Transcript Document 7169558

New Dimensions and
Landmark Practice Advances
Evolving Perspectives on the Role on
Beta-Blockers Across the
Risk Spectrum for Heart Disease
Program Chairman
Henry R. Black, MD
Clinical Professor of Medicine
NYU Medical Center
President – American Society of Hypertension
NYU Center for the Prevention of Cardiovascular Disease
New York, NY
Welcome and Program Overview
CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical School and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational grant
from Forest Laboratories
Mission statement: Improve patient care through evidence-based
education, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
Program Educational Objectives
As a result of this educational activity, participants will:
► Learn how to approach hypertension as a systematic disease, with
multiple manifestations, and associations, including assessment of
coexisting conditions that support use of specific classes or agents.
► Learn how to apply evidence-based support for cardioselective betablockers across the cardiovascular disease risk spectrum, including
hypertension, symptomatic CHD, and heart failure.
► Learn how to manage complicated patients with high blood pressure,
including those with ischemic heart disease and/or heart failure.
► Learn about the possible role of the new and emerging beta-1
cardioselective beta-blockers and their role in the management of
hypertension and related cardiovascular disorders, including heart
failure and CVD.
Program Faculty
Program Chairman
Henry R. Black, MD
Clinical Professor of Medicine
NYU Medical Center
President – American Society of
Hypertension
NYU Center for the Prevention of
Cardiovascular Disease
New York, NY
Michael A. Weber, MD
Professor of Medicine
SUNY Downstate College of
Medicine
Brooklyn, New York
Barry H. Greenberg, MD
Professor of Medicine
Director Advanced Heart Failure
Program
University of California, San Diego
UCSD Medical Center
San Diego, California
Faculty COI Disclosures
Henry R. Black, MD
Consultant: Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, Gilead, and
Intercure
Michael A. Weber, MD
Consultant: Novartis, Bristol-Myers Squibb, sanofi-aventis, Daiichi Sankyo,
Boehringer Ingelheim, GlaxoSmithKline, Forest Laboratories, Gilead, and
Takeda
Barry H. Greenberg, MD
Consultant: GlaxoSmithKline, Otsuka, and sanofi-aventis
Honoraria: GlaxoSmithKline, Merck, and Otsuka
New Dimensions and
Landmark Practice Advances
Introduction To Current Landscape of
Hypertension
Landmark Advance
And New Wisdom For
2009 And Beyond
Program Chairman
Henry R. Black, MD
Clinical Professor of Medicine
NYU Medical Center
President – American Society of Hypertension
NYU Center for the Prevention of Cardiovascular Disease
New York, NY
Leading Causes of Death for All Ages
United States
Deaths per 100,000 Population
(log scale)
10,000
SGR
STATINS
All causes
1000
Heart disease
Cancer
100
Stroke
Unintentional injuries
VA STUDY
DIURETICS
CLRD
10
1950
1960
1970
1980 1985 1990 1995
Year
CLRD=chronic lower respiratory diseases.
Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/nchs/data/hus/ hus05.pdf. Accessed July
4, 2006.
2002
Causes of Death in the USA—2005
A Total CVD
B Cancer
C Accidents
D Chronic Lower Respiratory Diseases
E Diabetes Mellitus
F Alzheimer’s Disease
CVD and other major causes of death for all males and females (United States: 2005). Source: NCHS.
Impact of Cardiovascular Disease
►
CVD No 1 killer in US: $403.1 billion
►
2500 CVD deaths each day: ~ 1 death every 35 seconds
►
CVD claims more lives each year than the next 3 leading causes of
death combined
Deaths per 100,000
300
250
200
150
100
50
CVD
Cancer
Respiratory
Disease
Trauma
0
AHA Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;1-69.
Global Mortality 2000:
Impact of Hypertension
High mortality,
developing region
Lower mortality,
developing region
Developed region
0
1000 2000 3000 4000 5000 6000 7000 8000
Attributable Mortality (in thousands; total 55,861,000)
BMI = body mass index.
Adapted with permission from Ezzati M, et al. Lancet. 2002;360:1347-1360.
Deaths From Cardiovascular Diseases %
Coronary Heart
Disease
Coronary
Heart
14
4
7
Disease
Stroke
14
Stroke
4
7
HF*
HF*Heart
7
52
17
7
52
17
(United States: 2006 preliminary) Source: NCHS and NHLBI.
Failure
High
Blood
High
Blood
Pressure
Pressure
Diseases
of the
Diseases
of the
Arteries
Arteries
Other
Other
Hospital Discharges For Heart Failure By Sex
Note: Hospital discharges include people discharged alive, dead and status unknown.
(United States: 2006 preliminary) Source: NCHS and NHLBI.
Factors Determining Blood Pressure
Volume
Vasoconstrictors
AII, Catechols,
Endothelin, etc.
Central Nervous
System
Peripheral
Nervous System
Vasodilators
NO, PG, etc.
Local Factors
Renal, Cardiac,
Adrenal
Consequences of Hypertension:
Organ Damage
Hypertension
Transient
ischemic attack,
stroke
Retinopathy
LVH, CHD, CHF
Peripheral
arterial
disease
Chronic kidney
disease
CHF=congestive heart failure; CHD=coronary heart disease; LVH=left ventricular hypertrophy.
Chobanian AV et al. JAMA. 2003;289:2560-2572.
The Cardiovascular Continuum
Oxidative Stress /
Endothelial
Dysfunction
Target Organ
Damage
Tissue Injury
(MI, Stroke)
Vascular Disease
Vascular
Dysfunction
Risk Factors:
Diabetes
Hypertension
Pathological
Remodeling
Target Organ
Dysfunction (HF, Renal)
End-stage
Organ Failure
MI: Myocardial
infarction
HF: Heart failure
Adapted from Dzau et al. Circulation. 2006;114:2850-2870.
Death
Percentage of the US Population
with 2 CV Risk Factors*
Risk Factors = High BP, High Cholesterol, Diabetes, Obesity, Smoking
1991
2003
Percentage of Population With 2 Risk Factors
<22%
22.0% to 24.9%
25.0% to 29.9%
30%
* Risk factors are self-reported
Greenlund et al. Arch Intern Med. 2004;164:181-188; Centers for Disease Control and Prevention.
MMWR Morb Mortal Wkly Rep. 2005;54:113-117.
NA
Hypertension Co-Morbidities
►
% of patients with BP >140/90 mm Hg:
●
69% of patients with 1st MI
●
77% of patients with 1st stroke
●
74% of patients with HF
►
Hypertension precedes HF in 91% of cases
►
Hypertension is associated with a 2- to 3-times
higher risk for HF
BP, blood pressure; HF, heart failure; MI, myocardial infarction.
Thom T et al. Circulation. 2006;113:e85-e151.
Residual Lifetime Risk of Hypertension
in Women and Men Aged 65 Years
100
Men
80
60
Risk of
hypertension
(%)
40
Women
20
0
0
2
4
6
8
10
12
Follow-up (y)
Vasan RS et al. JAMA. 2002;287:1003-1010.
