奇美醫學中心一般內科心臟內科陳志成醫師

Z.C Chen

奇美醫學中心奇美醫學中心一般內科心臟內科一般內科心臟內科

陳志成醫師陳志成醫師

The New Role of The New Role of ββ-Blocker in -Blocker in Cardiovascular DiseaseCardiovascular Disease

Z.C Chen

The New Role of The New Role of ββ-Blocker -Blocker in Cardiovascular Diseasein Cardiovascular DiseaseThe New Role of The New Role of ββ-Blocker -Blocker in Cardiovascular Diseasein Cardiovascular Disease

高血壓

冠狀動脈疾病 ( 冠心症 )

心律不整

心臟衰竭

高血壓


心律不整

心臟衰竭

U.S. Department of Health and Human

Services

National Institutes of Health

National Heart, Lung, and Blood Institute

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education ProgramNational Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program

4

For persons over age 50, SBP is a more important than DBP as CVD risk factor.

Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range.

Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN.

Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.

New Features and Key Messages

5

New Features and Key Messages (Continued)

Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes.

Certain high-risk conditions are compelling indications for other drug classes.

Most patients will require two or more antihypertensive drugs to achieve goal BP.

If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

6

Blood Pressure Classification

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension 140–159 or 90–99

Stage 2 Hypertension >160 or >100

BP Classification SBP mmHg DBP mmHg

7

CVD Risk

HTN prevalence ~ 50 million people in the United States.

The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors.

Each increment of 20/10 mmHg doubles the risk of CVD across the entire BP range starting from 115/75 mmHg.

Prehypertension signals the need for increased education to reduce BP in order to prevent hypertension.

8

BP Control Rates

Trends in awareness, treatment, and control of high blood pressure in adults ages 18–74

National Health and Nutrition Examination Survey, Percent

II1976–80

II(Phase 1)1988–91

II(Phase 2)1991–94 1999–2000

Awareness 51 73 68 70

Treatment 31 55 54 59

Control 10 29 27 34

Sources: Unpublished data for 1999–2000 computed by M. Wolz, National Heart, Lung, and Blood Institute; JNC 6.

9

Goals of Therapy

Reduce CVD and renal morbidity and mortality.

Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

10

Lifestyle Modification

Modification Approximate SBP reduction(range)

Weight reduction 5–20 mmHg/10 kg weight loss

Adopt DASH eating plan 8–14 mmHg

Dietary sodium reduction 2–8 mmHg

Physical activity 4–9 mmHg

Moderation of alcohol consumption

2–4 mmHg

1111

Management of Hypertension in Management of Hypertension in Adults in Primary CareAdults in Primary Care

Management of Hypertension in Management of Hypertension in Adults in Primary CareAdults in Primary Care

NICE NICE (National Institute for Health and (National Institute for Health and Clinical Excellence)Clinical Excellence) Guideline Updates Guideline Updates

June, 2006June, 2006

1212NOR-EM-060

Comparison Studies Total n Effect size RR (95% CI)

I2

MortalityMortality 33 15,76515,765 1.04 1.04 (0.91-1.20)(0.91-1.20) 44.144.1

MI 3 15,76515,765 1.15 1.15 (0.82-1.60)(0.82-1.60)

76.8

Stroke 3 15,76515,765 1.27 1.27 (0.73-2.23)(0.73-2.23)

77.6

ResultsResultsResultsResults

0.50 0.75 1.00 1.25

Favours Thiazide

Favours BB

Beta-blockers

vs thiazides

1313NOR-EM-060


I2

MortalityMortality 33 23,62523,625 1.04 1.04 (0.98-1.11)(0.98-1.11) 00

MI 3 23,61923,619 0.94 0.94 (0.74-1.19)(0.74-1.19)

69.3

Stroke 3 23,61923,619 1.15 1.15 (1.03-1.27)(1.03-1.27)

5.2

Heart Failure 3 23,61923,619 0.85 0.85 (0.78-0.93)(0.78-0.93)

0

Diabetes 2 15,50115,501 0.85 0.85 (0.76-0.94)(0.76-0.94)

