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 MedicineDeccan 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 supportSl. 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. Diurnal rhythm of blood pressure2. Diurnal rhythm of CV events3. Duration of action of drugs4. Effects of drugs on diurnal rhythm of blood

pressure5. Effects of timing of administration of drugs

Issues

1. Diurnal rhythm of blood pressure2. Diurnal rhythm of CV events3. Duration of action of drugs4. Effects of drugs on diurnal rhythm of

blood pressure5. Effects of timing of administration of

drugs

What is the True Blood Pressure?

Clinic BP?

Home BP?

24 Hr Average BP?

Daytime BP? Nighttime BP?

Dipping Pattern?

Morning Surge?

Variability of BP?

Ambulatory BP Differences for Normotensives, and Mild and

Established HTN Patients

120-110-100-

90-80-70-60-

0-

Diastolic Blood

Pressure

(mm Hg)

Clinic Work Home Sleep

Normotensives

Mild hypertensives

Established hypertensives

Clinical situations in which the normal diurnal rhythm of BP may be

lost

Autonomic Dysfunction SyndromesDiabetes MellitusRenal FailureSecondary forms of hypertension e.g. Cushing’s diseaseDrugs, e.g. cyclosporineAfrican-American ethnicity

Nocturnal BP Changes and CV Mortality: Ohasama study

(Ohkubo et al; AJH 1997; 10: 1201)

0.96 1

2.56

3.69

0

0.5

1

1.5

2

2.5

3

3.5

4

Extreme dippers

Dippers Non-dippers

Risers

Risk of CV Mortality

Issues



drugs

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

0

5

10

15

20

25

30

35

40

45

% of strokes

1-6 6 -12 12-18 18-24

Hour of day

IschemicHemorrhagic

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 eventsCovariates RR P valueAge (10 yrs) 1.80 (1.21-2.69) 0.004Male gender 1.42 (0.76-2.67) 0.266BMI 0.98 (0.90-1.07) 0.66324 hr SBP 1.37 (1.16-1.63 0.003Morning BP surge* 1.29 (1.10-1.51) 0.001Nocturnal BP fall* 0.88 (0.73-1.06) 0.167 Lowest sleep BP 1.05 (0.65-1.71) 0.837* per 10 mmHg

Issues



drugs

Efficacy: ARB(telmisartan) vs CCB (amlodipine)using 24-h ABPM

Placebo (n=58)

Amlodipine (5-10 mg) (n=65)

Telmisartan (40-120 mg) (n=62)

0800 1200 1600 2000 2400 04000800

BP (mm Hg)

Lacourcière Y et al, in press

160

140

120

100

0

Time

Week 12, SBP

Issues



drugs

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).



0 5 10 15 20 25

CCB-DHP

CCB-nonDHP

ACEI

ARB

D

ACEI+D

ARB+D

NightDay

Change of SBP with Treatment mmHg

0

5

10

15

20

25

30

35

40

100 120 140 160 180 2000

5

10

15

20

25

30

35

40

100 120 140 160 180 200

DAY NIGHT

Baseline Systolic BP mmHg

BP Change mmHg

ACEI, ARBs CCBs, Diuretics



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

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

Are there class differences in thresholds for lowering BP? (Sekino

et al, J Hum Hypertens 1998: 12: 719)

Drug Average Effect Threshold BP* on BP Level

CBP ABP Daytime NighttimeAmlodipine -20 -15 127 106Bisoprolol -19 -12 124 110Lisinopril -20 -19 97 108Combination1 -20 -14 128 106

* 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)

100

110

120

130

140

150

Systolic pressure mmHg

Day

Night

No Rx HCTZ No Rx HCTZ

Dippers Non-Dippers

Regression of Carotid Atherosclerosis by Controlling Morning BP

(Marfella et al, Am J Hypertens 2005: 18: 308)

-30

-25

-20

-15

-10

-5

0

MetoprololCarvedilol

-0.04

-0.03

-0.02

-0.01

0

Clinic Day Night Morning Carotid IMT

0

-0.02

-0.04

NS

NSNS

<0.001<0.02

SBP mmHg

IMT mm

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

Doxazosin

No Rx

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

Ramipril

Diltiazem ER

Issues



drugs

Effects of Time of Administration of ARB(Valsartan )on Diurnal Changes of BP

(Hermida et al Hypertens 2003: 42:283)

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0Day Night 24 hour

AwakeningBedtime

P=0.041 P=0.402 P=0.174

Change of SBP mmHg

80

100

90

110

120

130

140

150

160

Extremedippers

Dippers Non-dippers Risers

Daytime BP Reduction

8 / 7 7 / 7 11 / 810 / 8

p<0.001 p<0.001p<0.001 N.S.

n = 18 n = 46 n = 48 n = 6

mmHg

Blo

od

pre

ssu

re l

evel

60

70

80

90

100

110

120

130

140

150

160

Extremedippers

Dippers Non-dippers Reversedippers

Nighttime BP Reduction

4 / 2

1 / 218 /1212 / 9

N.S. p<0.001N.S.p<0.01

n = 18 n = 46 n = 48 n = 6

mmHg

Blo

od

pre

ssu

re l

evel

Effects of Time of Administration of CCBs on Diurnal Changes of BP

(Lemmer BPM 1996: 1;169)

Drug Dose Effect on BP Time Day Night 24 hr PatternAmlodipine (1) AM Unchanged

PM Unchanged Isradipine (2) AM Unchanged PM Unchanged Nifedipine GITS (3) AM Unchanged

PM Unchanged Nitrendipine (4) AM Unchanged

PM 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 Dose Effect on BP Time Day Night 24 hr PatternBenazepril (1) AM Nearly Unchanged

PM Changed Enalapril (2) AM Nearly Unchanged

PM Changed Quinapril (3) AM Nearly Unchanged

PM 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. 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.

2. In some categories of patients the normal dipping pattern of BP is lost or reversed; this may be associated with increased risk.

3. Drugs approved for once daily dose may have different durations of action, particularly after missed doses.

4. Most classes of antihypertensive drugs lower daytime BP more than nighttime BP.

5. 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.

Thank You

early morning bp surge

Health & Medicine

morning surge of bp

normal diurnal rhythm

diastolic bp

daytime bp

drugs effects of drugs

clinic bp

systolic bp

nighttime bp