Download - Calcium Channel Blockers in Management of Hypertension …circulation.or.kr/workshop/2007fall/file/1012m4_4-1.pdf · · 2013-03-21Calcium Channel Blockers in Management of Hypertension

Calcium Channel Blockers in

Management of Hypertension

Yong-Jin Kim, MD

Seoul National University Hospital

Contents

• Clinical significance of hypertension

• CCB: Brief introduction

• Evidences of CCB’s in HT and CAD

• Review on ‘beyond BP lowering effect’

• Practical usefulness of CCB’s

Headlines of the St. Louis Post-Dispatch, April 13, 1945

FDR’s Final Picture (April 11, 1945)

FDR’s BP recorded April 1944

WHO:WHFWHO:WHFWHO:WHF

CHD 6.2 12.4 11.1 16.2

Stroke 4.3 8.5 7.7 11.3

Other CVD 2.6 5.1 6.0 8.8

TOTAL CVD 13.1 26.0 24.8 36.3

All Cause Death 50.4 100 68.3 100

(%)Millions(%)MillionsCause

1990 2020

Global Burden of CHD

1. Acute lower respiratory infections 1. Coronary heart disease

2. HIV/AIDS 2. Unipolar major depression

3. Perinatal conditions 3. Road traffic accidents

4. Diarrhoeal diseases 4. Cerebrovascular disease

5. Unipolar major depression 5. COPD

6. Coronary heart disease 6. Lower respiratory infections

7. Cerebrovascular disease 7. Tuberculosis

8. Malaria 8. War

9. Traffic accidents 9. Diarrhoeal diseases

10. COPD 10. HIV

1999 Disease or Injury 2020 Disease or Injury

Rank Order of Disability (DALYs)

Kannel WB. JAMA. 1996;275:1571-1576.

HT: A Risk Factor for CV Disease

22.7

9.5

3.3 2.45.0

2.0 3.5 2.1

45.4

21.3

12.4

6.29.9

7.3

13.9

6.3

0

10

20

30

40

50

Men

2.0

Women

2.2

Men

3.8

Women

2.6

Men

2.0

Women

3.7

Men

4.0

Women

3.0

Coronarydisease

Stroke Peripheral arterydisease

Heartfailure

Risk ratio

Biennial

Age-

Adjusted

Rate per

1000

Patients

Normotensive Hypertensive

*Individuals aged 40 to 69 years, starting at blood pressure 115/75 mm Hg

Chobanian AV et al. JAMA. 2003;289:2560-2572. Lewington S et al. Lancet. 2002;360:1903-1913.

CV Mortality Risk with BP Increment

CV

Mortality

Risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

2x

4x

8x

Small Difference Produces Big Impact

• Meta-analysis of 61 observational studies

• 1 million adults

Lewington S et al. Lancet. 2002;360:1903-1913.

For every

2 mm Hg

decrease in

mean SBP

• 7% reduction in

CHD mortality

•10% reduction in

stroke mortality

Individual

risk of CHD

Distribution of cases

People with

low risk level

5%

People with high risk level

25%

People with

average risk level

70%

Individual Risk vs Proportional Attributable Risk

Treatment of Hypertension

1957 1962 1970 1976 1980 1990 2003

Chlorothiazide αααα-blockerCCB

ββββ-blocker JNC 1 JNC 7

ACEI ARB

Contents






Ion Channels and Ion Gradients

[Na+] 10 mM

[Na+] 140 mM0 mV

- 90 mV

Electrical Gradient [Cl-] 140 mM

[Cl-] 15 mM

Ion channel

[Ca++] 1 µM

[Ca++] 2 mM

[K+] 140 mM

[K+] 4 mM

Concentration Gradient

Ion Exchangers

Na+

Ca++

Cl-

OH-Cl-

HCO3- Ca++

Na+ Ca++Ion pump

ATP

Voltage-Dependent CaCa++++ CChannelhannelss

P

Phosphorylation Site

Extracellular

Intracellular Inactivation Gate

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

Activation Gate

Selectivity filter

Calcium Binding

Sites

ExcitationExcitation--Contraction CouplingContraction Coupling

� L-type Ca++ channels open at a level of depol. of ~-60 mV.

� The entry of small Ca++ triggers Ca++ release from SR.

αααα2

δδδδVOC

ββββSR

Contraction

Actin-myosin

interaction

Ca++ -Troponin relieves inhibition on contractile apparatus

Ca++-induced

Ca++ release

Excitation-Contraction Coupling

Types of Calcium Channels

Channel Blockers Properties Location/Role

L type Calcium Large, long-lasting Cardiac & smooth m.

antagonists current with neurons; excitation-slow activation contraction,

excitation-secretion coupling

T type Amiloride Tiny, transient SA & Purkinje cell;

current pacemaker activity

N type Conotoxin Neither L or T Neurons;

neurotransmitter release

First Observation about CCB in 1964Developed Ten

sion (g)

10

0

20

30

[Ca++]= 2.4 mM [Ca++]= 0 mM [Ca++]= 2.4 mM

[Ca++]= 2.4 mM Verapamil 1 µM Isoproterenol 1µM

Developed Tension (g)