15.2


0.50 0.75 1.00 1.25

Favours CCB

Favours ACEi

ACEi vs CCB

1414NOR-EM-060


I2

MortalityMortality 11 9,1039,103 0.89 0.89 (0.78-1.01)(0.78-1.01) NANA

MI 1 9,1039,103 1.05 1.05 (0.86-1.28)(0.86-1.28) NANA

Stroke 1 9,1039,103 0.75 0.75 (0.63-0.88)(0.63-0.88) NANA

Heart Failure 1 9,1039,103 0.95 0.95 (0.76-1.18)(0.76-1.18) NANA

Diabetes 1 7,9987,998 0.75 0.75 (0.64-0.88)(0.64-0.88) NANA


0.50 0.75 1.00 1.25

Favours BB

Favours ARB

ARB vs BB

1515NOR-EM-060


I2

MortalityMortality 11 15,31315,313 1.02 1.02 (0.93-1.12)(0.93-1.12) NANA

MI 1 15,31315,313 1.17 1.17 (1.01-1.36)(1.01-1.36) NANA

Stroke 1 15,31315,313 1.14 1.14 (0.97-1.33)(0.97-1.33) NANA

Heart Failure 1 15,31315,313 0.88 0.88 (0.76-1.01)(0.76-1.01) NANA


0.50 0.75 1.00 1.25

Favours CCB

Favours ARB

ARB vs CCB

1616NOR-EM-060


I2


MI 3 30,20430,204 0.87 0.87 (0.60-1.24)(0.60-1.24) 66.566.5

Stroke 3 30,20430,204 1.13 1.13 (1.02-1.25)(1.02-1.25) 00

Heart Failure 2 29,69729,697 1.07 1.07 (0.81-1.41)(0.81-1.41) 67.167.1


0.50 0.75 1.00 1.25

Favours Thiazide

Favours ACEi

ACEi vs thiazides

1717NOR-EM-060


I2

MortalityMortality 33 44,07544,075 0.94 0.94 (0.88-1.00)(0.88-1.00) 5.75.7

MI (Inc. silent MI) 3 44,07544,075 0.93 0.93

(0.83-1.03)(0.83-1.03) 0

MI (ex. silent MI) 33 44,07544,075 0.91 0.91

(0.81-1.02)(0.81-1.02) 00

Stroke 2 21,49921,499 0.77 0.77 (0.67-0.88)(0.67-0.88)

0

Heart Failure 2 41,83341,833 0.96 0.96 (0.74-1.26)(0.74-1.26)

67.4

Diabetes 1 14,11214,112 0.71 0.71 (0.64-0.78)(0.64-0.78)

NA


0.50 0.75 1.00 1.25

Favours BB

Favours CCB

CCB vs BB

1818NOR-EM-060


I2


MI 5 32,19532,195 1.02 1.02 (0.96-1.08)(0.96-1.08) 00

Stroke 5 32,19532,195 0.93 0.93 (0.84-1.04)(0.84-1.04) 00

Heart Failure 5 32,19532,195 1.38 1.38 (1.25-1.53)(1.25-1.53) 0.20.2

Diabetes 3 20,88520,885 0.82 0.82 (0.75-0.90)(0.75-0.90) 43.843.8


0.50 0.75 1.00 1.25

Favours thiazide

Favours CCB

CCB vs Thiazides

1919NOR-EM-060


I2


MI 3 9,7459,745 0.75 0.75 (0.62-0.91)(0.62-0.91)

0

Stroke 3 9,7459,745 0.64 0.64 (0.52-0.78)(0.52-0.78)

0


0.50 0.75 1.00 1.25

Favours Placebo

Favours AHD

AHD vs Placebo (ISH)

2020

RecommendationsRecommendationsRecommendationsRecommendations

2121NOR-EM-060

2222NOR-EM-060

RecommendationsRecommendationsRecommendationsRecommendations 55 歲以上之高血壓病人 , 第一線用藥應為 CCB 或 thiazide 利尿劑 .

55 歲以下之高血壓病人 , 第一線用藥應為 ACEi. ( 若不能耐受 , 則改為ARB, 以下同 )

若以 CCB 或 thiazide 利尿劑為第一線用藥 , 加藥時應選擇 ACEi. 若以ACEi 為第一線用藥 , 加藥時應選擇 CCB 或 thiazide 利尿劑 .

若需要第三線用藥 , 則採用 CCB+ thiazide 利尿劑 +ACEi.