14
16
18
20
Prevalence, Awareness, Treatment, and Control of
Hypertension Among United States Adults 1999-2004
Prevalence of HBP
> 60 yrs – OR - 27.35
compared to 18-30 yrs.
Prevalence of HBP in
Obese or overweight
OR – 1.73 – 3.39
compared to BMI < 25
Kwok Leung Ong, Bernard M.Y. Cheung, Yu Bun Man, Chu Pak Lau, Karen S. L. Lam.
Hypertension
JNC BP Classifications: DBP
130
125
Stage 4
120
115
DBP
(mm Hg)
110
Hypertensive
Severe
Severe
Severe
Moderate
Moderate
Moderate
105
100
95
Consider
therapy
Mild
90
85
80
JNC I
JNC II
JNC I. JAMA. 1977;237:255-261.
JNC II. Arch Intern Med. 1980;140:1280-1285.
JNC III. Arch Intern Med. 1984;144:1045-1057.
JNC IV. Arch Intern Med. 1988;148:1023-1038.
Mild
Stage 3
Stage 3
Stage 2
Stage 2
Stage 2
A,B,C
Stage 1
Stage 1
Stage 1
Mild
Highnormal
Highnormal
Highnormal
Highnormal
Normal
Normal
Normal
Normal
Prehypertension
Optimal
Optimal
Normal
JNC V
JNC VI
JNC 7
JNC III
JNC IV
JNC V. Arch Intern Med. 1993;153:154-183.
JNC VI. Arch Intern Med. 1997;157:2413-2446.
Chobanian AV et al. JAMA. 2003;289:2560-2572.
Hypertension
JNC BP Classifications: SBP
Stage 4
220
210
200
Stage 3
Stage 3
190
180
SBP
(mm Hg)
ISH
ISH
Stage 2
Stage 2
A,B,C
Stage 2
Borderline
Stage 1
Stage 1
Stage 1
Normal
Highnormal
Normal
Highnormal
Normal
Prehypertension
Optimal
Optimal
Normal
JNC V
JNC VI
JNC 7
170
160
Borderline
150
140
130
No recommendations
for SBP in JNC I
or JNC II
120
110
JNC I
JNC II
JNC I. JAMA. 1977;237:255-261.
JNC II. Arch Intern Med. 1980;140:1280-1285.
JNC III. Arch Intern Med. 1984;144:1045-1057.
JNC IV. Arch Intern Med. 1988;148:1023-1038.
JNC III
JNC IV
JNC V. Arch Intern Med. 1993;153:154-183.
JNC VI. Arch Intern Med. 1997;157:2413-2446.
Chobanian AV et al. JAMA. 2003;289:2560-2572.
Development of
Antihypertensive Therapies
Effective but
poorly tolerated
1940s
As effective and
better tolerated
1950
1957
1960s
1970s
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
Thiazides
diuretics
As effective and even
better tolerated
1980s
ACE
inhibitors
Direct
vasodilators
1990s
Calcium
antagonistsnon DHPs
-blockers
2001
ARBs
-blockers
Central 2
agonists
? More
effective for
SBP
2007
Direct
Renin
inhibitors
ETa
Blockers
Calcium
antagonistsDHPs
VPIs
Others
Development of Combination
Antihypertensive Therapies
1950s
1970s
1960s
Ser-Ap-Es
(reserpine/hydralazine/
hydrochlorothiazide)
Methyldopa/thiazide
Butiserpine (reserpine/butalbital)
Hyphex (hexamethonium/
hydralazine)
Hypotensin A, B, & C
(pentolinium/hydralazine/
resperine)
Renir (reserpine/ephedrine)
Verapene (rauwolfia/veratrum)
1990s2008s
1980s
ACE inhibitor/thiazide
Thiazide/K+-sparing
diuretic
-blocker/thiazide
Clonidine/thiazide
ACE inhibitor/CCB
ARB/thiazide
Low-dose
-blocker/thiazide
ARB/CCB
DRI/thiazide
Development of Hypertension Guidelines:
the JNCs and Drug Therapy
JNC I
1972
NHBPEP
STARTS
Earliest
Guidelines
JNC II
1973
1976 1980
JNC 7
JNC V
JNC IV
1984
JNC 8 (VIII)
JNC VI
1988 1993
1997
2003
84 drugs
50 drugs
7 options
ACEI, CAs
added
43 drugs
68 drugs
> 125 drugs
Low-dose
Diuretics
Diuretics/
diuretics,
-blockers
-blockers
Added
2009
34 drugs
Diuretics
28 drugs
DBP 105
Diuretics
HR Black, 2003.
JNC III
????
Clinical Trials in Hypertension
What is the
Should we treat
goal of
diastolic HBP? treatment?
1960s
1970s
Should we
treat DBP in
older persons?
1980s
2000 2000-03
HOT
UKPDS
EWPHE
MRC-1 SHEP
ANHBP-1
MRC-2
STOP-1
Syst-Eur
Syst-China
HYVET
CAPPP INSIGHT
STOP-2 NORDIL
HAPPHY
MAPHY TOMHS
VA MONORx
HR Black, 2003.
1996-1999
1990-1995
HDFP
VA
Cooperative
Studies
What is the
best way to
treat HBP?
Should we
treat ISH in Can we prevent
older
hypertension?
persons?
2004-08
SCOPE
VALUE
CONVINCE
ASCOT
ALLHAT
ANBP2 ACCOMPLISH
LIFE
ON TARGET
TROPHY
Clinical Trials in Patients With Disorders
Related to Hypertension
Heart failure/ Post-MI
Diabetes
Atherosclerosis
1990-1995
1996-1999
CVA/
Dementia
LVH
Renal disease
Dyslipidemia
2000
2001
2002
2003 2004-2008
SOLVD
SAVE
CAPTOPRIL
ELITE-2
UKPDS
RALES
HOPE
VAL-HeFT
AASK
IDNT
ALLHAT
LIFE
CHARM
EPHESUS
VALIANT
INVEST
SCOPE
EUROPA/
ON-TARGET/
PEACE
TRANSCEND
RENAAL
IRMA2
PROGRESS
HR Black, 2003.
I-PRESERVE
ASCOT
ACCORD
DREAM
JNC 7 Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
With Compelling
Indications
Without Compelling
Indications
Stage 1 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg)
2-drug combinations for most
(usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Chobanian AV et al. Hypertension. 2003;42:1206-1252.
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
The Seventh Report of
the Joint National Committee
Compelling
Indications
Heart failure
Diuretic
βB
ACEI
ARB






Post-MI



Diabetes






Recurrent stroke
prevention

AA


High CAD risk
Chronic kidney
disease
CCB



AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin II-receptor blocker; βB, ß-blocker; CCB, calcium channel
blocker; MI, myocardial infarction; CAD, coronary artery disease.
Chobanian AV, et al. JAMA. 2003;289(19):2560-2572.
