Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil...

Does the Pattern of Blood Pressure Effects During the Day

Matter?

Thomas Pickering MD, DPhilBehavioral Cardiovascular Health and

Hypertension Program

Division of General Medicine

Columbia Presbyterian Medical Center

New York

Issues

1. Diurnal rhythm of blood pressure

2. Diurnal rhythm of CV events

3. Duration of action of drugs

4. Effects of drugs on diurnal rhythm of blood pressure

5. 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 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)

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






Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator

(Tofler Circ 1995;92: 1203)

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Episodes of VT

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 value

Age (10 yrs) 1.80 (1.21-2.69) 0.004

Male gender 1.42 (0.76-2.67) 0.266

BMI 0.98 (0.90-1.07) 0.663

24 hr SBP 1.37 (1.16-1.63 0.003

SCI 4.40 (1.95-10.1) 0.001

Morning BP surge* 1.29 (1.10-1.51) 0.001

Nocturnal 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






Efficacy: telmisartan vs amlodipineEfficacy: telmisartan vs amlodipineusing 24-h ABPMusing 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

Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure

(Mancia et al AJC 1999: 84; 28S)

Missed Dose

Issues






Do different drug classes have different effects on Daytime vs.

Nighttime 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 Nighttime

Nilvadipine -26 -12.5 127 110

Amlodipine -20 -15 127 106

Bisoprolol -19 -12 124 110

Lisinopril -20 -19 97 108

* Estimated from regression line of baseline BP versus change

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 Nighttime

Nilvadipine -26 -12.5 127 110

Amlodipine -20 -15 127 106

Bisoprolol -19 -12 124 110

Lisinopril -20 -19 97 108

Combination1 -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

Metoprolol

Carvedilol-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

Regression of Carotid Atherosclerosis by Controlling Morning BP

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

-30

-25

-20

-15

-10

-5

0

Metoprolol

Carvedilol-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






Effects of Time of Administration of 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

Effects of Time of Administration of 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

“Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.”

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.

Duration of Action by Trough:Peak Ratio

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

0 Hours after dosing 24

Peak

Trough

Blood Pressure Change mmHg

Placebo

Drug

-25

-20

-15

-10

-5

08 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7 8

-25

-20

-15

-10

-5

08 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7

Peak

Trough

Smoothness Index: mean change/SD

Trough:peak ratio

Change of systolic pressure mmHg

Hours since drug dosing

Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201)

Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81)

Covariate Relative Risk

Men Women

Age>60 7.39 2.44

Diabetes 2.23 2.30

24 hr SBP>median - 3.90

Non-dipper 1.96 1.70

1522 subjects followed for 4.2 years after ABPM

Effects of ACEI and CCB on Low and High Ambulatory BP in 3 Studies

Study Effect of Drug on Systolic ABP mmHg

ACEI CCB

ABP Lo ABP Hi ABP Lo ABP Hi

Ashida -7.6 -8.9 -3.8 -12.7

Herpin -7 -9 -1 -7

Kristensen -14.5 -16.6 -2.7 -10.1

Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR

Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various.

Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

Effects of ACEI and CCB on Clinic SBP in Low and High Ambulatory BP Groups in 3

Studies

Study Effect of Drug on Systolic CBP mmHg

ACEI CCB

ABP Lo ABP Hi ABP Lo ABP Hi

Ashida -6.5 -9.5 -11 -16

Herpin -13 -9 -13 -7

Kristensen NA NA NA NA

Ashida et al AJC 1990: 66: 498. N=41; ACEI = Enalapril; CCB= Nifedipine SR

Herpin et al AJC 1992: 69: 923. N=236; ACEI = Various; CCB = Various.

Kristensen et al BPM; 1998; 3: 116. N=96; ACEI = Benazepril; CCB = Felodipine ER

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 / 21 / 2

18 /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

SB

P c

han

ge

(m

mH

g)

-50

-40

-30

-20

-10

0

10

20

30

40

50

90 100 110 120 130 140 150 160 170 180 190 200

Baseline SBP (mmHg)

Y = 51 - .42 Xr = .45, p<.0001

Nighttime BPDaytime BPY = 46 - .36 Xr = .44, p<.0001

n=118

Effect of Doxazosin on Daytime and Nighttime BPs

Kario, Schwartz, Pickering, Hypertension 2000; 35: 787-94.

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 Pattern

Amlodipine (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 Pattern

Benazepril (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

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

(Poirier J Clin Pharm 1993: 33:832)

-9

-8

-7

-6

-5

-4

-3

-2

-1

0Day Night 24 hour

0.5 mg bid

1mg qd

Change of SBP mmHg

Question: If you were allowed just one reading over 24 hours to predict CV morbidity,

which would you choose?

Gosse et al, J Hum Hypertens 2001; 15: 413

Awake AwakeSleep

Going to bed Arising

Evening BP

Lowest BP

Preawake BP

Morning BP

Factors Influencing Dipping Status

• Physical activity during day

• Sleep duration and quality

• Ethnicity

• Sympathetic nervous system

• Glucocorticoids

• Sodium/volume factors

• Renal disease

• Diabetes

Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil...

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