Does the Pattern of Blood Pressure Effects During the Day Matter

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?
Nighttime BP?
Dipping Pattern?
Morning Surge?
24 Hr Average BP?
Clinic BP?
Variability of BP?
Home BP?
5
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. Cushings
  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)
Risk of CV Mortality
Non-dippers
Dippers
Risers
Extreme dippers
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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

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Morning Peak of VT Detected by Implanted
Cardioverter/Defibrillator (Tofler Circ
199592 1203)
Episodes of VT
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Circadian Rhythm of Ischemic Hemorrhagic
Strokes Gallerani et al, Acta Neurol Scand 1993
87 482)
Ischemic
of strokes
Hemorrhagic
1-6 6 -12 12-18
18-24
Hour of day
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Analysis of The Influence of the Morning Surge of
BP on Stroke Incidence (Kario,
Pickering et al, Circ 2003 1071401))

• Cox regression analysis for clinical stroke
  events
• Covariates 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

• 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

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Efficacy telmisartan vs amlodipineusing 24-h
ABPM
Placebo (n58)
Week 12, SBP
Telmisartan (40-120 mg) (n62)
Amlodipine (5-10 mg) (n65)
BP (mm Hg)
160
140
120
100
0
0800 1200 1600 2000 2400 0400 0800
Time
Lacourcière Y et al, in press
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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

• 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

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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 BPWeiner,
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 (n10),
  CCBs Diuretics (n35), and combinations (n10).
• 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,
  plt0.01).
• The magnitude of the difference between the
  daytime nighttime changes did not differ
  between the groups (pgt0.7).

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Meta-Analysis of Effects of Antihypertensive Drug
Classes on Daytime Nighttime BPWeiner,
Rieckmann, Pickering, 2005
Change of SBP with Treatment mmHg
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Meta-Analysis of Effects of Antihypertensive Drug
Classes on Daytime Nighttime BP
Weiner, Rieckmann, Pickering, 2005
ACEI, ARBs CCBs, Diuretics
Day B.07 (p0.53) Night B.04 (p0.63)
Day B.55 (plt0.001) Night B.55 (plt0.001)
BP Change mmHg
DAY
NIGHT
Baseline Systolic BP mmHg
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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 1001635)
Day
Night
Systolic pressure mmHg
No Rx HCTZ No Rx
HCTZ Dippers
Non-Dippers
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Diuretics Convert Non-Dippers to Dippers (Uzu
Kimura Circ 1999 1001635)
Day
Night
Systolic pressure mmHg
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)
Clinic Day Night
Morning Carotid IMT
0
SBP mmHg
IMT mm
-0.02
NS
NS
NS
lt0.02
lt0.001
-0.04
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Regression of Carotid Atherosclerosis by
Controlling Morning BP
(Marfella et al, Am J Hypertens 2005
18 308)
Clinic Day Night
Morning Carotid IMT
0
SBP mmHg
IMT mm
?
-0.02
NS
NS
NS
lt0.02
lt0.001
-0.04
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Effects of Alpha-Blockade on the Morning Surge of
Blood Pressure
(Kario, Pickering, et al Am J
Hypertens 200417 668)
No Rx
Doxazosin
27
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

• 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

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Effects of Time of Administration of Valsartan
on Diurnal Changes of BP (Hermida et al Hypertens
2003 42283)
Change of SBP mmHg
P0.041 P0.402 P0.174
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Effects of Time of Administration of Valsartan
on Diurnal Changes of BP (Hermida et al Hypertens
2003 42283)
Change of SBP mmHg
Diovan may be used over a dose range of 80 mg to
320 mg daily, administered once-a-day.
P0.041 P0.402 P0.174
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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.

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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 TroughPeak Ratio
Placebo
Blood Pressure Change mmHg
Trough
Peak
Drug
0 Hours after dosing 24
36
TroughPeak Ratio vs Smoothness Index for
defining drug effects on 24 hour BP
(Omboni et al BPM, 1998 3201)
Trough
Troughpeak ratio
Change of systolic pressure mmHg
Peak
Smoothness Index mean change/SD
Hours since drug dosing
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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
• Agegt60 7.39 2.44
• Diabetes 2.23 2.30
• 24 hr SBPgtmedian - 3.90
• Non-dipper 1.96 1.70

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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. N41 ACEI
Enalapril CCB Nifedipine SR Herpin et al AJC
1992 69 923. N236 ACEI Various CCB
Various. Kristensen et al BPM 1998 3 116.
N96 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. N41 ACEI
Enalapril CCB Nifedipine SR Herpin et al AJC
1992 69 923. N236 ACEI Various CCB
Various. Kristensen et al BPM 1998 3 116.
N96 ACEI Benazepril CCB Felodipine ER
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Daytime BP Reduction
mmHg
N.S.
160
150
140
130
8 / 7
Blood pressure level
7 / 7
10 / 8
11 / 8
120
110
100
90
n 18
n 6
n 46
n 48
80
Extreme dippers
Dippers
Non-dippers
Risers
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Nighttime BP Reduction
mmHg
plt0.01
plt0.001
N.S.
Blood pressure level
18 /12
12 / 9
1 / 2
4 / 2
n 6
n 46
n 48
n 18
Extreme dippers
Dippers
Non-dippers
Reverse dippers

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Effect of Doxazosin on Daytime and Nighttime
BPs
Nighttime BP
Daytime BP
Y 51 - .42 X r .45, plt.0001
Y 46 - .36 X r .44, plt.0001
n118
SBP change (mmHg)
Baseline SBP (mmHg)
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
1169)

• 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 199210 (supp 4) S136
2. Fogari Br J Clin Pharm 1993 3551 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
1169)

• 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
199331295 2. Witte Clin Pharm Ther 1993
54177 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 33832)
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?
Going to bed
Arising
Awake
Awake
Sleep
Morning BP
Evening BP
Preawake BP
Lowest BP
Gosse et al, J Hum Hypertens 2001 15 413
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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