Clinical Aspect of Clinical Aspect of Clinical Aspect of Clinical Aspect of M i Bl d M i Bl d Morning Blood Morning Blood Pressure SurgePressure Surgegg

Eung Ju Kim Eung Ju Kim

Korea University Guro Hospital Korea University Guro Hospital Cardiovascular CenterCardiovascular CenterCardiovascular CenterCardiovascular Center

Seoul, KoreaSeoul, Korea

Ci di Rh thCi di Rh thCircadian RhythmCircadian Rhythm

DailyDaily cyclescycles ofof physiologyphysiology andandbehaviorbehavior thatthat areare drivendriven byby ananendogenousendogenous oscillatoroscillator withwith aa periodperiodendogenousendogenous oscillatoroscillator withwith aa periodperiodofof approximatelyapproximately ((circacirca--)) oneone dayday((diesdies oror diemdiem))..

=

SCN, suprachiasmatic nuclueus ATVB 2007;27:1694

CV or hemodynamic parameters y psuch as HR, BP, endothelial HR, BP, endothelial , ,, ,functionfunction, and fibrinolytic activityfibrinolytic activityexhibit variations consistent with circadian rhythmcircadian rhythm.

Diurnal Variation of BPDiurnal Variation of BPDiurnal Variation of BPDiurnal Variation of BPTi f

g)

Time of awakening

Sleep180

(mm

H 160

essu

re ( 140

120

ood p

re 120

100

Blo

18:00 22:00 02:00 06:00 10:00 14:00 18:0080

Time of day

18:00 22:00 02:00 06:00 10:00 14:00 18:00

Lancet 1978;1(8068):795–797Circ Res 1983;53:96–104

EEarly arly MMorning orning BPBP SSurgeurgeEEarly arly MMorning orning BPBP SSurgeurge

MorningMorning

Untreated hypertensives Normotensives200

mH

g)

Systolic (mean+S E )150

ssure

(m

m Systolic (mean+S.E.)

100

Blo

od p

re

9 12 15 18 21 24 3 6 9 9 12 15 18 21 24 3 6 9

50 Diastolic (mean+S.E.)

9 12 15 18 21 24 3 6 9 9 12 15 18 21 24 3 6 9

Time of day (hours) Time of day (hours)

Lancet 1978;1:795–797

Various Types of BPVarious Types of BPVarious Types of BPVarious Types of BP

Daytime BP? NighttimeDippingDaytime BP? Nighttime BP?

Dipping Pattern?

Morning Surge?

Clinic BP? 24 Hr AverageAverage BP?

Home BP?

Variability of BP?

Home BP?

DefinitionDefinitionDefinitionDefinitionThereThere isis nono universallyuniversally recognizedrecognized definitiondefinition ofofThereThere isis nono universallyuniversally recognizedrecognized definitiondefinition ofofthethe morningmorning surgesurge

Kario et al. Circulation 2003;107:1401

Leary et al J HTNLeary et al. J HTN 2002;20:865

4Hr4Hr 4Hr4Hr

Morning BP SurgeMorning BP SurgeMorning BP Surge Morning BP Surge & Subclinical& Subclinical& Subclinical & Subclinical Organ DamageOrgan DamageOrgan DamageOrgan Damage

MBPS Causes TODMBPS Causes TOD

► MBPS hemodynamic stress TOD► MBPS hemodynamic stress TOD

►High MBPS more likely to have LVH►High MBPS more likely to have LVH

►BP in the morning is a better predictor than office BP►BP in the morning is a better predictor than office BPof:

– the decline in GFR

albuminuria in patients with type 1 diabetes– albuminuria in patients with type 1 diabetes

– albuminuria in patients with type 2 diabetes

11

J Hypertens 2004;22:1113–1118Clin Exp Hypertens 2002;24:249–260

Diabetes Care 2002;25:2218–2223Diabetes Care 2003;26:2473–2475

Early Morning Attenuation of Early Morning Attenuation of y gy gEndothelialEndothelial Function in Function in

H lth HH lth HHealthy HumansHealthy Humans

Circulation 2004;109:2507–2510

Morning BP Surge or Morning BP Surge or Morning BP Surge or Morning BP Surge or Reactivity and LVHReactivity and LVH