若三種藥物合併治療仍無法控制血壓時 , 可加上第四線藥物且 / 或尋求專家意見 .

第四線藥物可為 : 較高劑量之 thiazide 利尿劑或其他類利尿劑 ( 需小心監測 ) Beta blocker 選擇性之 alpha blocker

55 歲以上之高血壓病人 , 第一線用藥應為 CCB 或 thiazide 利尿劑 .

55 歲以下之高血壓病人 , 第一線用藥應為 ACEi. ( 若不能耐受 , 則改為ARB, 以下同 )

若以 CCB 或 thiazide 利尿劑為第一線用藥 , 加藥時應選擇 ACEi. 若以ACEi 為第一線用藥 , 加藥時應選擇 CCB 或 thiazide 利尿劑 .

若需要第三線用藥 , 則採用 CCB+ thiazide 利尿劑 +ACEi.

若三種藥物合併治療仍無法控制血壓時 , 可加上第四線藥物且 / 或尋求專家意見 .

第四線藥物可為 : 較高劑量之 thiazide 利尿劑或其他類利尿劑 ( 需小心監測 ) Beta blocker 選擇性之 alpha blocker

AA

CC

BB

BB

CC

CC

2323NOR-EM-060

RecommendationsRecommendations RecommendationsRecommendations

若四種藥物合併治療仍無法控制血壓時 , 需尋求專家意見 .

Beta-blocker 非高血壓治療第一線建議用藥 . 但在年輕的病人 , 特別是有以下情況者 , 得以考慮第一線使用 :

對 ACEi / ARB 不能耐受 , 或有禁忌症者可能懷孕的婦女證實有交感神經反應增強的病人在上述情形下 , 當第一線用藥為 beta-blocker 時 , 建議使用 CCB

或 thiazide 類利尿劑當第二線用藥 , 以減少新生糖尿病之風險 .

若病人血壓控制不良 , 不論用藥組合中是否包含 beta-blocker, 均應依前述血壓治療規則用藥 .

若病人血壓控制良好 , 而用藥組合中包含 beta-blocker, 則需作長期評估 , 但並不一定要將 beta-blocker 換為其他用藥 .

若四種藥物合併治療仍無法控制血壓時 , 需尋求專家意見 .

Beta-blocker 非高血壓治療第一線建議用藥 . 但在年輕的病人 , 特別是有以下情況者 , 得以考慮第一線使用 :

對 ACEi / ARB 不能耐受 , 或有禁忌症者可能懷孕的婦女證實有交感神經反應增強的病人在上述情形下 , 當第一線用藥為 beta-blocker 時 , 建議使用 CCB

或 thiazide 類利尿劑當第二線用藥 , 以減少新生糖尿病之風險 .

若病人血壓控制不良 , 不論用藥組合中是否包含 beta-blocker, 均應依前述血壓治療規則用藥 .

若病人血壓控制良好 , 而用藥組合中包含 beta-blocker, 則需作長期評估 , 但並不一定要將 beta-blocker 換為其他用藥 .

CCBB

CC

CC

24

2007

Hypertensionas a Public

Health Risk

January, 2007

2007 Canadian Hypertension Education Program Recommendations

25

Usual blood pressure threshold values for initiation of pharmacological treatment of hypertension

Condition Initiation

SBP or DBP mmHg

• Systolic or Diastolic hypertension 140/90

• Diabetes

• Chronic Kidney Disease130/80

Indications for Pharmacotherapy


26

Treatment Algorithm for Isolated Systolic Hypertension without Other Compelling Indications

INITIAL TREATMENT AND MONOTHERAPY

Thiazide diuretic

Long-actingDHP CCB

Lifestyle modificationtherapy

ARB

TARGET <140 mmHg


27

Treatment of Hypertension in Patients with Ischemic Heart Disease

• Caution should be exercised when combining a non DHP-CCB and a beta-blocker• If abnormal systolic left ventricular function: avoid non DHP-CCB (Verapamil or

Diltiazem)

1. Beta-blocker2. Long-acting CCBStable angina

ACE-I are recommended for most patients with established CAD*

Short-actingnifedipine

Those at low risk with well controlled risk factors may not benefit from ACEI therapy


28

Treatment of Hypertension in Patients with Recent ST Segment Elevation-MI or non-ST Segment Elevation-MI

Long-actingDHP CCB

(Amlodipine, Felodipine)

Beta-blocker and ACE-I

Recentmyocardialinfarction

Heart Failure

?