Goal Of Antihypertensive Therapy
►
< 140 mm Hg and < 90 mm Hg for most patients
►
< 130 mm Hg and < 80 mm Hg for diabetics, patients
with HF and those with CRF and any day now for
those with CAD
Goal is not dependent on age, gender or co-morbidity
THE GOAL IS THE CEILING, NOT THE FLOOR.
BP-Lowering Treatment Trialists
Stroke
CHD
1.50
Relative Risk of CHD
1.50
1.25
1.25
1.00
1.00
0.75
0.75
0.50
0.50
0.25
-10
-8
-6
-4
-2
0
2
4
Systolic BP Difference Between
Randomized Groups (mm Hg)
0.25
-10
-8
-6
-4
-2
0
2
4
Systolic BP Difference Between
Randomized Groups (mm Hg)
Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.
Percentage of Patients Requiring ≥ 2
Antihypertensive Drugs to Reach BP Targets
100
90
90
Percent
80
73
70
60
78
63
60
50
40
30
20
10
0
HOT
LIFE
ALLHAT
1. HOT: Hansson et al. Lancet. 1998;351:1755–62.
2. LIFE: Dahlöf et al. Lancet. 2002;359:995-1003.
3. ALLHAT: Cushman et al. J Clin Hypertens. 2002;4:393–404.
CONVINCE
ASCOT
4. CONVINCE: Black et al. JAMA. 2003;289:2073-2082.
5. ASCOT: Dahlöf et al. Lancet. 2005;366:895-906.
Advantages of Multidrug Therapy in
Hypertension
►Increased efficacy of each
drug compared to either as
monotherapy
►More prompt achievement
of goal
►Reduced side effects,
clinical and metabolic
►Alterations in
pharmacodynamics allowing
longer duration of action
Adapted and updated from Black HR. Patient Care, 1997.
►Broader spectrum of
response
►Complementary
mechanisms
of action
►Fewer pills should mean
better adherence
►Fewer co-pays if given as a
fixed dose combination and
often cheaper than buying
each individually
JNC 7: Combination Therapy
►
“When BP is more than 20 mmHg above systolic
goal or 10 mmHg above diastolic goal,
consideration should be given to initiate therapy
with 2 drugs, either as separate prescriptions or
in fixed-dose combinations.”
Hypertension, 2003;42:1221b
Position Statement: Monotherapy
Versus Combination Therapy ESC/ESH
►
►
►
►
►
Regardless of the drug employed, monotherapy allows to
achieve BP target in only a limited number of hypertensive
patients.
Use of more than one agent is necessary to achieve target BP
in the majority of patients. A vast array of effective and well
tolerated combinations is available.
Initial treatment can make use of monotherapy or combination
of two drugs at low doses with a subsequent increase in drug
doses or number, if needed.
Monotherapy could be the initial treatment for a mild BP
elevation with a low or moderate total cardiovascular risk. A
combination of two drugs at low doses should be preferred as
first step treatment when initial BP is in the grade 2 or 3 range
or total cardiovascular risk is high or very high.
Fixed combinations of two drugs can simplify treatment
schedule and favor compliance.
ESH 2003: Possible Combinations of Different
Classes of Antihypertensive Agents
The most effective and well tolerated combinations are shown as solid lines
Diuretics
-blockers
AT1-receptor
blockers
-blockers
Calcium
antagonists
ACE inhibitors
ESH Guidelines. J Hypertens. 2007;25:1105-1087.
ESH= European Society of Hypertension
2006 Revision -Blockers Removed
<55 Years
A*
≥55 years or Black
Patients at any Age
C or D
Step 1
A* + C or A* + D
Step 2
A* + C + D
Step 3
Add:
• further diuretic therapy or
• alpha-blocker or
• beta-blocker
Consider seeking specialist advice
Step 4
CAFE: Differences in BP
Brachial vs Aortic SBP
Atenolol
140
Peripheral SBP
Diff Mean (AUC) = 0.7 (-0.4, 1.7) mm Hg
Amlodipine
135
mm Hg
133.9
130
133.2
125
120
N=2199
115
0
0.5
1
1.5
2
2.5
3 3.5
Years
4
4.5
5
5.5
6
CAFE, Conduit Artery Function Evaluation; AUC, area under the curve; SBP, systolic blood pressure.
Williams B et al. Circulation. 2006;113(9):1213-1225.
CAFE: Differences in BP
Brachial vs Aortic SBP
Atenolol
140
Peripheral SBP
Diff Mean (AUC) = 0.7 (-0.4, 1.7) mm Hg
Amlodipine
135
mm Hg
133.9
130
133.2
125
120
125.5
121.2
Central SBP
Diff Mean (AUC) = 4.3 (3.3, 5.4) mm Hg
115
0
0.5
1
1.5
2
2.5
3 3.5
Years
4
4.5
5
5.5
6
N=2199
CAFE, Conduit Artery Function Evaluation; AUC, area under the curve; SBP, systolic blood
pressure.
Williams B et al. Circulation. 2006;113(9):1213-1225.
Incident Diabetes in Clinical Trials of Antihypertensive
Drugs – A Network Meta-analysis
ARBs
0.57 (0.46-0.72) p<0.0001
ACE Inhibitors
0.67 (0.56-0.80) p<0.0001
CCBs
0.75 (0.62-0.90) p=0.002
Placebo
0.77 (0.63-0.94) p=0.009
Β blockers
0.90 (0.75-1.09) p=0.30
Referent
Diuretics
0.50
0.70 0.90
1.26
Odds ratio of incident diabetes
Elliott WJ, Meyer PM. Lancet. 2007;369:201–207.
Incoherence=0.000017
Potential Cardiac Benefits of β-Blockade
in Patients With Hypertension
►
Antiatherogenic—reduces inflammation,
shear stress, endothelial dysfunction, and
risk for plaque rupture1,2,3
►
Antiarrhythmic1
●
●
●
►
Anti-ischemic1
●
●
►
decreases HR2
decreases sympathetic activity1
increases cardiac vagal tone1
decreases HR and BP2
prolongs diastole (filling coronary arteries)2
Reverses cardiac remodeling2
HR, heart rate; BP, blood pressure.
1. Tse WY et al. Diabet Med. 1994;11(2):137-144.
2. Fonarow GC. Am J Med. 2004;116(Suppl 5A):76S-88S.
3. Bell DS. The Endocrinologist. 2003;13:116-123.
New Dimensions and
Landmark Practice Advances
Vasodilating β-Blockers in
the Management of Hypertension
A Clinical Update of Efficacy
and Tolerability
Michael A. Weber, MD
Professor of Medicine
SUNY Downstate College of Medicine
Brooklyn, New York
JNC 7:
First-Line Treatment with β-Blockers
Compelling Indications
 Post-MI
 High CAD risk
 Heart failure
 Diabetes
Chobanian AV et al. JAMA. 2003;289(19):2560-2572.
