does the pattern of blood pressure effects during the day matter? thomas pickering md, dphil...
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![Page 1: Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program](https://reader035.vdocuments.site/reader035/viewer/2022081516/56649d845503460f94a6ac11/html5/thumbnails/1.jpg)
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
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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
![Page 3: Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program](https://reader035.vdocuments.site/reader035/viewer/2022081516/56649d845503460f94a6ac11/html5/thumbnails/3.jpg)
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
![Page 4: Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program](https://reader035.vdocuments.site/reader035/viewer/2022081516/56649d845503460f94a6ac11/html5/thumbnails/4.jpg)
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?
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure
(Mancia et al AJC 1999: 84; 28S)
Missed Dose
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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
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Do different drug classes have different effects on Daytime vs.
Nighttime BP?
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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).
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Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP
Weiner, Rieckmann, & Pickering, 2005
0 5 10 15 20 25
CCB-DHP
CCB-nonDHP
ACEI
ARB
D
ACEI+D
ARB+D
NightDay
Change of SBP with Treatment mmHg
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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
Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP
Weiner, Rieckmann, & Pickering, 2005
Day: B=.07 (p=0.53)Night: B=.04 (p=0.63)
Day: B=.55 (p<0.001)Night: B=.55 (p<0.001)
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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
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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
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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
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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
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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
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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?
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Effects of Alpha-Blockade on the Morning Surge of Blood Pressure
(Kario, Pickering, et al Am J Hypertens 2004;17; 668)
Doxazosin
No Rx
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Effects of graded release Diltiazem vs. Enalapril on Morning BP (White et al, Am Heart J 2004: 148: 628)
Ramipril
Diltiazem ER
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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
![Page 29: Does the Pattern of Blood Pressure Effects During the Day Matter? Thomas Pickering MD, DPhil Behavioral Cardiovascular Health and Hypertension Program](https://reader035.vdocuments.site/reader035/viewer/2022081516/56649d845503460f94a6ac11/html5/thumbnails/29.jpg)
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
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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.”
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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.
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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.
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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
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-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)
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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Factors Influencing Dipping Status
• Physical activity during day
• Sleep duration and quality
• Ethnicity
• Sympathetic nervous system
• Glucocorticoids
• Sodium/volume factors
• Renal disease
• Diabetes