NO

YES

Long-acting CCB

If beta-blocker contraindicated or not effective

An ARB can be used if the patient is intolerant to ACE-I


29

The benefits of treating smokers with beta-blockersremain uncertain in the absence of a specific

indications like angina or post-MI

Smoking Beta-blocker

Treatment of Hypertension for Patients Who Use Tobacco

Compelling and possible indications, contraindications, and cautions for the major classes of antihypertensive drugs Class of drug

Compelling indications

Possible indications

Caution

Compelling contraindications

Beta-blockers MI, Angina

Heart failure Heart failure, PVD,

Diabetes (except with CHD)

Asthma/COPD, Heart block

CCBs (dihydropyridine)

Elderly, ISH Angina - -

CCBs (rate limiting)

Angina Elderly Combination with beta-blockade

Heart block Heart failure

Thiazide/thiazide-like diuretics

Elderly ISH Heart failure 2 o stroke prevention

Gout



高血壓


心律不整

心臟衰竭

高血壓


心律不整

心臟衰竭

Z.C Chen

冠狀動脈心臟病的病理機轉冠狀動脈心臟病的病理機轉冠狀動脈心臟病的病理機轉冠狀動脈心臟病的病理機轉

氧氣供應氧氣需求

冠狀動脈血流冠狀動脈內徑冠狀動脈血流灌流壓血紅素含氧量疾病時程

心跳速率血壓心肌收縮力量左心室大小收縮期時程

Z.C Chen

Pharmacological Treatment in CAD

Z.C Chen

ß-Blockersß-Blockersß-Blockersß-Blockers

Mechanism of actionBlocks catecholamines from binding

to ß-adrenergic receptors

Reduces HR, BP, myocardial contractility

Decreases AV nodal conduction Decreases incidence of primary VF

Mechanism of actionBlocks catecholamines from binding

to ß-adrenergic receptors

Reduces HR, BP, myocardial contractility

Decreases AV nodal conduction Decreases incidence of primary VF

Z.C Chen

ß-Blockersß-Blockersß-Blockersß-Blockers

Severe CHF/PE SBP <100 mm HgAcute asthma (bronchospasm)2nd- or 3rd-degree

AV block

Severe CHF/PE SBP <100 mm HgAcute asthma (bronchospasm)2nd- or 3rd-degree

AV block

Mild/moderate CHFHR <60 bpmHistory of asthmaIDDMSevere peripheral vascular disease

Mild/moderate CHFHR <60 bpmHistory of asthmaIDDMSevere peripheral vascular disease

AbsoluteContraindications Cautions

Z.C Chen

The New Role of The New Role of ββ-Blocker -Blocker in Cardiovascular Diseasein Cardiovascular DiseaseThe New Role of The New Role of ββ-Blocker -Blocker in Cardiovascular Diseasein Cardiovascular Disease

高血壓


心律不整

心臟衰竭

高血壓


心律不整

心臟衰竭

Z.C Chen

抗心律不整藥物抗心律不整藥物抗心律不整藥物抗心律不整藥物

1971 Vaughn Williams classification

-Class I: 鈉離子通道阻斷劑-Class II: β-blocker-Class III: 鉀離子通道阻斷劑-Class IV: 鈣離子通道阻斷劑

1971 Vaughn Williams classification

-Class I: 鈉離子通道阻斷劑-Class II: β-blocker-Class III: 鉀離子通道阻斷劑-Class IV: 鈣離子通道阻斷劑

Z.C Chen

Indiction ofβ-blocker for Indiction ofβ-blocker for ArrhythmiaArrhythmiaIndiction ofβ-blocker for Indiction ofβ-blocker for ArrhythmiaArrhythmia

Inappropriate or unwanted sinus tachycardiaParoxymal atrial tachycardia provoked by emotion or exerciseExercise-induced ventricular arrhythmiasArrhythmia of pheochromocytoma ( with α-blocker)Hereditary prolonged QT syndromeSome heart failureArrhythmia in mitral valve prolapse