10

0

20

30

Classes of L-Type CCB

Class V (T-type blocker) Mibefradil (withdrawn)

Class I (diphenylalkylamine) Verapamil Isoptin™

Class III (benzothiazepine) Diltiazem Angizem, Altiazem

Class IV (miscellaneous) Bepridil Vascor™

Amlodipine Norvasc™, Lotrel™

Felodipine Plendil™, Lexxel™

Isradipine Dynacirc™

Nicardipine Cardene™

Nifedipine Adalat™, Procardia™

Nimodipine Nimotop ™

Nisoldipine Sular™

Class II (1,4-dihydropyridines)

Pharmacodynamic Effects of CCBs

Phenylalkylamine DihydropyridinesBenzothiazepine

(Verapamil) (Nifedipine)(Nimodipine) (Diltiazem)

Vasodilation

peripheral ++ +++ + +

coronary ++ +++ + +++

cerebral + + +++ +

Heart rate ↓↓↓↓ ↑↑↑↑ -- ↓↓↓↓

SA node ↓↓↓↓ -- -- ↓↓↓↓ ↓↓↓↓

AV node ↓↓↓↓ ↓↓↓↓ -- -- ↓↓↓↓

Contractility ↓↓↓↓ ↓↓↓↓ ↑↑↑↑ -- ↓↓↓↓

Classification of CCB’s

Group First Second generation Third

New active principles and/or

novel formulations

Dihydropyridine Nifedipine Nifedipine Benidipine Amlodipine

(artery > cardiac) Nicardipine SR/GITS Isradipine Lacidipine

Felodipine ER Manidipine

Nicardipine SR Nilvadipine

Nimodipine

Nisoldipine

Nitrendipine

Benzothiazepine Diltiazem Diltiazem SR

(artery = cardiac)

Phenylalkylamine Verapamil Verapamil SR

(artery < cardiac) Gallopamil

Abbreviations: ER = extended release; GITS = gastrointestinal therapeutic system; SR = sustained

release

generationgeneration(specificity)

Zanchetti, 1997

Contents






CCB Controversy in 1990’s

Circulation 1995

Evidences of CCB’s in HT, CAD

•CCB vs Placebo

– Syst-EUR nitrendipine, Lancet 1997

– PREVENT amlodipine, Circulation 2000

– ACTION nifedipine GITS, Lancet 2004

Systolic Hypertension in Europe. Staessen et al, Lancet, 1997.

-5%

-15%

-25%

-35%

-45%

4695 Elderly (> 60yr) pts with ISH: SBP>160, DBP<95)

Reduction (%)

Syst-EUR

Nitrendipine reduces CV events

-31%-29%

-42%

-30%

Stroke MI HF All CV events

PrimaryPrimary

QCAQCA

EndpointEndpoint

PREVENT: Primary QCA EndpointMean Change (mm)

Mean Change (mm)

≤30% >30% to ≤50% All Segments>50%

* * Values are mean Values are mean ±± SE, adjusted for segment, clinic, and PTCA during baseline angiSE, adjusted for segment, clinic, and PTCA during baseline angiogram.ogram.

PP=NS for all comparisons of =NS for all comparisons of amlodipineamlodipine versus placebo.versus placebo.

Pitt et al. Pitt et al. CirculationCirculation. 2000;102:1503. 2000;102:1503--1510.1510.

Amlodipine Placebo

-0.15

-0.10

-0.05

0.00

0.05

0.10

0.15

825 symptomatic CAD with 3yr f/u

Change in Minimum Lumen Diameter (MLD)

PREVENT: Vascular Event or Procedure

Pitt et al. Pitt et al. CirculationCirculation. 2000;102:1503. 2000;102:1503--1510.1510.

Cumulative Event/

Cumulative Event/

Procedure Rate (%)

Procedure Rate (%)

Months of FollowMonths of Follow--upup

AmlodipineAmlodipine (n=417)(n=417)

31%31%

PP=.01=.01

30.030.0

25.025.0

20.020.0

15.015.0

10.010.0

5.05.0

0.00.0

00 66 1212 1818 2424 3030 3636

Placebo (n=408)Placebo (n=408)

Evidences of CCB’s in HT, CAD

• CCB vs Active control

– ABCD nisoldipine vs ACEI, NEJM1998

– STOP-2 felodipine or isradipine vs ACEI or

diuretic/BB, Lancet 1999

– INSIGHT nifedipine GITS vs diuretics, Lancet 2000

– ALLHAT amlodipine vs diuretics vs ACEI, JAMA 2002

– AASK amlodipine vs BB vs ACEI, JAMA 2002

– CONVINCE verapamil vs diuretic/BB, JAMA 2003

– CAMELOT amlodipine vs ACEI, JAMA 2004

– VALUE amlodipine vs ARB, Lancet 2004

International Nifedipine Study 30

Number of Patients

3157 3164

6321 randomised, eligible for intention-to-treat analysis

7434 enrolled

Diuretic combination:Hydrochlorothiazide

& Amiloride(”Active control”)