MBPR

= MBPS /

(sum of 2-h activity(sum of 2 h activity after arising)0.5

Am J Hypertens 2005;18:1528–1533

Morning BP HyperMorning BP Hyper--Reactivity Reactivity Morning BP HyperMorning BP Hyper Reactivity Reactivity and LVHand LVH

M i BP R ti itM i BP R ti itMorning BP ReactivityMorning BP Reactivity was independentlyindependently associated with

cardiac h pertrophcardiac h pertrophAm J Hypertens 2005;18:1528–1533

cardiac hypertrophycardiac hypertrophy

MMorning orning BP BP is a is a BBetter etter PPredictor redictor hh Cli iCli i ff lb i i ilb i i ithan than Clinic BPClinic BP ofof AAlbuminuria in lbuminuria in

TType 2ype 2 DMDMTType 2ype 2 DMDM

Sens 100%Sens 49%

Specificity 75%Specificity 68%

Specificity 75%

Sens 18%

Specificity 85%

Sens 43%

Specificity 73%

Threshold 135mmHg Threshold 85mmHg

Diabetes Care 2002;25:2218–2223

CV Events OccurCV Events OccurCV Events OccurCV Events OccurMore FrequentlyMore FrequentlyMore FrequentlyMore FrequentlyIn the Morning !In the Morning !In the Morning !In the Morning !

The Early Morning BP SurgeThe Early Morning BP SurgeCoincides with peak time of cardiovascular complications

►Sudden death

Coincides with peak time of cardiovascular complications

►Acute myocardial infarction

►Typical angina pectorisy g

►Silent ischemia

►T t l i h i b d06:00-12:00

►Total ischemic burden

►Ischemic stroke

►Variant angina pectoris (02:00-04:00)

►Platelet aggregability17

►Platelet aggregabilityLancet. 1988;2:755–759; Am Heart J. 1989;118:1098–1099;

Stroke. 1989;20:473–476; Circulation. 1989;80:1617–1626; Ter Arkh 2000;72:47–51

Circadian Variation of Acute CVDCircadian Variation of Acute CVDCircadian Variation of Acute CVDCircadian Variation of Acute CVDM I Thrombotic Stroke

S C D T I AS C D

Circulation. 1989 Apr;79(4):733-43.

Circadian Patterns of Onset Circadian Patterns of Onset of Symptoms of Stroke of Symptoms of Stroke

A: all

B IschemicB: Ischemic

C: Hemorrhagic

D: TIA

Stroke. 1998 May;29(5):992-6

Morning Excess of AMI and Morning Excess of AMI and Morning Excess of AMI and Morning Excess of AMI and Sudden Cardiac Death Sudden Cardiac Death

Am J Cardiol. 1997 Jun 1;79(11):1512-6

Morning Peak of VT Morning Peak of VT Morning Peak of VT Morning Peak of VT Detected by ICDDetected by ICD

120

80

100

E i d60

80Episodes

of VT

20

40

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Circulation 1995;92: 1203

Morning BP SurgeMorning BP SurgeMorning BP SurgeMorning BP Surgeis Independentlyis Independentlyis Independentlyis Independently

Associated WithAssociated WithAssociated With…Associated With…

MBPS is Independently Associated MBPS is Independently Associated MBPS is Independently Associated MBPS is Independently Associated With CV ComplicationsWith CV Complications

• Baseline• Baseline

: Untreated 507 HTN

• Then treated

• Mean 7yr f/uM lti i t l i Mean 7yr f/uMultivariate analysis

SBP change on rising

• CV Cx: MI, Angina, CVA, SCD, CRF, HF, PAD, AAA, Carotid stenosis

Journal of Hypertension 2004, 22:1113–1118

MBPS is Independently MBPS is Independently MBPS is Independently MBPS is Independently Associated With StrokeAssociated With Stroke

519 ld HTN• 519 older HTN

• Mean 41mo f/u

22-25% /

f f 2 S

10mmHg

Circulation. 2003;107:1401-1406

After controlling for age, sex, BMI, 24h SBP

WhWhWhy Why yyM i S ?M i S ?Morning Surge ?Morning Surge ?g gg g

MBPS MBPS –– CV Events ; MechanismCV Events ; MechanismVascularMBPS MBPS CV Events ; MechanismCV Events ; Mechanism

SteepSteep BPBP surgesurge

Vascular RemodelingSteepSteep BPBP surgesurgeRemodeling Cardiac

↑↑ oscillatoryoscillatory shearshear stressstress inin vesselvessel wallwallRemodeling↑↑ t i lt i l tifftiff

RemodelingOther CV ↑↑ arterialarterial stiffnessstiffness↑↑ IMTIMT ++ ααRisk Factors CV ↑↑ IMTIMT ++ αα↑↑ LVHLVH

Risk Factors ↑ in Morning Events !↑↑↑ in Morning Events !