Inappropriate or unwanted sinus tachycardiaParoxymal atrial tachycardia provoked by emotion or exerciseExercise-induced ventricular arrhythmiasArrhythmia of pheochromocytoma ( with α-blocker)Hereditary prolonged QT syndromeSome heart failureArrhythmia in mitral valve prolapse



高血壓


心律不整

心臟衰竭

高血壓


心律不整

心臟衰竭

Population of CHFPopulation of CHFPopulation of CHFPopulation of CHF

Prevalence1-3% (general population)

10% (very elderly)

Incidence0.1-0.2% (general population)

Double with each decade

CHF populationEU: 6.5 millionUSA: 5 million

Japan: 2.4 millionNew CHF 1million/yr

(worldwide)

Destinies of Heart Destinies of Heart FailureFailure

Destinies of Heart Destinies of Heart FailureFailure

Pumping failure Arrhythmogenicity

Failing Heart

Progressive HF

Sudden cardiac death

The Lancet 1999;353:2001-2007. MERIT-HF study group.

NYHA II (5-15%)

12%

64% 24%

NYHA IV(30-70%)

56%

11%

33%

CHF

Other

Sudden Death

NYHA III (20-50%)

26%

15%

59%

Death in Heart FailureDeath in Heart FailureDeath in Heart FailureDeath in Heart Failure

Overall mortality 60%/5 years

Myocardial

infarctionEarly Late

Ventricular

dysfunction

Overt heart failure

Time

ANFCatecholamines

Renin-angiotensin system

(use of diuretics)

Horm

one

Hormone Activation in Heart Hormone Activation in Heart FailureFailure

Hormone Activation in Heart Hormone Activation in Heart FailureFailure

Remodeling• Hypertrophy & dilatation• Apoptosis• Regression to fetal phenotype• Change of matrix

1receptors

2receptors

myocyte hypertrophy + death,remodeling, ischemia + arrhythmias

1receptors

Cardiacsympathetic activity

Sympatheticactivity to kidneys& blood vessels

vasoconstrictionsodium retention

CNS sympatheticoutflow

Why Why Are Are ßß--Blockers Blockers Useful in Useful in CHFCHF??

Why Why Are Are ßß--Blockers Blockers Useful in Useful in CHFCHF??

Packer AHA 2000

Mechanisms of Mechanisms of Sudden Cardiac DeathSudden Cardiac Death

Mechanisms of Mechanisms of Sudden Cardiac DeathSudden Cardiac Death

Ischaemia / infarction

Myocardial damage

Tachyarrhythmias

Sudden Death

Left ventricularremodelling CHF

Sympatheticactivation

-receptor blockade

ßß-Blockers for Heart -Blockers for Heart FailureFailure

ßß-Blockers for Heart -Blockers for Heart FailureFailure

Frog turns into Prince?

Carvedilol(n=696)

Placebo(n=398)

Survival

Days

0 50 100 150 200 250 300 350 400

1.0

0.9

0.8

0.7

0.6

0.5

Risk reduction = 65%Risk reduction = 65%p<0.001

Packer et al (1996)

Lancet (1999)0 200 400 600 800

1.0

0.8

0.6

0

Bisoprolol

Placebo

Time after inclusion (days)

p<0.0001

Survival

Risk reduction = 34%Risk reduction = 34%

The MERIT-HF Study Group (1999)

Months of follow-up

Mortality %

0 3 6 9 12 15 18 21

20

15

10

5

0

Placebo

Metoprolol CR/XL

p=0.0062

Risk reduction = 34%Risk reduction = 34%

US Carvedilol StudyUS Carvedilol Study

blockers in blockers in heart failure -heart failure -

all-cause mortalityall-cause mortality

CIBIS-IICIBIS-II MERIT-HFMERIT-HF

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2

Relative risk and 95% confidence intervals

CIBIS-II: 1.3 yearsplacebo 228/1320 (17%); bisoprolol 156/1327 (12%)P=.0001

MERIT-HF: 12 monthsplacebo 217/2001 (11%); metoprolol 145/1990 (7%)P=.006

CIBIS-I: 1.9 yearsplacebo 67/321 (20%); bisoprolol 53/320 (16%)

P=.22

US Carvedilol Trials: 7.6 months*placebo 31/398 (8%); carvedilol 22/696 (3%)

P=.001

* Not a planned endpoint.