β-Blockers in Primary Prevention
MAPHY
Beta-blocker (n=1609)
Thiazide diuretics (n=1625)
Total mortality
Sudden CV death
90
80
70
50
40
Cumulative 60
number of 50
deaths
40
30
RRR 22%
P=0.028
30
20
20
RRR 30%
P=0.017
10
10
0
0
0
5
Years
RRR, relative risk reduction
Olsson G et al. Am J Hypertens. 1991;4(2 pt 1):151-158.
Wikstrand J et al. JAMA. 1988;259(13):1976-1982.
10
0
5
Years
10
Clinical Outcomes with -Blocker
Therapy in Diabetics: UKPDS Study
Relative Risk and 95% CI
RR
P
Any diabetes-related endpoint
1.10
.43
Diabetes-related deaths
1.27
.28
All-cause mortality
1.14
.44
Myocardial infarction
1.20
.35
Stroke
1.12
.74
Microvascular disease
1.29
.30
0.5
Favors
ACE inhibitor
United Kingdom Prospective Diabetes Study Group. BMJ. 1998;317:713-720.
1
2
Favors
β-blocker
Meta-analysis of Beta-blockers in Hypertension:
Outcome Data for Atenolol vs Non-beta-blocker Antihypertensive Therapy
Stroke
1.26 (1.15-1.38)
MI
1.05 (0.91-1.21)
All-cause mortality
1.08 (1.02-1.14)
0
Decreased risk
Lindholm LH et al. Lancet. 2005;366:1545-1553.
1
2
Increased risk
Meta-analysis of Beta-blockers in Hypertension:
Outcome Data for Non-atenolol Beta-blockers vs Non-beta-blocker
Antihypertensive Therapy
Stroke
1.20 (0.30-4.71)
MI
0.86 (0.67-1.11)
All-cause mortality
0.89 (0.70-1.12)
0
1
2
Favors – beta-blocker
Lindholm LH et al. Lancet. 2005;366:1545-1553.
3
4
Favors other drug
5
Perceived Barriers to Optimizing
β-Blocker Treatment
Metabolic Concerns*
► Negative
effects on lipid
metabolism
► Negative
effects on
glucose metabolism
► Negative
effects on renal
blood flow
► Masked
hypoglycemia
Tolerability Concerns
► Fatigue
► Impotence
► Weight
increase
► Peripheral
vasoconstriction
(cold extremities)
► Depression
*Primarily in patients with hypertension and diabetes
Bell DS et al. Endocr Pract. 1999;5(1):51-53. Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 6):S38-S49.
Bell DSH et al. Endocrinologist. 2003;13:116-123. Packer M. Prog Cardiovasc Dis. 1998;41(suppl 1): 39-52.
β1/β2-Receptor Selectivity
Among β-Blockers
350
300
250
β1/β2 200
selectivity
150
100
50
0
Nebivolol
Bisoprolol
Metoprolol Bucindolol Propranolol Carvedilol
Bristow MR et al. Am J Hypertens. 2005;18(pt 2):51A-52A. Abstract P-121.
Nebivolol Profile with Respect to Side Effects
Commonly Associated with ß-Blockers*
Incidence Rate (%)
Adverse
Event (%)
Placebo
(n=205)
Nebivolol
5mg-40mg
Fatigue
1.5
Dyspnea
Discontinuation Rate (%)
(n=205)
Nebivolol
5mg-40mg
3.6
0.5
0.0
0.5
1.0
0.0
0.1
Bradycardia
0.5
0.8
0.0
0.2
Erectile
Dysfunction†
0.9
0.6
0.0
0.0
Depression
0.0
0.3
0.0
0.0
(n=1597)
Placebo
*Pooled data from the three monotherapy US registration trials with nebivolol
†For erectile dysfunction n=108 for placebo and n=853 for nebivolol. 5 mg to 40 mg
Registration trials. Data on file, Forest Laboratories, Inc. New York, NY
(n=1597)
Metabolic Effects of
Vasodilatory Beta Blockers
Change in Hemoglobin A1c
GEMINI
P<0.001
7.6
Treatment
Difference
7.4
Mean
HbA1c
(%)
P=0.65
Carvedilol
vs
Metoprolol
-0.13%
7.2
(-0.22, -0.04)
P=0.004
7.0
Baseline Month 5
Carvedilol
(n=454)
Baseline Month 5
Metoprolol tartrate
(n=657)
1,111 patients (90%) were evaluable for efficacy, having both a valid baseline and at least one on-therapy HbA1c
assessment. GEMINI, Glycemic Effects in Diabetes Mellitus: Carvedilol - Metoprolol Comparison in Hypertensives
Bakris GL et al. JAMA. 2004;292(18):2227-2236.
Change in Insulin Resistance by
Homeostasis Model Assessment (HOMA) GEMINI
P=NS
6.3
6.2
6.1
Mean
HOMA
insulin
resistance
P=0.004
Treatment
Difference
Carvedilol
vs
Metoprolol
6.0
5.9
–7.2%
5.8
(–13.8, –0.20)
P=0.004
5.7
5.6
Baseline
Month 5
Carvedilol
(n=371)
Bakris GL et al. JAMA. 2004;292(18):2227-2236.
Baseline
Month 5
Metoprolol Tartrate
(n=540)
Change in Insulin Sensitivity in Hypertensive
Patients With Glucose Intolerance
≈20%
reduction
Insulin sensitivity
EH clamp
IVGTT
†
*
5
2
≈10%
reduction
4.5
4
Glucose
disposal
rate (M)
(mg/kg
per min)
Glucose
disappearanc
e rate (K)
(min-1)
3.5
3
2.5
2
*
1.5
1
1.5
0.5
1
0.5
0
0
Placebo
Nebivolol Atenolol
Placebo
Nebivolol Atenolol
N=25. Crossover; 16-week treatments. Nebivolol 2.5-5 mg and atenolol 50-100 mg daily
†P<0.05 vs nebivolol
*P<0.05 vs placebo
EH, euglycemic-hyperinsulinemic; IVGTT, intravenous glucose tolerance test
Poirier L et al. J Hypertens. 2001;19(8):1429-1435.
Change in Insulin Sensitivity in Newly Diagnosed
Hypertension (w/o Glucose Intolerance) After 6 Months
P=0.003
HOMA-IR
Before
Nebivolol
After
5 mg
Before
After
Metoprolol 100 mg
N=72. HOMA-IR, homeostasis model assessment–insulin resistance
Celik T et al. J Hypertens. 2006;24(3):591-596.
Hemodynamic Effects of
Vasodilatory Beta Blockers
The Vasodilating β-Blockers
Different Mechanisms of Vasodilation
Via . . .
Agent(s)
Site of Activity
Effect
α1-receptor
antagonism
carvedilol
labetalol
bucindolol
receptors located in smooth
muscle, heart
stimulation
causes
contraction
β2-agonism
dilevalol
celiprolol
receptors located in bronchi,
blood vessels, gut
stimulation
causes
vasodilation
L-arginine/
nitric oxide
pathways
nebivolol
pathways located in blood vessel
walls
stimulation
causes
release/activi
ty of NO, and
vasodilation
Bristow MR. Circulation. 2000;101(5):558-569. Berecek KH, Carey RM. Adrenergic and dopaminergic receptors and actions.