MBPS MBPS O id ti StO id ti StMBPS MBPS –– Oxidative StressOxidative Stress

HTN

From PMN

N= 31 O

SFrom

RO

MNC

Hypertens Res 2005;28:755-761

in Carotid Plaque of MBPSin Carotid Plaque of MBPS

Hypertension 2007;49:784-791 HypertensivesHypertensives

↑↑ UP in Carotid Plaque of MBPSUP in Carotid Plaque of MBPS

Hypertension 2007;49:784-791 HypertensivesHypertensives

Circadian Variation of PAICircadian Variation of PAI--1 1 and tPA Activities and tPA Activities

J Am Coll Cardiol, 1998; 32:1962-1968

TherapeuticTherapeuticTherapeutic Therapeutic Strategies toStrategies toStrategies to Strategies to

Control MBPSControl MBPSControl MBPSControl MBPS

Hypertension Hypertension AAwareness, wareness, Hypertension Hypertension AAwareness, wareness, TTreatment and reatment and CControlontrol

7 0

8 0 U S AC a n a d aI t a l yS w e d e n

5 0

6 0

%)

S w e d e nS p a i nE n g l a n dG e r m a n y

Poor rates of control* in western countries

3 0

4 0

idu

als

(%

1 0

2 0

Ind

ivi

0A w a r e T r e a t e d C o n t r o l l e dAware Treated Controlled

Wolf-Maier et al. Hypertension 2004;43:10–17* Threshold of SBP/DBP 140/90 mm Hg

Aware Treated Controlled

In Pts with Controlled Office BP; Also During Morning Hours ?

70

Controlled (morning < 135/85mmHg)

Not controlled

50

60

)

30

40

ients

(%

)

20

30

Pati

0

10

34

ACAMPA study J-MORE

Redón et al. Blood Press Monit 2002;7:111–116Kario et al. Circulation 2003;108:72e–73e

Early Morning BP Surge as a Early Morning BP Surge as a Early Morning BP Surge as a Early Morning BP Surge as a Target for TherapyTarget for Therapy

Consider…Consider…

Pharmacokinetic profile with Pharmacokinetic profile with morning dosingmorning dosingmorning dosing morning dosing

Underlying mechanisms for MBPSUnderlying mechanisms for MBPS

A Therapeutic Blind Spot With A Therapeutic Blind Spot With A Therapeutic Blind Spot With A Therapeutic Blind Spot With Current Therapy in the MorningCurrent Therapy in the Morning

OneOne ofof thethe suggestedsuggested reasonreasonss forfor morningmorningOneOne ofof thethe suggestedsuggested reasonreasonss forfor morningmorninghypertensionhypertension inin treatedtreated subjectssubjects..

InsufficientInsufficient durationduration ofof actionaction (short(short TT11//22))ofof antihyertensiveantihyertensive drugsdrugs leavingleaving patientspatientsofof antihyertensiveantihyertensive drugs,drugs, leavingleaving patientspatientsvulnerablevulnerable..

Ch th ti T St t iCh th ti T St t iChronotherapeutic Tx StrategiesChronotherapeutic Tx Strategies

ChooseChoose drugdrug withwith longlong halfhalf--lifelife withwith highhightroughtrough--toto--peakpeak ratiosratios,, ensuringensuring coveragecoverageduringduring thethe morningmorning surgesurgegg gg ggExtendedExtended--release,release, delayeddelayed--onset,onset, bedtimebedtimedosingdosingdosingdosingTwiceTwice dailydaily dosesdosesCoupledCoupled withwith aa diureticdiuretic

HalfHalf--lives of Various Blood lives of Various Blood HalfHalf lives of Various Blood lives of Various Blood Pressure MedicationsPressure Medications