Effect of Effect of ßß-Blocker on-Blocker onAll-Cause MortalityAll-Cause Mortality

Effect of Effect of ßß-Blocker on-Blocker onAll-Cause MortalityAll-Cause Mortality

Class IIClass IIClass IIIClass III

Class IClass I Class IVClass IV

US Carvedilol Programme (carvedilol)US Carvedilol Programme (carvedilol)CIBIS II (bisoprolol)CIBIS II (bisoprolol)

MERIT-HF (metoprolol)MERIT-HF (metoprolol)

?? ??

Packer, AHA 2000Packer, AHA 2000

.

100

90

80

60

70

50

240 20161284 28

Placebo 18.5%

Carvedilol 11.4%

Months

% Survival

Nominal p=0.00014

35% risk reduction

COPERNICUS - COPERNICUS - All-cause mortality All-cause mortality 20022002

COPERNICUS - COPERNICUS - All-cause mortality All-cause mortality 20022002

11 receptors receptors 22 receptors receptors

Myocyte hypertrophy & death,Myocyte hypertrophy & death,dilatation, ischaemia & arrhythmia'sdilatation, ischaemia & arrhythmia's

11 receptors receptors

CardiacCardiacsympathetic activitysympathetic activity

SympatheticSympatheticactivity to kidneysactivity to kidneys& blood vessels& blood vessels

VasoconstrictionVasoconstrictionSodium retentionSodium retention

CNS sympatheticCNS sympatheticoutflowoutflow

Adrenergic activationAdrenergic activationAdrenergic activationAdrenergic activation


CAPRICORNCAPRICORN(carvedilol)(carvedilol)


US Carvedilol (carvedilol)US Carvedilol (carvedilol)CIBIS II (bisoprolol)CIBIS II (bisoprolol)

MERIT-HF (metoprolol)MERIT-HF (metoprolol)

COPERNICUSCOPERNICUS(carvedilol)(carvedilol)



COMETCOMET - - Primary Endpoint of Primary Endpoint of MortalityMortality

COMETCOMET - - Primary Endpoint of Primary Endpoint of MortalityMortality

Lancet 2003

Time (years)

Mo

rtal

ity

(%)

0

10

20

30

40

0 1 2 3 4 5

Metoprolol

Carvedilol

hazard ratio 0.83, 95% CI 0.74-0.93, P = 0.0017

Number at risk

Carvedilol 1511 1367 1259 1155 1002 383Metoprolol 1518 1359 1234 1105 933 352

17%



COMETCOMET(carvedilol vs metoprolol)(carvedilol vs metoprolol)




Target doseTarget dose Mortality effectMortality effect

MetoprololMetoprololMDCMDC 100-150 mg100-150 mg No No MERIT-HFMERIT-HF 200 mg200 mg 34% (sig) 34% (sig)

BisoprololBisoprololCIBISCIBIS 5 mg5 mg 20% (ns) 20% (ns)CIBIS-IICIBIS-II 10 mg10 mg 34% (sig) 34% (sig)

What should be the target dose?What should be the target dose?

What should the target What should the target dose of carvedilol be?dose of carvedilol be?

What should the target What should the target dose of carvedilol be?dose of carvedilol be?

..

00

00..11

00..22

00..33

00..44

CarvedilolCarvedilol

00

44

88

1122

1166

pp<0.05<0.05

pp=0.07=0.07

pp=0.01=0.01 pp=0.01=0.01

pp=0.01=0.01

Mortality %Mortality % Mean number per subjectMean number per subject

MortalityMortality Cardiovascular hospitalisationsCardiovascular hospitalisations

PlaceboPlacebo 6.25 mg bid6.25 mg bid 12.5 mg bid12.5 mg bid 25 mg bid25 mg bid PlaceboPlacebo 6.25 mg bid6.25 mg bid 12.5 mg bid12.5 mg bid 25 mg bid25 mg bid


pp<0.001<0.001

Dosing for Dosing for blockers in heart failure blockers in heart failure

DrugDrug Starting doseStarting dose Target Target dosedose

BisoprololBisoprolol 1.25 mg qd1.25 mg qd 10 mg qd10 mg qd

CarvedilolCarvedilol 3.125 mg bid3.125 mg bid 6.256.25––25 mg 25 mg bidbid

MetoprololMetoprolol 12.512.5––25 mg qd25 mg qd 200 mg qd200 mg qd(extended-release)(extended-release)