Long-acting calcium antagonistNifedipine GITS

International Nifedipine Study 31mmHg

138 mmHg

82 mmHg

180

160

140

120

100

80

60

Systolic

Diastolic

173 mmHg

99 mmHg

Antihypertensive Efficacy

Mean Blood PressureNifedipine GITS

Hydrochlorothiazide

& Amiloride

0 2 4 8 12 18 36 70 87 121 138 173 190 225 242

Year

1

Year

2

Year

3

Year

4

Week


100

Beats per Minute

80

60

40

20

-4Year

1

Week -2/0 0 2 4 8 12 18 36 70 87Year

2

Year

4

121 138 173 190 225 242 EndYear

3

Sympathetic System

Heart RateNifedipine GITS

Hydrochlorothiazide

& Amiloride


Main Clinical OutcomeKaplan Meier Curves

All Cardiovascular Morbidity and All-Cause Mortality (Sum of Primary and Secondary Endpoints)

Nifedipine GITS

Hydrochlorothiazide & Amiloride

Myocardial Infarction, Sudden Death, Stroke, Heart Failure, Other Cardiovascular Death (Primary Endpoints)

0 400 800 1,200 1,600 2,000

Cumulative Proportion

Surviving

p = 0.32

1.01

1.00

0.99

0.98

0.97

0.96

0.95

0.94

0.93

0.92

0.91

0 400 800 1,200 1,600 2,000

Time (Days)

Cumulative Proportion

Surviving

1.041.02

1.00

0.98

0.96

0.94

0.92

0.900.88

0.86

0.84

p = 0.54


Overview: Individual and Combined EndpointsRelative Risk and 95% Confidence Interval

All Cardiovascular Morbidityand All-Cause MortalityAll Primary and Secondary Endpoints

All Primary Endpoints

p

0.62

Hydrochlorothiazide & Amiloride better

0.34

1.8

Nifedipine GITSbetter

1.0 1.2 1.4 1.60.80.60.40.2

0.96

1.11

Stroke

Sudden Death 0.43

0.610.91

Other Cardiovascular Death 0.851.09

Heart Failure 0.0232.17

Myocardial Infarction 0.171.27

0.74


Emergence

of New Diseases*

% ofPatients

0

2

4

6

1.3

3.0

2.1

5.3

Gout1 Peripheral Vascular Disorder1

p < 0.01 p < 0.01

4.3

5.6

Diabetes2

p = 0.02

*or Recurrence; 1 Reported by investigator; 2 WHO definition of random glucosemeasurement >11.0 mmol/l or use of anti-diabetic drugs

Nifedipine GITS

Hydrochlorothiazide

& Amiloride

Randomized Design of ALLHAT

HighHigh--risk risk

hypertensive hypertensive

patientspatients

Consent/ Consent/

RandomizeRandomize

(42,448)(42,448)

Amlodipine besylate 2.5-10 mg (n=9048)

Chlorthalidone 12.5-25 mg (n=15,255)

Doxazosin 2-8 mg (n=9067)*

Lisinopril 10-40 mg (n=9054)

Amlodipine Amlodipine besylatebesylate 2.52.5--10 mg (n=9048)10 mg (n=9048)

Chlorthalidone 12.5Chlorthalidone 12.5--25 mg (n=15,255)25 mg (n=15,255)

Doxazosin 2Doxazosin 2--8 mg (n=9067)*8 mg (n=9067)*

Lisinopril 10Lisinopril 10--40 mg (n=9054)40 mg (n=9054)

Eligible for Eligible for

lipidlipid--loweringloweringNot eligible for Not eligible for

lipidlipid--loweringlowering

Consent/Randomize (10,355)Consent/Randomize (10,355)

Pravastatin Usual carePravastatin Usual care

Follow for CHD and other outcomes until death or end of study (up to 8 years).Follow for CHD and other outcomes until death or end of study (uFollow for CHD and other outcomes until death or end of study (up to 8 years).p to 8 years).

**In January 2000, the National Heart, Lung, and Blood Institute dIn January 2000, the National Heart, Lung, and Blood Institute decided to discontinue the doxazosin ecided to discontinue the doxazosin

arm of the antihypertensive trial and report results.arm of the antihypertensive trial and report results.

ALLHAT Collaborative Research Group. ALLHAT Collaborative Research Group. JAMAJAMA. 2000;283:1967. 2000;283:1967--1975.1975.

ALLHAT Collaborative Research Group. ALLHAT Collaborative Research Group. JAMAJAMA. 2002;288:2981. 2002;288:2981--2997.2997.

Compared with chlorthalidone:Compared with chlorthalidone:

SBP significantly higher in the SBP significantly higher in the amlodipineamlodipine

group (0group (0.8.8 mm Hg) and the mm Hg) and the lisinoprillisinopril group group

(2 mm Hg) at 5 years(2 mm Hg) at 5 years

Compared with chlorthalidone:Compared with chlorthalidone:

DBP significantly lower in the DBP significantly lower in the

amlodipineamlodipine group (0group (0.8.8 mm Hg) at mm Hg) at

5 years5 years

ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.

130130

135135

140140

145145

150150

00 11 22 33 44 55 66

YearsYears

mm Hg

mm Hg

ChlorthalidoneChlorthalidoneAmlodipineAmlodipine besylatebesylateLisinoprilLisinopril

7070

7575

8080

8585

9090

00 11 22 33 44 55 66

YearsYearsmm Hg

mm Hg

ALLHAT: BP by Treatment Group

% <140/90 mm Hg% <140/90 mm Hg

68.2%68.2%

66.3%66.3%

61.2%61.2%

Systolic BPSystolic BP Diastolic BPDiastolic BP

Cumulative CHD Event Rate

Cumulative CHD Event Rate

ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.