In: Izzo JL, Black HR, eds. Hypertension Primer, Third Edition. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:1-4.
COREG Maintains Cardiac Output and
Decreases Total Peripheral Resistance
Weber K et al. Cardiovasc Drugs Ther. 1996; 10:113-117.
Rhoades RA, Tanner GA, eds. Medical Physiology. 1st edition. Boston, MA: Little, Brown and Company; 1995.
Differing Effects of β-Blockers on
Hemodynamics in Hypertensive Patients
3.6
Stroke volume (mL)
Cardiac output (L/min)
20.6
–24.0
–2.1
7.8
–28.2
–10.8
5.8
Peripheral resistance
(dyne/cm-5)
–13.2
5.7
LV end-diastolic
volume (mL)
10.6
LV endsystolic
volume (mL)
–40
Nebivolol
(5 mg/d)
7.1
Ejection fraction (%)
Heart rate (beats/min)
Atenolol
(100 mg/d)
9.2
–1.4
–30
At 2 weeks
Kamp O et al. Am J Cardiol. 2003;92(3):344-348.
–20
–10
0
10
Percent change vs baseline
20
30
Effect of nebivolol and metoprolol
on Sexual Function: IIEF
Nebivolol 5 mg
Metoprolol succinate 95 mg†
Improved
Sexual
Function
 in score from Baseline
1.5
*
1.0
0.5
*
*
*
0.0
-0.5
-1.0
*
Erectile
function
Orgasmic
function
*P<0.05. †Equivalent to metoprolol 100 mg
IIEF=International Index of Erectile Function
Brixius K et al. Clin Exp Pharmacol Physiol. 2007;34(4):327-331.
Sexual
desire
Intercourse Overall
satisfaction satisfaction
CAFE: Differences in BP
Brachial vs Aortic SBP
Atenolol
Peripheral SBP
Diff mean (AUC) = 0.7 (-0.4, 1.7) mm Hg
140
Amlodipine
135
133.9
Mm
Hg
130
133.2
125
125.5
121.2
120
Central SBP
Diff mean (AUC) = 4.3 (3.3, 5.4) mm Hg
115
0
0.5
1
1.5
2
2.5
3
3.5
Years
N=2199.
CAFE, Conduit Artery Function Evaluation
AUC, area under the curve; SBP, systolic blood pressure
Williams B et al. Circulation. 2006;113:1213-1225.
4
4.5
5
5.5
6
Differential Effects of β-Blockers on
Hemodynamic and Atherosclerotic Indices
AI, augmentation index; PWV, pulse wave velocity; MAIMT, aortic intima-media thickness
Olafiranye O et al. J Am Soc Hypertens. 2008;2:64-69.
Effects of a Vasodilating vs a Non-vasodilating
β-Blocker on Central Aortic Pressure in Patients
With Previously Untreated Hypertension
2
Brachial
Aortic
0
-2
-4
Change in
pulse pressure
(mm Hg)
-6
P<0.05
-8
-10
-12
-14
NS
-16
N=16
5 weeks of crossover treatment with atenolol and nebivolol
Dhakam Z et al. J Hypertens. 2008;26:351-356.
Atenolol
Nebivolol
BP Reduction With β-Blocker as Add-On
Trough sitting systolic BP
Nebivolol (mg)
Placebo
5
10
20
Trough sitting diastolic BP
Nebivolol (mg)
Placebo 5
10
20
–0.1
Least
squares
means
reduction
from
baseline
(mm hg)
–3.3
†
–3.7
*
–6.6
*
–5.7
*
–6.8
*
–6.3
*
–7.9
N=598. *P<0.001; †P0.015
ACEI, angiotensin-converting enzyme inhibitor; ARB
Patients were on stable regimen of
at least one and no more than 2
of either an ACEI, ARB, &/or diuretic
Gradman AH. Poster presented at American Society of Hypertension Twenty-Second Annual Scientific Meeting. May,
2007. Chicago, IL.
The Role of Nitric Oxide in
Cardiovascular Disease and in
the Actions of Nebivolol
Endothelial Dysfunction Predicts
CV Events in Hypertensive Patients
1.0
0.8
3rd tertile of FBF
0.6
Event-free survival
0.4
2nd tertile of FBF
1st tertile of FBF
P=0.0012
(Log-rank test)
0.2
0
0
12
60
72
84
Follow-up (mo)
Patients exposed
to risk:
225 164 132 73 52 41
27
10
FBF, forearm blood flow
Perticone F et al. Circulation. 2001;104(2):191-196.
24
36
48
Different Effects of β-Blockers on NO-Mediated
Endothelial Dysfunction in Hypertensive Patients
Change
from
baseline
in
forearm
blood
flow
†
500
400
300
*
†
*
200
100
0
25
50
100
ACh (nmol/min)
Placebo
Atenolol
350
300
250
200
150
100
50
0
4.2
37.8
Sodium nitroprusside
(nmol/min)
Nebivolol
N=12.
*P<0.05; †P<0.001 for differences between treatments. Values are mean±SEM
ACh, acetylcholine; L-NMMA, NG-monomethyl-L-arginine
Adapted from Tzemos N et al. Circulation. 2001;104(5):511-514.
12.6
Endothelial NO/ROS Balance Likely Contributes to Rate
and Severity of CV Disease in Black Americans
25
NO
Superoxide
Peroxynitrate
*
*
*
20
nmol/L
15
10
5
0
*P<0.01.
NO, nitric oxide; ROS, reactive oxygen species
Kalinowski L et al. Circulation. 2004;109(21):2511-2517.
Healthy whites (n=12)
Healthy Black Americans (n=12)
Effect of β-Blockers on NO Release in
Endothelial Cells of Black Americans
550
*
500
450
400
NO release
350
(nM)
300
250
200
0
Control
Metoprolol
Atenolol
Nebivolol
*P<0.01 vs control (NO release stimulated with acetylcholine [ACh] alone); n=5-7
[Drug] = 10 µM; [ACh] = 1 µM. NO, nitric oxide
Mason RP et al. Circulation. 2005;112(24):3795-3801.
Efficacy of Nebivolol in Black Patients:
Diastolic and Systolic BP
Baseline DBP (mm Hg)
100.6
Baseline SBP (mm Hg)
151.4
Dose: Placebo
0
Mean  in BP vs baseline
(mm Hg)
46
51
49
99.9
151.7
5 mg
100.3
154.2
10 mg
101.4
156.4
20 mg
47
N
-2
-4
-6
-4.4
-3.6
-5.9
-8
-10
-12
-14
DBP
SBP
Placebo DBP
Placebo SBP
-9.1
†
-10.3
†
-10.2
†
-10.6
†
-12
*Only data for patients randomized to placebo, 5 mg, 10 mg, and 20 mg are shown (n=193). †P<0.05 vs placebo.