403 5

4 04

3 0

3 5

242 0

2 5

Hou

rs

129

1 0

1 5H

1 96 5 20

5

A m l o T e l m i L i s i n o C a n d e V a l s a r V e r a p a L o s a rA m l o T e l m i L i s i n o C a n d e V a l s a r V e r a p a L o s a r

J Clin Hypertens 2008;10:140-145

Effects of Two ARBs Approved for Effects of Two ARBs Approved for Effects of Two ARBs Approved for Effects of Two ARBs Approved for Once Daily Dosing on 24 Hour BPOnce Daily Dosing on 24 Hour BP

Missed Dose

Mancia et al AJC 1999: 84; 28SMancia et al AJC 1999: 84; 28S

Duration of Action by Duration of Action by yyTrough:Peak RatioTrough:Peak Ratio

46

Placebo

202

T h

Blood Pressure Ch

Placebo

- 6- 4- 2

P k

TroughChange mmHg

1 2- 1 0

- 8 PeakDrug

- 1 4- 1 2

0 Hours after dosing 240 Hours after dosing 24

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

- 1

0D a y N ig h t 2 4 h o u r

3

- 2

1 y g

Change

of

5

- 4

- 3

0 . 5 m g b id1 m g q d

of

SBP, mmHg

7

- 6

- 5 1 m g q dmmHg

- 8

- 7

- 9

Poirier J Clin Pharm 1993: 33:832Poirier J Clin Pharm 1993: 33:832TrandolaprilTrandolapril

Adherence to Treatment Greater with Once-daily Dosing

1 0 0 1 0 0 ****8 0

9 0

1 0 0

8 0

9 0

1 0 0 ****

6 0

7 0

%) 6 0

7 0

%)

3 0

4 0

5 0

eren

ce (

%

3 0

4 0

5 0

eren

ce (

%1 0

2 0

3 0

Ad

h

1 0

2 0

3 0

Ad

h0

O n c e - d a i l y T w i c e - d a i l y0

O n c e - d a i l y M u l t i p l e d a i l yd o s e s

OD BID OD MultipleClin Ther 2002;24:302–316

d o s e s* P<0.05 vs twice-daily dosing*** P<0.001 vs multiple daily doses

p

Targeting Mechanisms Targeting Mechanisms Targeting Mechanisms Targeting Mechanisms Responsible for MBPSResponsible for MBPS

SympatheticSympathetic NervousNervous SystemSystem↑ Morning BP surge ↑ Morning BP surge Platelet hyperactivationPlatelet hyperactivationPlatelet hyperactivationPlatelet hyperactivationEndothelial cell dysfunctionEndothelial cell dysfunction↑ Bl d i it↑ Bl d i it↑ Blood viscosity↑ Blood viscosity

ReninRenin--AngiotensinAngiotensin--AldosteroneAldosterone SystemSystem↑ Morning BP surge↑ Morning BP surge↑ Morning BP surge↑ Morning BP surge

SNS RAAS

Effects of Effects of αα--Blockade on the Blockade on the Effects of Effects of αα Blockade on the Blockade on the Morning Surge of BPMorning Surge of BP

No Rx

Doxazosin

DosingDosing

Kario, Pickering, et al Am J Hypertens 2004;17; 668Kario, Pickering, et al Am J Hypertens 2004;17; 668

Effects of Bedtime Dosing of Effects of Bedtime Dosing of C t ll A ti C t ll A ti 22 i t i t Centrally Acting Centrally Acting αα22--agonists agonists

on Morning HTNon Morning HTNon Morning HTNon Morning HTNGuanabenz

morningmorning

Cl idievening Clonidineevening

U f l f th i hibit ti &/ fUsefulness of sympathoinhibitory action, &/or of night-time dosing in controlling Morning HTN

J HTN 2003;21:805-811

g g g g

Regression of Carotid Regression of Carotid Atherosclerosis by Controlling Atherosclerosis by Controlling

Morning BP by Morning BP by αα1/ß Antagonist1/ß AntagonistMorning BP by Morning BP by αα1/ß Antagonist1/ß Antagonist