Years to CHD EventYears to CHD Event

ALLHAT: Fatal CHD or Nonfatal MI

.810.99 (0.91-1.08)L/C

.650.98 (0.90-1.07)A/C

P ValueRR (95% CI)

Number at Risk:Number at Risk:

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine

LisinoprilLisinopril

15,25515,255

90489048

90549054

14,47714,477

85768576

85358535

13,82013,820

82188218

81238123

13,10213,102

78437843

77117711

11,36211,362

68246824

66626662

63406340

38703870

38323832

29562956

18781878

17701770

209209

215215

195195

00 11 22 33 44 55 66 77

00

.04.04

.08.08

.12.12

.16.16

.20.20

ChlorthalidoneChlorthalidone

AmlodipineAmlodipine besylatebesylate

LisinoprilLisinopril

15245 HT 15245 HT pt with ept with elective titration to target BPlective titration to target BP

*Patient visits every 6 months for months 6*Patient visits every 6 months for months 6--72.72.

Julius S et al. Julius S et al. LancetLancet. June 2004;363.. June 2004;363.

VALUE: Design

MonthMonth 0.50.5 00 11 22 33 4 6 *4 6 * 7272

A 10 mg +A 10 mg +

HCTZ 25 mgHCTZ 25 mg

A 5 mgA 5 mg

A 10 mg +A 10 mg +

HCTZ 12.5 mgHCTZ 12.5 mg

A 10 mgA 10 mg

V 80 mgV 80 mg

V 160 mgV 160 mg

V 160 mg +V 160 mg +

HCTZ 12.5 mgHCTZ 12.5 mg

V 160 mg +V 160 mg +

HCTZ 25 mgHCTZ 25 mg

Amlodipine-

based regimen

V 160 mg +V 160 mg +

HCTZ 25 mg + HCTZ 25 mg + ""FreeFree"" addadd--onon

A 10 mg +A 10 mg +

HCTZ 25 mg + HCTZ 25 mg + ""FreeFree"" addadd--onon

Valsartan-

based regimen

ScreeningScreeningRandomisationRandomisation

End of treatment adjustment period

RolloverRollover

fromfrom

previous previous

therapytherapy

(92%)(92%)

Julius et al. Julius et al. LancetLancet. June 2004;363.. June 2004;363.

ValsartanValsartan--based regimenbased regimen

AmlodipineAmlodipine besylatebesylate --based regimenbased regimen

Proportion of Patients


With First Event (%)


HR=1.03; 95% CI 0.94HR=1.03; 95% CI 0.94--1.14: 1.14: PP=0.49=0.49

1414

1212

1010

88

66

44

22

0000 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

Time (months)Time (months)Number at riskNumber at risk

ValsartanValsartan 76497649 74597459 74077407 72507250 70857085 69066906 67326732 65366536 63496349 59115911 37643764 14741474

AmlodipineAmlodipine besylatebesylate 75967596 74697469 74247424 72677267 71177117 69556955 67726772 65766576 63916391 59595959 37253725 14741474

VALUE: Primary Composite Endpoint






66

55

44

33

22

11

00

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

HR=1.19; 95% CI 1.02HR=1.19; 95% CI 1.02--1.38; 1.38; PP=0.02=0.02

Time (months)Time (months)Number at riskNumber at risk

Valsartan Valsartan 76497649 74997499 74587458 73197319 71777177 70167016 68536853 66806680 65046504 60786078 38643864 15201520


VALUE: Fatal and Non-Fatal MI


AmlodipineAmlodipine besylatebesylate--based regimenbased regimen

77

19%19%


VALUE: Fatal and Non-fatal Stroke

Number at riskNumber at risk

Valsartan Valsartan 76497649 74947494 74487448 73127312 71707170 70227022 68776877 66926692 65156515 60936093 38593859 15161516






66

55

44

33

22

11

00

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

HR=1.15; 95% CI 0.98HR=1.15; 95% CI 0.98--1.35; 1.35; PP=0.08=0.08

Time (months)Time (months)


AmlodipineAmlodipine besylatebesylate--based regimenbased regimen


VALUE: Systolic BP in Study

Valsartan Valsartan

(N=7649)(N=7649)AmlodipineAmlodipine besylatebesylate

(N=7596)(N=7596)

135135

140140

145145

150150

155155

mmHg

mmHg

MonthsMonths

Sitting SBP by Time and Treatment GroupSitting SBP by Time and Treatment Group

BaselineBaseline 11 2424 484822 33 44 66 1212 1818 3030 3636 4242 5454 6060 6666(or final visit)(or final visit)

001.01.02.02.03.03.04.04.0

mmHg

mmHg

11 2424 484822 33 44 66 1212 1818 3030 3636 4242 5454 6060 6666

MonthsMonths

5.05.0Difference in SBP Between Valsartan and Difference in SBP Between Valsartan and AmlodipineAmlodipine besylatebesylate