Effectiveness was established in Black patients but as monotherapy the magnitude of effect was somewhat less
than in Caucasians.
BP=sitting blood pressure; DBP=sitting diastolic blood pressure; SBP=sitting systolic blood pressure
Saunders E et al. J Clin Hypertens. 2007;9:866-875.
†
The Vasodilatory Beta Blockers
►
There are two such agents available: carvedilol and nebivolol.
►
Carvedilol causes vasodilation by alpha blockade, nebivolol
by nitric oxide mechanisms.
►
These agents appear to avoid the adverse metabolic effects
observed with older beta blockers.
►
Unlike the original agents, these drugs reduce peripheral
resistance and maintain cardiac output.
►
Nebivolol has been shown to work equally as well in the aorta
as in the brachial artery, but it is not yet known whether this
affects CV outcomes.
►
A major attribute of newer agents like nebivolol is the
avoidance of adverse effects on mood, exercise performance
and sexual activity.
New Dimensions and
Landmark Practice Advances
Beta Blockers in the Setting of Heart
Failure and Other
Compelling Indications:
When, How, What and in Whom?
Barry H. Greenberg, MD
Professor of Medicine
Director Advanced Heart Failure Program
University of California, San Diego
UCSD Medical Center
San Diego, California
Chain of Events Leading to
End-Stage Heart Failure
MyocardiaI
infarction
Arrhythmia
and
loss of muscle
Coronary
thrombosis
Myocardial
ischemia
Silent angina
Hibernation
CAD
Atherosclerosis
LVH
Risk factors
(lipids, BP, DM)
insulin resistance
platelets, fibrinogen, etc.
Adapted from Dzau and Braunwald. Am Heart J. 1991;121(4 part 1):1244.
Remodeling
Ventricular
dilatation
CHF
End-stage
heart disease
Sudden death
Revised Staging System for HF
Refractory HF
requiring
specialized
interventions
Structural heart disease
with prior or current
HF symptoms
Structural heart disease but
without signs or symptoms of HF
At high risk of HF but without
structural heart disease or HF symptoms
Stage D
Stage C
Stage B
Stage A
Adapted from: Hunt SA et al. ACC/AHA 2005 CHF Guideline Update. Circulation 2005;112:e154-235.
Focus on -Blocker Therapy in Stages B-C
Heart Failure
Patients with LV dysfunction
and HF symptoms
Post-MI patients and patients
with asymptomatic LV
systolic dysfunction
Stage C
Stage B
Modified from: Hunt SA et al. ACC/AHA 2005 CHF Guideline Update. Circulation 2005;112:e154-235.
Focus on -Blocker Therapy in Stages B-C
Heart Failure
Patients with LV dysfunction
and HF symptoms
Post-MI patients and patients
with asymptomatic LV
systolic dysfunction
Stage C
Stage B
Modified from: Hunt SA et al. ACC/AHA 2005 CHF Guideline Update. Circulation 2005;112:e154-235.
-Blockade Post-MI Is Strongly Recommended
►
-blockade (long-term use)
●
●
●
23% reduction in all-cause mortality (n=54,234)
30% reduction in risk of sudden death (n=15,819)
26% reduction in nonfatal reinfarction (n=18,841)
*Defined by ejection fraction, age, serum creatinine, length of hospital stay, and standardized testing
scores (APACHE II scores).
Gottlieb SS et al. N Engl J Med. 1998;339:489-497.
-Blocker Recommendations
ACC/AHA Guidelines
I IIa IIb III
Indicated in all patients with a recent
or remote history of MI regardless
of LVEF or presence of HF1.
HFSA Guidelines
ACE inhibitors and beta blockers are
recommended for all patients with prior MI2.
Strength of Evidence = A
1.
2.
Hunt SA, et al. ACC/AHA 2005 Practice Guidelines. Available at: http://www.acc.org.
HFSA 2006 Practice Guideline (3.3-3.4).
Rationale for the Use of -Blockers
in Post-MI Patients
►
Reduce myocardial ischemia
►
Anti-arrhythmic properties
►
Effects on remodeling
Remodeling Is The Major Cause of Progressive
Cardiac Dysfunction
6 months post-MI
14 months post-MI
Risk of Heart Failure After MI: Framingham
Heart Study Subjects Aged 35–94 Years
0.50
MI—Male
MI—Female
0.40
Matched—Male
Matched—Female
0.30
0.20
0.10
0.00
0
2
4
6
8 10 12 14 16
Years after MI
Cupples et al. DHHS Pub No. (NIH) 87-2703, 1987.
18
20 22
Structural Remodeling Post-MI
Days
MI due to coronary
occlusion
F. Netter CIBA.
Weeks
Scarring and reshaping
of the heart (remodeling)
Months - Years
Heart enlarges and
leads to congestive
heart failure
LV Remodeling Occurs After Successful
PTCA in 30% of Patients
180
160
(mL)
140
EDV
120
100
ESV
80
60
Baseline
6 Months
LV remodeling after successful PTCA with TIMI flow grade 3occurred despite sustained patency of the
infarct-related artery and preservation of regional and global LV function in 85 of 284 consecutive patients.
Bolognese L et al. Circulation. 2002;106:2351-2357.
Survival and Remodeling Post-PTCA
100
Survival (%)
95
90
85
80
75
P=.005
70
0 10 20 30 40 50 60 70 80
Months
No LV remodeling
(n=199)
Event-Free Survival (%)
100
95
90
85
80
75
P=.025
70
0 10 20 30 40 50 60 70 80
LV remodeling
(n=85)
Months
Prospective study of 284 patients with AMI treated with successful PTCA.
Major cardiac events defined as cardiac death, nonfatal AMI, and hospitalization for HF.
Bolognese L et al. Circulation. 2002;106:2351-2357.
Post-MI Cardiac Remodeling
►
Most common cause of heart failure in post-MI
patients.
►
Likelihood of remodeling increased with larger
infarct size and/or presence of LVD.
►
Patients often remain asymptomatic while
remodeling progresses.
►
Increased LV wall stress and neurohormonal
factors are responsible for remodeling.
CAPRICORN: Effect of -Blockade Added to
ACEI on Post-MI Remodeling
LVEDV
Placebo
Carvedilol
50
LVEDV
D = -9.0 mL
140
LVEF (%)
LV Volume
160
LV Ejection Fraction
Placebo
Carvedilol
45
D = +4.2%
2P = .0096
40
2P = .042
120
Baseline
35
6 Months
LVESV
2.50
D = -11.1 mL
80
2P = .0023
Placebo
Carvedilol
Wall Motion
Score Index
6 Months
Doughty RN et al. Circulation. 2001;104:511–517. Abstract 2447.
