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The New Role of β -Blocker in Cardiovascular Disease. 奇美醫學中心 一般內科 心臟內科 陳志成醫師. The New Role of β -Blocker in Cardiovascular Disease. 高血壓 冠狀動脈疾病 ( 冠心症 ) 心律不整 心臟衰竭. U.S. Department of Health and Human Services. National Institutes of Health. - PowerPoint PPT Presentation
Citation preview
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
冠狀動脈疾病 ( 冠心症 )
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
Comparison Studies Total n Effect size RR (95% CI)
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours CCB
Favours ACEi
ACEi vs CCB
1414NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours BB
Favours ARB
ARB vs BB
1515NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours CCB
Favours ARB
ARB vs CCB
1616NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
I2
MortalityMortality 22 29,69729,697 1.00 1.00 (0.94-1.06)(0.94-1.06) 00
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours Thiazide
Favours ACEi
ACEi vs thiazides
1717NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours BB
Favours CCB
CCB vs BB
1818NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
I2
MortalityMortality 55 32,19532,195 0.97 0.97 (0.93-1.02)(0.93-1.02) 00
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
ResultsResultsResultsResults
0.50 0.75 1.00 1.25
Favours thiazide
Favours CCB
CCB vs Thiazides
1919NOR-EM-060
Comparison Studies Total n Effect size RR (95% CI)
I2
MortalityMortality 33 9,7459,745 0.88 0.88 (0.77-1.01)(0.77-1.01) 00
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
ResultsResultsResultsResults
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
2007 Canadian Hypertension Education Program Recommendations
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
2007 Canadian Hypertension Education Program Recommendations
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
2007 Canadian Hypertension Education Program Recommendations
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
2007 Canadian Hypertension Education Program Recommendations
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
The New Role of The New Role of ββ-Blocker in -Blocker in Cardiovascular DiseaseCardiovascular Disease
The New Role of The New Role of ββ-Blocker in -Blocker in Cardiovascular DiseaseCardiovascular Disease
高血壓
冠狀動脈疾病 ( 冠心症 )
心律不整
心臟衰竭
高血壓
冠狀動脈疾病 ( 冠心症 )
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
冠狀動脈疾病 ( 冠心症 )
心律不整
心臟衰竭
高血壓
冠狀動脈疾病 ( 冠心症 )
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
The New Role of The New Role of ββ-Blocker in -Blocker in Cardiovascular DiseaseCardiovascular Disease
The New Role of The New Role of ββ-Blocker in -Blocker in Cardiovascular DiseaseCardiovascular Disease
高血壓
冠狀動脈疾病 ( 冠心症 )
心律不整
心臟衰竭
高血壓
冠狀動脈疾病 ( 冠心症 )
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
Packer, AHA 2000Packer, AHA 2000
CAPRICORNCAPRICORN(carvedilol)(carvedilol)
Class IClass I Class IVClass IV
US Carvedilol (carvedilol)US Carvedilol (carvedilol)CIBIS II (bisoprolol)CIBIS II (bisoprolol)
MERIT-HF (metoprolol)MERIT-HF (metoprolol)
COPERNICUSCOPERNICUS(carvedilol)(carvedilol)
Class IIClass IIClass IIIClass III
Packer, AHA 2000Packer, AHA 2000
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%
CAPRICORNCAPRICORN(carvedilol)(carvedilol)
Class IClass I Class IVClass IV
COMETCOMET(carvedilol vs metoprolol)(carvedilol vs metoprolol)
COPERNICUSCOPERNICUS(carvedilol)(carvedilol)
Class IIClass IIClass IIIClass III
Packer, AHA 2000Packer, AHA 2000
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
CarvedilolCarvedilol
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
CAPRICORNCAPRICORN(carvedilol)(carvedilol)
Class IClass I Class IVClass IV
COMETCOMET(carvedilol vs metoprolol)(carvedilol vs metoprolol)
COPERNICUSCOPERNICUS(carvedilol)(carvedilol)
Class IIClass IIClass IIIClass III
Packer, AHA 2000Packer, AHA 2000
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
Packer, AHA 2000Packer, AHA 2000
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
CarvedilolCarvedilol
Antiadrenergic therapy by Antiadrenergic therapy by blockadeblockadeAntiadrenergic therapy by Antiadrenergic therapy by blockadeblockade
Packer, AHA 2000Packer, AHA 2000
MetoprololMetoprolol
CardiacCardiacnorepinephrinenorepinephrine
AntioxidantAntioxidanteffectseffects
CarvedilolCarvedilol
CardiacCardiacnorepinephrinenorepinephrine
SympatheticSympatheticantagonismantagonism
11 receptor receptor
blockadeblockade
11 and and 22 receptor receptor
blockadeblockade
receptorreceptorupregulationupregulation
receptorreceptorsuppressionsuppression
Packer, AHA 2000Packer, AHA 2000
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