Cli i D Ni ht M i C tid IMT

5

0 0

Clinic Day Night Morning Carotid IMT

0

SBP

-10

-5-0.01

SBP mmHg IMT

mm

20

-15 -0.02-0.02NS

NS

-25

-20

MetoprololCarvedilol

-0.03

NS

<0 001<0.02

-30 -0.04-0.04<0.001

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

CYT006CYT006--AngQb, a Vaccine Against AngQb, a Vaccine Against Hypertension Targeting Hypertension Targeting Hypertension Targeting Hypertension Targeting

Angiotensin IIAngiotensin IIgg

Lancet 2008;371:821-827

Change of Daytime BPChange of Daytime BPChange of Daytime BPChange of Daytime BP(week 14 vs. Baseline(week 14 vs. Baseline))

Lancet 2008;371:821-827

24h BP P fil t W k 1424h BP P fil t W k 1424hr BP Profile at Week 1424hr BP Profile at Week 14

Lancet 2008;371:821-827

Change of Early Morning BPChange of Early Morning BPChange of Early Morning BPChange of Early Morning BP(week 14 vs. Baseline. 300(week 14 vs. Baseline. 300µg CYT006µg CYT006--AngQb)AngQb)

DBPDBPDBPDBP

SBPSBP

Usefulness of RAAS-inhibitory action, &/or of l T1/2 i t lli M i HTN

Lancet 2008;371:821-827

long T1/2 in controlling Morning HTN

S (I)S (I)Summary (I)Summary (I)

There is a pronounced diurnal rhythm of BP and CV BP and CV eventsevents, with a peakpeak of both in the morning morning hours, and a decrease during the night. DrugsDrugs approved for once daily dose may haveDrugsDrugs approved for once daily dose may have different durations of actiondifferent durations of action, particularly after missed dosesmissed doses.With some antihypertensive drugs the time of dosingtime of dosingmay have significant effects on the diurnal pattern of BP.

S (II)S (II)Summary (II)Summary (II)

Inhibition of SNS or RAASInhibition of SNS or RAAS may be useful for may be useful for controlling MBPScontrolling MBPSggDifferent antihypertensive drugsDifferent antihypertensive drugs may have different effects on the morningdifferent effects on the morning surge of BPdifferent effects on the morningdifferent effects on the morning surge of BP.

C l iC l iConclusionsConclusions

Morning BP surge is an independent risk for Morning BP surge is an independent risk for advancing the atherosclerosis process , TOD advancing the atherosclerosis process , TOD g p ,g p ,and triggering CV events.and triggering CV events.

In addition to strict BP control, In addition to strict BP control, antihypertensive therapy targeting MBPS antihypertensive therapy targeting MBPS could achieve more beneficial effect forcould achieve more beneficial effect forcould achieve more beneficial effect for could achieve more beneficial effect for prevention of CV disease in highprevention of CV disease in high--risk risk hypertensive patientshypertensive patientshypertensive patients.hypertensive patients.

KOALA SymposiumKOALA SymposiumKOALA SymposiumKOALA Symposium

Thank you Thank you Thank you Thank you for your for your for your for your

attention !attention !attention !attention !

Factors Influencing Morning SurgeFactors Influencing Morning SurgeFactors Influencing Morning SurgeFactors Influencing Morning Surge

Brain Sympathetic system

Aging Renin-angiotensin system

Clock gene

Stress

HPA axis

Nitric oxidesStress

Cold temp

Nitric oxides

Cold temp

Morning BPMorning BP

Factors Influencing Exaggerated Morning SurgeFactors Influencing Exaggerated Morning SurgeFactors Influencing Exaggerated Morning SurgeFactors Influencing Exaggerated Morning Surge

AgeAge (( >> 7070 yr)yr)AfricanAfrican--AmericanAmerican EthnicityEthnicityDayDay ofof weekweek (Mon)(Mon) // SeasonSeason ofof yearyear (Winter)(Winter)DayDay ofof weekweek (Mon)(Mon) // SeasonSeason ofof yearyear (Winter)(Winter)TobaccoTobacco // AlcoholAlcohol useuseSodiumSodium // CaffeineCaffeine // MedicationMedication (e(e..gg.. oraloralcontraceptives)contraceptives)contraceptives)contraceptives)

Controlled onset extended release Controlled onset extended release V il At l l V il At l l Verapamil vs. Atenolol or Verapamil vs. Atenolol or

