1. Does the Pattern of Blood Pressure Effects During the Day Matter?
Thomas Pickering MD, DPhil
Behavioral Cardiovascular Health and Hypertension Program
Division of General Medicine
Columbia Presbyterian Medical Center
New York

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

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

4. 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?

5. Diastolic Blood Pressure
Ambulatory BP Differences for Normotensives, and Mild and Established HTN Patients
120-
110-
100-
90-
80-
70-
60- 0-
Diastolic Blood Pressure
(mm Hg)
Established hypertensives
Mild hypertensives
Normotensives
Clinic
Work
Home
Sleep

6. 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

7. Nocturnal BP Changes and CV Mortality: Ohasama study (Ohkubo et al; AJH 1997; 10: 1201)
Risk of CV Mortality
Non-dippers
Dippers
Risers
Extreme dippers

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

9. Morning Peak of VT Detected by Implanted Cardioverter/Defibrillator (Tofler Circ 1995;92: 1203)
Episodes of VT

10. Circadian Rhythm of Ischemic & Hemorrhagic Strokes Gallerani et al, Acta Neurol Scand 1993; 87: 482)
% of strokes
Hemorrhagic
Hour of day

11. 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 RR P value
Age (10 yrs) ( ) 0.004
Male gender ( ) 0.266
BMI ( ) 0.663
24 hr SBP (
SCI ( )
Morning BP surge* ( ) 0.001
Nocturnal BP fall* ( ) 0.167
Lowest sleep BP ( ) 0.837
* per 10 mmHg

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

13. Efficacy: telmisartan vs amlodipine using 24-h ABPM
Placebo (n=58)
Week 12, SBP
Telmisartan ( mg) (n=62)
BP (mm Hg)
160
Amlodipine (5-10 mg) (n=65)
140
120
100
Time
Lacourcière Y et al, in press

14. Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour Blood Pressure (Mancia et al AJC 1999: 84; 28S)
Missed Dose

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

16. Do different drug classes have different effects on Daytime vs
Do different drug classes have different effects on Daytime vs. Nighttime BP?

17. 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).

18. Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP Weiner, Rieckmann, & Pickering, 2005
Change of SBP with Treatment mmHg

19. ACEI, ARBs CCBs, Diuretics
Meta-Analysis of Effects of Antihypertensive Drug Classes on Daytime & Nighttime BP
Weiner, Rieckmann, & Pickering, 2005
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)
BP Change mmHg
DAY
NIGHT
Baseline Systolic BP mmHg

20. Are there class differences in thresholds for lowering BP
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
Amlodipine
Bisoprolol
Lisinopril
* Estimated from regression line of baseline BP versus change

21. Are there class differences in thresholds for lowering BP
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
Amlodipine
Bisoprolol
Lisinopril
Combination
* Estimated from regression line of baseline BP versus change
1- ACEI + CCB- Fagard et al Am J Hypertens 1993: 6: 648

22. Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635)
Day
Night
Systolic pressure mmHg
No Rx HCTZ No Rx HCTZ
Dippers Non-Dippers

23. Diuretics Convert Non-Dippers to Dippers (Uzu & Kimura Circ 1999; 100:1635)
Day
Night
Systolic pressure mmHg
No Rx HCTZ No Rx HCTZ
Dippers Non-Dippers

24. Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308)
Clinic Day Night Morning Carotid IMT
SBP mmHg
IMT mm NS
-0.02 NS NS
<0.02
<0.001
-0.04

25. Regression of Carotid Atherosclerosis by Controlling Morning BP (Marfella et al, Am J Hypertens 2005: 18: 308)
Clinic Day Night Morning Carotid IMT
SBP mmHg
IMT mm ? NS
-0.02 NS NS
<0.02
<0.001
-0.04

26. Effects of Alpha-Blockade on the Morning Surge of Blood Pressure (Kario, Pickering, et al Am J Hypertens 2004;17; 668)
No Rx
Doxazosin

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

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

29. Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283)
Change of SBP mmHg
P= P= P=0.174

30. Effects of Time of Administration of Valsartan on Diurnal Changes of BP (Hermida et al Hypertens 2003: 42:283)
Change of SBP mmHg
“Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day.”
P= P= P=0.174

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

34. 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.

35. Duration of Action by Trough:Peak Ratio
Placebo
Blood Pressure Change mmHg
Trough
Peak
Drug
0 Hours after dosing

36. Trough:Peak Ratio vs Smoothness Index for defining drug effects on 24 hour BP (Omboni et al BPM, 1998; 3:201)
Trough
Trough:peak ratio
Change of systolic pressure mmHg
Peak
Smoothness Index: mean change/SD
Hours since drug dosing

37. Prognostic Significance of Non-Dipping (Verdecchia et al, BPM 1996; 1 (Suppl 2) ;S81)
1522 subjects followed for 4.2 years after ABPM
Covariate Relative Risk
Men Women
Age>
Diabetes
24 hr SBP>median
Non-dipper

38. 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
Herpin
Kristensen
Ashida et al AJC 1990: 66: 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

39. 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
Herpin
Kristensen NA NA NA NA
Ashida et al AJC 1990: 66: 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

40. Daytime BP Reduction mmHg 160 150 140 130 Blood pressure level 8 / 7
N.S.
160
150
140
130
Blood pressure level
8 / 7
7 / 7
10 / 8
120
11 / 8
110
100 90
n = 18
n = 46
n = 48
n = 6 80
Extreme
dippers
Dippers
Non-dippers
Risers

41. Nighttime BP Reduction
mmHg
p<0.01 60 70 80 90
100
110
120
130
140
150
160
N.S.
N.S.
p<0.001
Blood pressure level
12 / 9
18 /12
1 / 2
4 / 2
n = 18
n = 46
n = 48
n = 6
Extreme
dippers
Dippers
Non-dippers
Reverse
dippers

42. Effect of Doxazosin on Daytime and Nighttime BPs
Daytime BP
Nighttime BP
Y = X
r = .44, p<.0001
Y = X
r = .45, p<.0001
-50
-40
-30
-20
-10 10 20 30 40 50
n=118
SBP change (mmHg) 90
100
110
120
130
140
150
160
170
180
190
200
Baseline SBP (mmHg)
Kario, Schwartz, Pickering, Hypertension 2000; 35:

43. 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 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); S Fogari Br J Clin Pharm 1993: 35: Lemmer Naunyn- Schmiederberg Arch Pharm 1994; 349(supp); R Meilhac Therapie 1992: 47: 205

44. 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 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: Witte Clin Pharm Ther 1993: 54: Paltini Clin Pharm Ther 1992; 52: 378

45. Effects of Time of Administration of Trandolapril on Diurnal Changes of BP (Poirier J Clin Pharm 1993: 33:832)
Change of SBP mmHg

46. Question: If you were allowed just one reading over 24 hours to predict CV morbidity, which would you choose?
Going to bed
Arising
Awake
Sleep
Awake
Morning BP
Evening BP
Preawake BP
Lowest BP
Gosse et al, J Hum Hypertens 2001; 15: 413

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