––1.01.0

(or final visit)(or final visit)

Time IntervalTime Interval

(months)(months)

Overall studyOverall study

3636––4848

2424––3636

1212––2424

66––1212

00––33

Study endStudy end

FavoursFavours amlodipineamlodipine besylatebesylate

1.01.0 2.02.00.50.5

PRIMARY ENDPOINT PRIMARY ENDPOINT

Odds Ratios and 95% Odds Ratios and 95% CIsCIs∆∆∆∆∆∆∆∆SBPSBP

mm Hgmm Hg

1.41.4

1.61.6

1.81.8

2.02.0

3.83.8

1.71.7

2.22.2

33––66 2.32.3

FavoursFavours valsartanvalsartan

4.04.0


VALUE: Outcome and SBP Differences

VALUE: Outcome and SBP Differences

New ESC Guideline: Early Treatment

BP-Lowering Treatment TrialistsComparisons of Active Treatments and Control

Blood Pressure Lowering Treatment Blood Pressure Lowering Treatment TrialistsTrialists’’ Collaboration. Collaboration. LancetLancet. 2003;362:1527. 2003;362:1527--1535.1535.

FavorsFavorsActiveActive

FavorsFavorsControlControl

0.5 1.0 2.0

Relative Risk RR (95% CI)RR (95% CI)BP DifferenceBP Difference(mm Hg)(mm Hg)

StrokeStroke

0.72 (0.64, 0.81)0.72 (0.64, 0.81)ACEI vs placeboACEI vs placebo --5/5/--22

0.62 (0.47, 0.82)0.62 (0.47, 0.82)CA vs placebo CA vs placebo --8/8/--44

Coronary heart diseaseCoronary heart disease

0.80 (0.73, 0.88)0.80 (0.73, 0.88)--5/5/--22ACEI vs placeboACEI vs placebo

0.78 (0.62, 0.99)0.78 (0.62, 0.99)--8/8/--44CA vs placeboCA vs placebo

ACEI vs placeboACEI vs placebo 0.78 (0.73, 0.83)0.78 (0.73, 0.83)--5/5/--22

CA vs placeboCA vs placebo 0.82 (0.71, 0.95)0.82 (0.71, 0.95)--8/8/--44

Heart failureHeart failure

Major CV eventsMajor CV events

--5/5/--22 0.82 (0.69, 0.98)0.82 (0.69, 0.98)ACEI vs placeboACEI vs placebo

1.21 (0.93, 1.58)1.21 (0.93, 1.58)CA vs placeboCA vs placebo --8/8/--44

CV mortalityCV mortality



Total mortalityTotal mortality



FavorsFavors

First ListedFirst ListedFavorsFavors

Second ListedSecond Listed0.5 1.0 2.0

BP-Lowering Treatment TrialistsComparisons of Different Active Treatments


CA vs D/BBCA vs D/BB 1.33 (1.21, 1.47)1.33 (1.21, 1.47)1/01/0

0.93 (0.86, 1.01)0.93 (0.86, 1.01)CA vs D/BBCA vs D/BB 1/01/0

1.01 (0.94, 1.08)1.01 (0.94, 1.08)CA vs D/BBCA vs D/BB 1/01/0

ACE Inhibitor vs CAACE Inhibitor vs CA 0.82 (0.73, 0.92)0.82 (0.73, 0.92)1/11/1

1.12 (1.01, 1.25)1.12 (1.01, 1.25)ACE Inhibitor vs CAACE Inhibitor vs CA 1/11/1

0.96 (0.88, 1.05)0.96 (0.88, 1.05)ACE Inhibitor vs CAACE Inhibitor vs CA 1/11/1

StrokeStroke

CHDCHD

1.09 (1.00, 1.18)1.09 (1.00, 1.18)ACE Inhibitor vs D/BBACE Inhibitor vs D/BB 2/02/0




HFHF

0.5 1.0 2.0

BP-Lowering Treatment TrialistsComparisons of Different Active Treatments


FavorsFavors

First ListedFirst ListedFavorsFavors

Second ListedSecond Listed

Major CV eventsMajor CV events

CV mortalityCV mortality

Total mortalityTotal mortality

1.02 (0.98, 1.07)1.02 (0.98, 1.07)2/02/0ACEI vs D/BBACEI vs D/BB



1.04 (0.99, 1.08)1.04 (0.99, 1.08)1/01/0CA vs D/BBCA vs D/BB

1.05 (0.97, 1.13)1.05 (0.97, 1.13)1/01/0CA vs D/BBCA vs D/BB

0.99 (0.95, 1.04)0.99 (0.95, 1.04)1/01/0CA vs D/BBCA vs D/BB

0.97 (0.92, 1.03)0.97 (0.92, 1.03)1/11/1ACEI vs CAACEI vs CA




Contents






HOPE Trial

Ramipril 10mg/day

n=4,645

Primary Endpoint

Composite of cardiac death, MI, or stroke

follow-up: 5 years

Primary Endpoint

Composite of cardiac death, MI, or stroke

follow-up: 5 years

Placebo

n=4,652

9,297 pt with CAD or DM plus 1 RF (no CHF, LV dysfxn)