HydrochlorthiazideHydrochlorthiazideHydrochlorthiazideHydrochlorthiazide

n=8241n 8241

3yr f/u

JAMA 2003;289:2073-2082

Reducing targetReducing target--organ damageorgan damageMean arterial pressure (mmHg)

Reduced blood pressure slows the rate of GFR decline

95 98 101 104 107 110 113 116 1190

r = 0.69; P < 0.05

min

/yea

r) -2

-4

GFR

(m

L/m

Untreated

-6

8

eclin

e in

G hypertension-8

-10

De

130/85 140/90-12

-14-14

Bakris et al. Am J Kidney Dis 2000;36:646–661

M i BP SM i BP SMorning BP Surge Morning BP Surge g gg g& CV E t& CV E t& CV Events& CV Events

TargetTarget--organ organ DDamage amage IIncreases ncreases CCardiovascular ardiovascular IIncreases ncreases CCardiovascular ardiovascular

RRiskiskEndothelial dysfunction

EEndotheliumndothelium playsplays aa keykey rolerole inin controllingcontrollingperipheralperipheral arteriolararteriolar resistanceresistance

y

peripheralperipheral arteriolararteriolar resistanceresistanceEndothelialEndothelial dysfunctiondysfunction cancan bebe observedobserved asasyyanan inapropriateinapropriate responseresponse totovasodilators/vasoconstrictorsvasodilators/vasoconstrictorsvasodilators/vasoconstrictorsvasodilators/vasoconstrictors

Nitric oxide is a key endogenous vasodilatorNitric oxide is a key endogenous vasodilatorNitric oxide is a key endogenous vasodilatorNitric oxide is a key endogenous vasodilatorItIt isis oneone ofof thethe earliestearliest markersmarkers forfor targettarget--organorgan damagedamageItIt contributescontributes toto cardiovascularcardiovascular disordersdisorders

Klahr, Morrissey. Kidney Int Suppl 2000;75:S7–S14

TargetTarget--organ Damage organ Damage Precedes Precedes Precedes Precedes

Clinical EventsClinical EventsRi k f t di b t b it ki

Apoptosis Arrhythmia

Risk factors: diabetes, obesity, smoking, age

LVH

FibrosisHeart failure

MI

Vasoconstriction

Vascular hypertrophy

Hypertension

ThrombosisVascular hypertrophy

Endothelial dysfunction

Atherosclerosis

DeathStroke

Cognitive Vascular disease

Decreased GFR

g

dysfunctiondisease

Proteinuria/albuminuria

GlomerulosclerosisRenal failure

TargetTarget--organ organ DDamage amage IIncreases ncreases IIncreases ncreases

CCardiovascular ardiovascular RRiskiskLeft ventricular hypertrophy120

HypertensionHypertension + LVH

Left ventricular hypertrophy

80

100

nciden

cets

)

Hypertension + LVH

60

80

dju

sted

in

00 p

atie

nt

40

ear

age-

ad(p

er 1

0

202-y

e

0Stroke Heart failure Coronary disease

Kannel. Eur Heart J 1992;13 (Suppl D):82–88

TargetTarget--organ organ DDamage amage IIncreases ncreases CCardiovascular ardiovascular RRiskisk

Carotid IMT

Daniel HO et al. NEJM 1997;340:14–22

TargetTarget--organ organ DDamage amage IIncreases ncreases CVCV RRiskisk

*

14

16

nts

*

Albuminuria (in type 2 diabetes)

10

12

14

ascu

lar ev

en

per

yea

r)

Albuminuria (in type 2 diabetes)

6

8

e of ca

rdio

va

of pat

ients

p

*

2

4

Inciden

ce

(% o

0Normoalbuminuria Microalbuminuria Macroproteinuria

*P<0 05 versus normoalbuminuria

Gimeno Orna et al. Rev Clin Esp 2003;203:526–531

*P<0.05 versus normoalbuminuria after adjusting for other risk markers

Lowering Lowering BPBP reduces reduces CVCVi ki kriskrisk

Meta-analysis of 61 prospective, observational studiesOne million adults, 12.7 million person-years

7% reduction in risk of ischaemic heart disease

2 mmHg decrease in mean SBP

heart disease mortality

mean SBP10% reduction in risk of stroke mortalitymortality

Lewington et al. Lancet. 2002;360:1903–1913

Characteristics of Morning BP Characteristics of Morning BP Characteristics of Morning BP Characteristics of Morning BP Reactivity SubgroupReactivity SubgroupReactivity SubgroupReactivity Subgroup

<<<

Am J Hypertens 2005;18:1528–1533

24h Profiles of SBP & SBP 24h Profiles of SBP & SBP VariationVariation

NormoNormoHTNHTN

Hypertension. 2005;45:505-512.