The Medical Letter, June 26, 2000The Medical Letter, June 26, 2000



COMETCOMET(carvedilol vs metoprolol)(carvedilol vs metoprolol)




Trial NNT

WOSCOPS (primary prevention) 551

4S (secondary prevention) 163

Enalapril in NYHA I/II 100

MERIT-HF 27

CIBIS II 23

COPERNICUS 15

NNT ~ placebo mortality rate

NNT NNT to Prevent One Death in HF to Prevent One Death in HF

TrialsTrials

NNT NNT to Prevent One Death in HF to Prevent One Death in HF

TrialsTrials

COPERNICUSCOPERNICUS

Implications for public healthImplications for public health

Lives saved by treatingLives saved by treating1000 patients for 1 year1000 patients for 1 year

HOPE (ramipril)HOPE (ramipril) <1<1

SOLVD Prevention (enalapril)SOLVD Prevention (enalapril) 7 7

SOLVD Treatment (enalapril)SOLVD Treatment (enalapril) 17 17

MERIT-HF (metoprolol)MERIT-HF (metoprolol) 38 38

CIBIS-II (bisoprolol)CIBIS-II (bisoprolol) 42 42

RALES (spironolactone)RALES (spironolactone) 52 52

COPERNICUS (carvedilol)COPERNICUS (carvedilol) 70 70


CAPRICON(carvedilol

postMI)

All patients treated with ACE inhibitors

USCP(carvedilol)

- 54%

CIBIS II(bisoprolol)

- 44%

MERIT-HF(metoprolol)

- 41% - 26%

ß-ß-Blockers Reduce SCD in HFBlockers Reduce SCD in HFß-ß-Blockers Reduce SCD in HFBlockers Reduce SCD in HF

COPERNICUS(carvedilol)

- 23%

CIBIS II(bisoprolol)

- 33%

MERIT-HF(metoprolol)

All patients treated with ACE inhibitors

- 20% - 36% - 15% - 33%

All-cause hospitalisation CHF hospitalisation

ßß-Blockers Prevent -Blockers Prevent HospitalisationHospitalisation

ßß-Blockers Prevent -Blockers Prevent HospitalisationHospitalisation

11 receptors receptors 11 receptors receptors

CARDIOTOXICITYCARDIOTOXICITY

22 receptors receptors

Sympathetic activationSympathetic activation

BisoprololBisoprololMetoproloMetoprolollPropranololPropranolol


Antiadrenergic therapy by Antiadrenergic therapy by blockadeblockadeAntiadrenergic therapy by Antiadrenergic therapy by blockadeblockade


MetoprololMetoprolol

CardiacCardiacnorepinephrinenorepinephrine

AntioxidantAntioxidanteffectseffects


CardiacCardiacnorepinephrinenorepinephrine

SympatheticSympatheticantagonismantagonism

11 receptor receptor

blockadeblockade

11 and and 22 receptor receptor

blockadeblockade

receptorreceptorupregulationupregulation

receptorreceptorsuppressionsuppression


Carvedilol provides comprehensive Carvedilol provides comprehensive adrenergic blockadeadrenergic blockade

Adapted from M PackerAdapted from M Packer

blockadeblockade

Cardiac Cardiac outputoutput

Renal Renal blood flowblood flow

Worsening Worsening heart failureheart failure

Sodium Sodium retentionretention

Carvedilol provides comprehensive Carvedilol provides comprehensive adrenergic blockadeadrenergic blockade

Adapted from M PackerAdapted from M Packer

blockadeblockade

blockadeblockade

blockadeblockade

Cardiac Cardiac outputoutput

Renal Renal blood flowblood flow

Worsening Worsening heart failureheart failure

Sodium Sodium retentionretention

Drug Treatments For CHFDrug Treatments For CHFDrug Treatments For CHFDrug Treatments For CHF

C H F

ACE inhibitors

-blockers

ARBs

Vasodilators

Aldosterone antagonists

Digoxin

ß-AgonistsInodilators (PDEI)PDEI with calcium sensitizer

Documents

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