75% Aspirin, 40% beta-blocker, 30% statin

The HOPE investigators. N Engl J Med 2000 ; 342 : 145-53

HOPE: Primary Endpoint

Ramipril

RRR = 28%

p < 0.001 Placebo

0

5

10

15

20

0 500 1000 1500 days

Primary endpoints (%)

The HOPE investigators. N Engl J Med 2000 ; 342 : 145-53

cardiac death, MI, or stroke

HOPE: Events per Patient Group

0

5

10

15

20Placebo Ramipril

Primary Primary

OutcomeOutcomeCV CV

DeathDeathMIMI StrokeStroke NonNon--

CV CV

DeathDeath

Total Total

MortalityMortality

**MI, stroke, or CV death.MI, stroke, or CV death.

YusufYusuf et al. et al. N N EnglEngl J MedJ Med. 2000;342:145. 2000;342:145--153.153.

RR=22%RR=22%

PP<.001<.001

RR=26%RR=26%

PP<.001<.001

RR=20%RR=20%

PP<.001<.001

RR=32%RR=32%

PP<.001<.001

RR=16%RR=16%

PP=.005=.005

RR=0%RR=0%

PP=NS=NS

1414

6.16.1

3.43.44.14.1 4.34.3

10.410.4

17.817.8

8.18.1

12.312.3

4.94.9

12.212.2

Events per Patient Group (%)

Events per Patient Group (%)

9.99.9

Ambulatory BP in HOPE Trial

SvenssonSvensson et al. et al. Hypertension.Hypertension. 2001;38:e282001;38:e28--e32.e32.

SBP baselineSBP baseline

DBP baselineDBP baseline

SBP year 1SBP year 1

DBP year 1DBP year 1

BP (mm Hg)

BP (mm Hg)

180180

160160

140140

120120

100100

8080

6060

404011 33 55 77 99 1111 1313 1515 1717 1919 2121 2323

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

Time (hours)Time (hours)

Ramipril Group (n=20)Ramipril Group (n=20)

NightNight ∆∆∆∆∆∆∆∆=17/8 mm Hg (=17/8 mm Hg (PP<.001)<.001)

2424--hh ∆∆∆∆∆∆∆∆=10/4 mm Hg (=10/4 mm Hg (PP<.03)<.03)

EUROPA Trial

Perindopril 8mg/day

n=6,110

Primary Endpoint

Composite of cardiac death, MI, or cardiac arrest

mean follow-up: 4.2 years

Primary Endpoint

Composite of cardiac death, MI, or cardiac arrest

mean follow-up: 4.2 years

Placebo

n=6,108

12,218 patients with stable angina without CHF

90% Aspirin, 60% beta-blocker, 60% statin

Lancet 2003; 362: 782-88

% % CV death, MI or cardiac arrestCV death, MI or cardiac arrest

Placebo annual event ratePlacebo annual event rate

: 2.4%: 2.4%

Perindopril Perindopril

PlaceboPlacebo

p = 0.0003p = 0.0003

RRR: 20%RRR: 20%

YearsYears

00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55

10%10%12%12%

14%14%

EUROPA: Primary Endpoint

Lancet 2003; 362: 782-88

CAD Mortality and Usual BP by Age

Prospective Studies Collaboration. Prospective Studies Collaboration. LancetLancet. 2002;360:1903. 2002;360:1903--1913.1913.


Usual Diastolic BP (mm Hg)Usual Diastolic BP (mm Hg)

5050--59 years59 years





256256

128128

6464

3232

1616

88

44

22

11

00

8080 9090 100100 1101107070

IHD Mortality

IHD Mortality

(Floating Absolute Risk and 95% CI)


Usual Systolic BP (mm Hg)Usual Systolic BP (mm Hg)






256256

128128

6464

3232

1616

88

44

22

11

00

120120 140140 160160 180180

Stroke Mortality and Usual BP by Age

Prospective Studies Collaboration. Prospective Studies Collaboration. LancetLancet. 2002;360:1903. 2002;360:1903--1913.1913.

Stroke Mortality

Stroke Mortality



Usual Systolic BP (mm Hg)Usual Systolic BP (mm Hg)





Usual Diastolic BP (mm Hg)Usual Diastolic BP (mm Hg)




8080--89 years89 years256256

128128

6464

3232

1616

88

44

22

11

00

120120 140140 160160 180180

256256

128128

6464

3232

1616

88

44

22

11

00

7070 8080 9090 110110100100


Odds Ratio for CV Events & SBP Difference

StaessenStaessen et al. et al. J J HypertensHypertens. 2003;21:1055. 2003;21:1055--1076.1076.