D = -0.15
2P = .036
2.00
1.75
1.50
1.25
60
6 Months
2.25
LVESV
WMSI
LV Volume
100
Baseline
Baseline
1.00
Baseline
Placebo
Carvedilol
6 Months
CAPRICORN Results
All-Cause Mortality1
100
Proportion Event-Free (%)
Proportion Event-Free (%)
100
90
Risk Reduction
23%
80
(2%, 40%)
P=.031
70
Recurrent Fatal or Nonfatal MI2
90
Risk Reduction
40%
80
(11%, 60%)
P=.01
70
Event rates:
Mortality rates:
Placebo 15%; COREG 12%
0
0
.5
1
1.5
2
Placebo 7%; COREG 4%
0
2.5
Years
COREG plus standard therapy (n=975)
1. The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
2. Fonarow GC. Rev Cardiovasc Med. 2006;7:1–9.
0
.2
.4
.6
.8
1
1.2 1.4 1.6 1.8
Years
Placebo plus standard therapy (n=984)
Outpatient Adherence to Beta Blockers Post-MI
80
-Blocker Users (%)
Discharged on -blockers
60
40
Not discharged on -blockers
20
0
0
30
90
180
270
Days Since Discharge
Prescription data on 846 patients surviving acute MI were studied by the Tennessee Quality
Improvement Organization.
Butler J et al. J Am Coll Cardiol. 2002;40:1589–1595.
365
Focus on -Blocker Therapy in
Stages B-C Heart Failure
Stage C
Patients with LV dysfunction
and HF symptoms
Patients with LV dysfunction
and HF symptoms
Post-MI patients and patients
with asymptomatic LV
systolic dysfunction
Stage B
Modified from: Hunt SA et al. ACC/AHA 2005 CHF Guideline Update. Circulation 2005;112:e154-235.
US Carvedilol Trials
1.0
MERIT-HF
Carvedilol (n=696)
0.9
Placebo
(n=398)
65% 
0.8
P<.001
0.7
0.0
Cumulative Mortality
(%)
Probability of Survival
Addition of -Blockers to ACEIs
Reduces Mortality in Heart Failure
20
34% 
10
Metoprolol CR/XL
(n=1,990)
5
0
0
100
200
300
0
400
100 200 300 400 500 600
Days
Days
CIBIS-II
Survival
Bisoprolol (n=1,327)
34% 
0.8
Placebo
(n=1,320)
P<.0001
COPERNICUS
100
0.6
Survival (%)
1.0
0.0
Placebo
(n=2,001)
P=.0062
(adjusted)
15
Carvedilol (n=1,156)
90
80
35% 
70
P=.0014
Placebo
(n=1,133)
(adjusted)
60
0
0
200
400
Days
600
800
0
3
6
9
12 15 18 21
Months
Packer M et al. N Engl J Med. 1996;334:1349-1355. MERIT-HF Study Group. Lancet. 1999;253:2001-2007.
CIBIS-II Investigators. Lancet. 1999;353:9-13. Packer M et al. N Engl J Med. 2001;344:1651-1658.
SENIORS
►
Nebivolol -1 blocker with
vasodilating properties
related to NO modulation
►
N=2135
►
Randomized to placebo vs.
Nebivolol
►
Primary Endpoint
● All cause mortality or CV
hospitalization
►
Pts ≥70 yrs, SHF or DHF
● Prespecified subgroup
analysis – interaction
with LVEF
Flather, MD, Euro Heart Journal, 2005.
EF>40%
SENIORS
Proportion Having an Event (%)
50
Nebivolol
Placebo
40
30
HR 0.85 (0.74-0.99);
P=0.039
20
10
0
6
12
18
Time in Study (Months)
Flather, MD, Euro Heart Journal, 2005,26:215-225.
24
30
SENIORS
Flather, MD, Euro Heart Journal, 2005,26:215-225.
How To Use Beta Blockers
Suboptimal Utilization of Evidence-Based
HF Therapies in ADHERE
LVEF Documented and .40
Patients Treated (%)
ACE Inhibitor
100
90
80
70
60
50
40
30
20
10
0
ARB
-Blocker
Diuretic
Digoxin
79
53
44
32
13
Outpatient HF Medication
46,272 patients hospitalized with HF; prior known diagnosis of systolic dysfunction HF; outpatient
medical regimen.
The ADHERE Registry [database]. Third quarter 2003 Benchmark Report (10/02–9/03). Scios Inc. Sunnyvale, California.
September 2003.
Risk-Treatment Mismatch in HF
100
At Hospital Discharge
90-Day Follow-Up
90
Patients (%)
80
70
60
50
40
30
20
10
0
ACEI
ACEI or
ARB
Low Risk
(17.7% or less mortality at 1 year)
-Blocker
ACEI
ACEI or
ARB
Average Risk
(26% to 34% mortality at 1 year)
-Blocker
High Risk
(50% mortality at 1 year)
1418 patients hospitalized from 1999 to 2001 in Ontario, Canada, with documented LVEF 40% and age 79 years who
were followed in the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) observational study. Use of ACEIs,
ARBs, and -blockers was evaluated at the time of hospital discharge and 90 days postdischarge according to risk for
mortality at one year. One-year mortality risk determined by validated EFFECT risk score, including age, vital signs at
presentation, comorbidities, and lab values.
Use rates in absence of contraindications. For all drug classes, P.001 for trend.
Lee D et al. JAMA. 2005;294:1240–1247.
Majority of LVSD and/or HF Patients Are Eligible for
-Blocker Therapy at the Time of Hospital Discharge
Symptomatic
Bradycardia 1.0%
N=20,118
Eligible
89.7%
Reactive Airway
Disease 3.4%
Symptomatic
Hypotension 2.7%
Not
Eligible
10.3%
2nd/3rd Degree
Heart Block 0.2%
Other 3.1%
Cohort with documented LVSD, alive at hospital discharge (N=20,118).
OPTIMIZE-HF=Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure- a
registry and performance-improvement program enrolling 48,612 patients hospitalized with HF at 259 US hospitals from
March 2003 to December 2004. A pre-specified subgroup (10%) had 60-90-day follow-up data collected.
Fonarow G. J Card Fail. 2005;11:S182. Poster presented at HFSA 2005. The OPTIMIZE-HF Registry [database].
Final Data Report. Duke Clinical Research Institute. July 2005.
Strategies To Improve HF Management
ACC/AHA HF
Guidelines1
In-hospital
Initiation2,3
Increasing
Outpatient
Compliance2,3
I IIa IIb III
• Clinical trial
evidence
incorporated into
recommendations
for patient care
• Implement evidence-based
care and therapies
• Majority of patients eligible
for treatment
• Early benefit of therapy
not missed
• Higher persistence rates
postdischarge
• Improve quality of
care and outcomes
1. Hunt SA et al. Circulation. 2005;112:1825–1852. 2. Fonarow GC. Rev Cardiovasc Med. 2002;3:S2–S10.
3. Gattis W et al. J Am Coll Cardiol. 2004;43:1534–1541.
OPTIMIZE-HF: Use of Evidence-Based HF
Therapy at Discharge in Eligible Patients
100
83.0
83.0
Eligible Patients Treated (%)
80
65.4
60
52.3
39.2
40
18.0
20
0
ACEI/ARB at
Discharge
(11,976/14,493)
-Blocker at
Discharge
(13,032/15,675)
Evidence-Based
-Blocker
(10,248/15,675)
Aldosterone
Antagonist
(3,621/20,118)
Statin
(14,904/38,066)
Warfarin
(6,571/12,560)
ACEI/ARB, -blocker, and aldosterone antagonist use in eligible patients with LVSD; statin in HF patients
with a history of CAD, PVD, CVD and/or diabetes; and warfarin use in patients with HF and atrial fibrillation.
