

Awakening
Bedtime

-14
-16
-18
-20

P=0.041

P=0.402

P=0.174

Daytime BP Reduction
mmHg
160

p<0.001

p<0.001

p<0.001

N.S.

150

Blood pressure level

140
130
120

8/7

7/7

10 / 8

11 / 8

110
100
90
80

n = 18
Extreme
dippers

n = 46
Dippers

n = 48
Non-dippers

n=6
Risers

Nighttime BP Reduction
mmHg
160

p<0.01
N.S.

N.S.

p<0.001

150
140
Blood pressure level

130
120
12 / 9

110

18 /12

1/2

100
4/2
90
80
70
60

n = 18
Extreme
dippers

n = 46
Dippers

n = 48
Non-dippers

n=6
Reverse
dippers

Effects of Time of Administration of CCBs
on Diurnal Changes of BP
(Lemmer BPM 1996: 1;169)

Drug
Amlodipine (1)
Isradipine (2)
Nifedipine GITS (3)
Nitrendipine (4)

Dose
Time
AM
PM
AM
PM
AM
PM
AM
PM

Day

Effect on BP
Night
24 hr Pattern
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged
Unchanged

1. Mengden J Hypertens 1992:10 (supp 4); S136 2. Fogari Br J Clin Pharm 1993:
35:51
3. Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp);
R141
4. Meilhac Therapie 1992: 47: 205

Effects of Time of Administration of
ACEIs on Diurnal Changes of BP
(Lemmer BPM 1996: 1;169)

Drug
Benazepril (1)
Enalapril (2)
Quinapril (3)

Dose
Time
AM
PM
AM
PM
AM
PM

Day

Effect on BP
Night
24 hr Pattern
Nearly Unchanged
Changed
Nearly Unchanged
Changed
Nearly Unchanged
Changed

1. Palatini Int J Clin Pharm Ther Toxicol 1993:31:295 2. Witte Clin Pharm Ther
1993: 54:177
3. Paltini Clin Pharm Ther 1992; 52: 378

Anti-HTN strategy targeting MBPS
and morning HTN
 Strict BP control <130/80
 Adequate circardian rhythm
 Suppression of elevated MBPS

How to achieve
• Anti Hypertensives that decrease the pressor effects of
neurohumoral factors (which are potentiated in the morning)
like the sympathetic activity inhibitors.

• In particular bedtime dosing ---- more extensive BP lowering
effect in the morning.( Kario K. Pickering TG, Hoshide et al – 2004. Am J
Hypertens 17:668--675)

Supportive studies:
• JMS-1 ( Japan Morning Surge-1) study: (611 subjects)
-

Demonstrated that bed time dosing of alpha blocker( doxazosin) along with base
line anti-HTN medication reduced morning BP and albuminuria.

Kario K, Matsui Y, Shibasaki S et al. 2008. J Hypertens 26:1257-1265

• J-TOP ( Japan Morning Surge-Target organ
Protection) study: (450 subjects)
-

Demonstrated bed time dosing of an ARB may be more effective in in reducing
albuminuria as it may more potently suppress tissue RAS during the sleep –early
morning period than awakening dosing .

Kario K (2010) Atlas medical publishing of Oxford, Oxford. Pp 27—38

• MAPEC ( Monitorizacion Ambulatoria para
Prediccion de Eventos Cardiovasculares)
study : ( 2156 subjects)
-

Subjects ingesting one or more anti -hypertensive drugs at bed time
exibited a significantly lower relative risk of total cardiovascular events
than those ingesting all medications on awakening.

Hermida RC , Ayala DE, Mojon A, Fernandez JR (2010). Chronobiol Int 27:1629—1651 .

Conclusions: Does the Pattern of Blood Pressure
Effects During the Day Matter?
1.

2.

3.
4.
5.

There is a pronounced diurnal rhythm of BP and
cardiovascular events, with a peak of both in the morning
hours, and a decrease during the night.
In some categories of patients the normal dipping
pattern of BP is lost or reversed; this may be associated
with increased risk.
Drugs approved for once daily dose may have different
durations of action, particularly after missed doses.
Most classes of antihypertensive drugs lower daytime BP
more than nighttime BP.
The effects of CCBs may be more closely related to
baseline BP than ARBs/ACEI.

Conclusions: Does the Pattern of Blood Pressure
Effects During the Day Matter?
6. Different antihypertensive drugs may have different effects
on the morning surge of BP.
7. With some antihypertensive drugs the time of dosing may
have significant effects on the diurnal pattern of BP.
8. The implications of these time-dependent differences of
antihypertensive drugs for CV morbidity are largely
unknown, and need to be more fully investigated.
9. Implications of BP-independent effects of antihypertensive
drugs based on small differences of clinic BP may be
unwarranted.

Early morning BP surge

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