Odds Ratio (Experimental/Reference)

Odds Ratio (Experimental/Reference) 1.501.50

1.251.25

1.001.00

0.750.75

0.500.50

0.250.25

--55 00 55 1010 1515 2020 2525

PP<.0001<.0001

Difference (reference minus experimental) Difference (reference minus experimental) in Systolic BP (mm Hg)in Systolic BP (mm Hg)

Recent trialsRecent trials

Older trials placeboOlder trials placebo

STONESTONE

UKPDS L vs HUKPDS L vs H

PROGRESSION/ComPROGRESSION/Com

STOP 1STOP 1

RCT70RCT70--8080

EWPHEEWPHE

HEPHEP

MRC2MRC2

SHEPSHEP

SystSyst--EurEur

PART2/SCATPART2/SCAT

HOPEHOPE

STOP2/ACEIsSTOP2/ACEIs

ALLHAT/ALLHAT/DoxDox

UKPDS C vs AUKPDS C vs A

MIDAS/NICS/VHASMIDAS/NICS/VHAS

STOP2/CCBsSTOP2/CCBs

HOT M vs HHOT M vs H

INSIGHTINSIGHT

HOTHOT

PROGRESS/PerPROGRESS/PerPATSPATS

RENAALRENAAL

L vs HL vs H

MRCMRC

ATMHATMH

SystSyst--ChinaChina

OlderOlderRecentRecent

AASK L vs HAASK L vs H

ABCD/NT L vs HABCD/NT L vs H

ALLHAT/Lis ALLHAT/Lis BlcksBlcksALLHAT/Lis ALLHAT/Lis ≥≥≥≥≥≥≥≥6565ALLHAT/LisALLHAT/LisALLHAT/ALLHAT/AmlAml

CONVINCECONVINCE

DIABHYCARDIABHYCAR

ANBP2ANBP2

LIFE/ALLLIFE/ALL

ELSAELSA

LIFE/DMLIFE/DM

NICOLENICOLE

PREVENTPREVENT

IDNT2IDNT2

SCOPESCOPE

Older trials activeOlder trials active

HOPEHOPE

Fox. Fox. Lancet.Lancet. 2003;362:7822003;362:782--788; 788; StaessenStaessen et al. et al. J J HypertensHypertens. 2003;21:1055. 2003;21:1055--1076.1076.

Odds Ratio (Experimental/Reference)

Odds Ratio (Experimental/Reference) 1.501.50

1.251.25

1.001.00

0.750.75

0.500.50

0.250.25

--55 00 55 1010 1515 2020 2525

PP<.0001<.0001

Difference (reference minus experimental) Difference (reference minus experimental) in Systolic BP (mm Hg)in Systolic BP (mm Hg)

Recent trialsRecent trials

Older trials placeboOlder trials placebo

STONESTONE

UKPDS L vs HUKPDS L vs H

PROGRESSION/ComPROGRESSION/Com

STOP 1STOP 1

RCT70RCT70--8080

EWPHEEWPHE

HEPHEP

MRC2MRC2

SHEPSHEP

SystSyst--EurEur

PART2/SCATPART2/SCAT

HOPEHOPE

STOP2/ACEIsSTOP2/ACEIs

ALLHAT/ALLHAT/DoxDox

UKPDS C vs AUKPDS C vs A

MIDAS/NICS/VHASMIDAS/NICS/VHAS

STOP2/CCBsSTOP2/CCBs

HOT M vs HHOT M vs H

INSIGHTINSIGHT

HOTHOT

PROGRESS/PerPROGRESS/PerPATSPATS

RENAALRENAAL

L vs HL vs H

MRCMRC

ATMHATMH

SystSyst--ChinaChina

OlderOlderRecentRecent

AASK L vs HAASK L vs H

ABCD/NT L vs HABCD/NT L vs H

ALLHAT/Lis ALLHAT/Lis BlcksBlcksALLHAT/Lis ALLHAT/Lis ≥≥≥≥≥≥≥≥6565ALLHAT/LisALLHAT/LisALLHAT/ALLHAT/AmlAml

CONVINCECONVINCE

DIABHYCARDIABHYCAR

ANBP2ANBP2

LIFE/ALLLIFE/ALL

ELSAELSA

LIFE/DMLIFE/DM

NICOLENICOLE

PREVENTPREVENT

IDNT2IDNT2

SCOPESCOPE

Older trials activeOlder trials active

EUROPAEUROPA

Odds Ratio for CV Events & SBP Difference

Target BP in HT

• JNC 7, 2004

- 140/90

- 130/80: DM, renal disease

• ESC guideline, 2007

- 140/90

- 130/80: DM,

established CV ds ( stroke, MI, renal ds)

BP-Lowering Treatment Trialists

StrokeStroke

SBP Difference Between (mm Hg)SBP Difference Between (mm Hg)

0.250.25

0.500.50

0.750.75

1.001.00

1.251.25

1.501.50

--1010 --88 --66 --44 --22 00 22 440.250.25

0.500.50

0.750.75

1.001.00

1.251.25

1.501.50

--1010 --88 --66 --44 --22 00 22 44

CHDCHD

A = CA A = CA vsvs placebo; B = ACE inhibitor vs placebo; C = more intensive vs leplacebo; B = ACE inhibitor vs placebo; C = more intensive vs less intensive bloodss intensive blood-- pressurepressure--

lowering; D = ARB vs control; E = ACE lowering; D = ARB vs control; E = ACE inihibitorinihibitor vs CA; F = CA vs diuretic or vs CA; F = CA vs diuretic or ββ--blocker; G = ACE inhibitor vs blocker; G = ACE inhibitor vs

diuretic and diuretic and ββ--blocker.blocker.