RRate of SBP ate of SBP VVariation ariation DDuring uring ii SS CC l dl dMMorning BP orning BP SSurge urge CCorrelated orrelated

IIndependently to ndependently to LLarger CCAarger CCA--IMTIMTIIndependently to ndependently to LLarger CCAarger CCA IMTIMT

Hypertension. 2005;45:505-512.

A significant increase in physical and A significant increase in physical and l i il i i dj d i h i i dj d i h i i mental activitymental activity––adjusted ischemic time at adjusted ischemic time at

the hour of awakening the hour of awakening gg

Circulation. 1996;93:1364-1371

Telmisartan compared with Telmisartan compared with

P<0 05 24-h mean Telmisartan

Perindopril Perindopril –– last 8 hourslast 8 hours100

Pretreatment

P<0.05 24 h mean Telmisartan versus Perindopril

95

mHg)

P≤0.05

90

DBP (

mm

P≤0.05Telmisartan versus Perindopril

85

D Post-treatment

Telmisartan 80 mg P i d il 4

80208 10 12 14 16 18 22 24 2 4 6 8

Perindopril 4 mg

Double-blind

Time of day (hours) comparative studyNalbantgil et al. Int J Clin Pract 2004;58:50–54

Diuretics Convert NonDiuretics Convert Non--Dippers to DippersDippers to Dippers

1 5 0Day

Ni ht

1 3 0

1 4 0Systolic pressure

Night

1 2 0

1 3 0pressure mmHg

1 1 0

1 0 0No Rx HCTZ No Rx HCTZ

Dippers Non-DippersUzu & Kimura Circ 1999; 100:1635Uzu & Kimura Circ 1999; 100:1635

Telmisartan vs AmlodipineTelmisartan vs Amlodipinei 24i 24 h ABPMh ABPMusing 24using 24--h ABPMh ABPM

Placebo (n=58)

Amlodipine (5-10 mg) (n=65)Telmisartan (40-120 mg) (n=62)

BP (mm Hg) 160

Week 12, SBP

140

120

100100

0

0800 1200 1600 2000 2400 0400 0800

Lacourcière Y et al, in press

0

Time

Relevance of trough:peak Relevance of trough:peak ratios to 24ratios to 24--h h BPBP controlcontrol

)

180

Placebo

e (m

mH

g 160Trough

Drug A

pre

ssure

20

140Peak

ug(T:P ratio =75%)

Blo

od 120

100Drug B

(T:P ratio =45%)

07:00 11:00 15:00 19:00 23:00 03:00 07:00

100Dose

(T:P ratio =45%)Dose

Time of day

Ellioit, Meredith. J Hypertension 1995;13:279–283

Diuretics Convert NonDiuretics Convert Non--Dippers to DippersDippers to Dippers

150Day

Night

130

140Systolic pressure

g

120

130pressure mmHg

110

100No Rx HCTZ No Rx HCTZ

Dippers Non-DippersUzu & Kimura Circ 1999; 100:1635Uzu & Kimura Circ 1999; 100:1635

Ci di ChCi di ChCircadian ChangeCircadian Change

Adverse Events of Adverse Events of CYT006CYT006--AngQbAngQb

Placebo 100μg 300μg pPlacebo(n=24)

100μg(n=24)

300μg(n=24)

p

Injection-site 16 (66 7%) 23 (95 8%) 19 (79 2%) 0 045Injection-siteinduration

16 (66.7%) 23 (95.8%) 19 (79.2%) 0.045

Injection-site 8 (33 3%) 18 (75 0%) 21 (87 5%) 0 000Injection-siteedema

8 (33.3%) 18 (75.0%) 21 (87.5%) 0.0003

Headache 8 (33 3%) 6 (25 0%) 15 (62 5%) 0 024Headache 8 (33.3%) 6 (25.0%) 15 (62.5%) 0.024