RR of Outcome Event

RR of Outcome Event

RR of Outcome Event

RR of Outcome Event

AA BB CC DD EE FF GG AA BB CC DD EE FF GG

SBP Difference Between (mm Hg)SBP Difference Between (mm Hg)

BP-Lowering Treatment Trialists

Heart FailureHeart Failure

SBP Difference Between Groups (mm Hg)SBP Difference Between Groups (mm Hg)

RR of Outcome Event

RR of Outcome Event

--1010 --88 --66 --44 --22 00 22 440.250.25

0.500.50

0.750.75

1.001.00

1.251.25

1.501.50AA BB CC DD EE FF GG

A = CA A = CA vsvs placebo; B = ACE inhibitor vs placebo; C = more intensive vs leplacebo; B = ACE inhibitor vs placebo; C = more intensive vs less intensive bloodss intensive blood-- pressurepressure--

lowering; D = ARB vs control; E = ACE lowering; D = ARB vs control; E = ACE inihibitorinihibitor vs CA; F = CA vs diuretic or vs CA; F = CA vs diuretic or ββ--blocker; G = ACE inhibitor vs blocker; G = ACE inhibitor vs

diuretic and diuretic and ββ--blocker.blocker.


“Regimens based on each of the most commonly

used drug classes produce reductions in the risk

of major cardiovascular events that appear to be

roughly proportional to the size of the blood

pressure reductions achieved With the

exception of heart failure, the intensity of

blood pressure lowering appears to be a more

important determinant of outcome than the

choice of drug class.”

BP Lowering Treatment Trialists’ Collaboration,

The Lancet (2003)

Target BP lowering in ALLHAT

Adequate BP Control First !

source: National health and nutrition examination survey, 2005

Adequate BP Control First !

CVD Survival in Treated HT

BenetosBenetos et al. et al. J J HypertensHypertens. 2003;21:1635. 2003;21:1635--1640.1640.

FollowFollow--up (Years)up (Years)

Survival (%)

Survival (%)

11

0.960.96

0.920.92

0.880.88

0.840.84

0.80.8

11 33 55 77 99 1111 1313 1515 1717 1919 2121 2323 2525

PP=.03=.03

PP<.0001<.0001

PP=.001=.001

Treated BP not at goal Treated BP not at goal ≥≥140/90 mm Hg140/90 mm Hg

Untreated BP <140/90 mm Hg Untreated BP <140/90 mm Hg

Untreated BP Untreated BP ≥≥140/90 mm Hg140/90 mm Hg

Treated BP at goal <140/90 mm HgTreated BP at goal <140/90 mm Hg

Contents






BakrisBakris et al. et al. Am J Kidney DisAm J Kidney Dis. 2000;36:646. 2000;36:646--661; 661; BakrisBakris et al. et al. Arch Intern Med.Arch Intern Med. 2003;163:15552003;163:1555--1565; Lewis et 1565; Lewis et

al. al. N N EnglEngl J MedJ Med. 2001;345:851. 2001;345:851--860.860.

Number of BP Medications

No. of agents to Achieve BP Goal

UKPDS (<85 mm Hg, diastolic)

4321

MDRD (<92 mm Hg, MAP)

HOT (<80 mm Hg, diastolic)

AASK (<92 mm Hg, MAP)

RENAAL (<140/90 mm Hg)

IDNT (≤135/85 mm Hg)

Combination Therapy in Korea

Note: * Consider small base number for implementation especially when n<30

28 31 26 31 3325 22

4144

39

42

4134

2319

2519 19

26

31

8 710

7 7 814

44

>4 drugs

3 drugs

2 drugs

Monotherapy

Effect of CCB for Add-on Therapy

-20

-10

0

**The DHP CCB was NorvascThe DHP CCB was Norvasc®® ((amlodipineamlodipine besylatebesylate).).††P<P<.001 vs baseline..001 vs baseline.

McLaughlin et al. McLaughlin et al. Am J Am J HypertensHypertens. 2003;16:123A. Abstract P. 2003;16:123A. Abstract P--237.237.

No Previous

Therapy

(n=421)

No Previous No Previous

Therapy Therapy

(n=421)(n=421)ACEI/ARB

(n=117)

ACEI/ARB ACEI/ARB

(n=117)(n=117)ββββ-Blocker(n=70)

ββββββββ--BlockerBlocker

(n=70)(n=70)Diuretic

(n=119)

Diuretic Diuretic

(n=119)(n=119)

ACE/ARB

+ diuretic

(n=165)

ACE/ARBACE/ARB

+ diuretic + diuretic

(n=165)(n=165)

ββββ-Blocker+ diuretic

(n=47)

ββββββββ--BlockerBlocker

+ diuretic+ diuretic

(n=47)(n=47)

∆∆ ∆∆SBP mm Hg

∆∆ ∆∆SBP mm Hg

--15.915.9††--15.115.1††

--18.118.1††

--19.319.3††--17.317.3††

--13.913.9††

Guideline on Combination Therapy

ESC guideline 2007

ARB

CCB

BB

Thiazide

Alpha

ACEI

Summary

• CCB: strong evidences in management in HT

• Benefit of HT drugs: mainly from BP lowering

effect

• Early initiation of HT drug: high risk patients

• Importance of BP lowering at goal

Thank You for Your Attention!

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