The OPTIMIZE-HF Registry [database]. Final Data Report. Duke Clinical Research Institute. July 2005.
Which Patients Should Get a β-blocker?
Indications, based upon patients enrolled in the RCTs:
► LVEF <40%.
► Mild to severe symptoms (NYHA FC II–IV); also patients with
asymptomatic LV systolic dysfunction post-MI.
► On optimal dose of an ACEI or/and ARB (and aldosterone antagonist, if
indicated).
► Patients should be clinically stable (e.g. no recent change in dose of
diuretic).
► Cautious, pre-discharge initiation in a recently decompensated patient
provided that the patient has improved with other treatments, is not
dependent on an i.v. inotropic agent, and can be observed in hospital
for at least 24 h after β-blocker initiation.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008.
European Heart Journal 2008 29(19):2388-2442.
Initiation of a β-blocker
► Starting dose: bisoprolol 1.25 mg o.d., carvedilol 3.125–6.25 mg b.i.d.,
metoprolol CR/XL 12.5–25 mg o.d., or nebivolol 1.25 mg o.d.—under
supervision in outpatient setting.
► Dose up-titration
► Visits every 2–4 weeks to up-titrate the dose of β-blocker (slower dose
up-titration may be needed in some patients). Do not increase dose if
signs of worsening HF, symptomatic hypotension, or excessive
bradycardia (pulse rate <50/min) at each visit.
► In absence of the above problems, double the dose of β-blocker at each
visit until the evidence-based target dose is reached—bisoprolol 10 mg
o.d., carvedilol 25–50 mg b.i.d., metoprolol CR/XL 200 mg o.d., or
nebivolol 10 mg o.d.—or maximum tolerated dose.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008.
European Heart Journal 2008 29(19):2388-2442.
Summary/Conclusions
►
Beta blockers are strongly indicated post-MI and in
all patients with LVD regardless of symptoms.
►
Evidence-based beta blockers should be used at
doses targeted in clinical trials.
►
In-hospital initiation of a beta blocker is an excellent
strategy for increasing utilization.
New Dimensions and
Landmark Practice Advances
The Year 2009 Clinical Bottom Line:
What Do the Clinical Trials Teach Us?
How Do We Apply Evidence to Optimize Practice
for Patients with Hypertension
and Heart Disease
Program Chairman
Henry R. Black, MD
Clinical Professor of Medicine
NYU Medical Center
President – American Society of Hypertension
NYU Center for the Prevention of Cardiovascular Disease
New York, NY
BP-Lowering Treatment Trialists
Comparisons of Different Active Treatments
BP Difference (mmHg)
Stroke
ACE vs D/BB
2/0
CA vs D/BB
1/0
ACE vs CA
1/1
Coronary Heart Disease
ACE vs D/BB
2/0
CA vs D/BB
1/0
ACE vs CA
1/1
Heart Failure
ACE vs D/BB
2/0
CA vs D/BB
1/0
ACE vs CA
1/1
1.09 (1.00, 1.18)
0.93 (0.86, 1.01)
1.12 (1.01, 1.25)
0.98 (0.91, 1.05)
1.01 (0.94, 1.08)
0.96 (0.88, 1.05)
1.07 (0.96, 1.19)
1.33 (1.21, 1.47)
0.82 (0.73, 0.92)
0.5 Favors
First Listed
Lancet. 2002;360:1903–1913.
RR (95% CI)
Relative Risk
1.0
Favors 2.0
Second Listed
BP-Lowering Treatment Trialists
Comparisons of Different Active Treatments
BP Difference (mmHg)
Major CV Events
ACE vs D/BB
CA vs D/BB
ACE vs CA
CV Mortality
ACE vs D/BB
CA vs D/BB
ACE vs CA
Total Mortality
ACE vs D/BB
CA vs D/BB
ACE vs CA
2/0
1/0
1/1
1.02 (0.98, 1.07)
1.04 (0.99, 1.08)
0.97 (0.95, 1.03)
2/0
1/0
1/1
1.03 (0.95, 1.11)
1.05 (0.97, 1.13)
1.03 (0.94, 1.13)
2/0
1/0
1/1
1.00 (0.95, 1.05)
0.99 (0.95, 1.04)
1.04 (0.98, 1.10)
0.5 Favors
First Listed
Lancet. 2002;360:1903–1913.
RR (95% CI)
Relative Risk
1.0
Favors 2.0
Second Listed
Major Cardiovascular Events
Men vs. Women
Patients
(N)
Δ BP
Favors
Favors
st
(mm Hg) 1 listed 2nd listed RR (95% CI)
24,196
23,234
1.6/0.1
1.00 (0.94 to 1.06)
1.8/0.6
1.04 (0.96 to 1.11)
43,006
46,705
0.9/-0.3
0.6/-0.2
1.05 (1.00 to 1.11)
0.99 (0.93 to 1.06)
13,559
12,799
0.9/0.6
1.0/1.1
0.91 (0.83 to 1.01)
1.02 (0.94 to 1.11)
ACE-I vs D/BB
Men
Women
Ca vs D/BB
Men
Women
ACE-I vs Ca
Men
Women
All p homogeneity >0.05
Eur Heart J 2008; 29: 2669-2680.
0.5
1.0
Risk ratio
2.0
Major Cardiovascular Events
Men vs. Women
Patients
(N)
Δ BP
(mm Hg)
Men
26,724
-4.4/-2.1
0.81 (0.75 to 0.88)
Women
8,353
-4.6/-2.0
0.79 (0.66 to 0.94)
Men
3,186
Women
3,765
-7.6/-2.1
-9.0/-3.5
0.75 (0.57 to 0.98)
0.78 (0.59 to1.03)
11,792
10,190
-4.3/-3.6
-3.7/-3.3
0.87 (0.74 to 1.02)
0.88 (0.73 to 1.07)
Favors
active
Favors
control RR (95% CI)
ACE-I vs placebo
Ca vs placebo
More vs less
Men
Women
0.5
All p homogeneity >0.8
Eur Heart J 2008; 29: 2669-2680.
1.0
Risk ratio
2.0
Major Cardiovascular Events
Men vs. Women
Patients
(N)
ARB vs. other
Men
Women
Δ BP
Favors
(mm Hg) ARB
RR (95% CI)
3,442
-1.8/-1.2
0.88 (0.77 to 1.00)
4,360
-1.5/-1.0
0.93 (0.81 to 1.06)
0.5
p homogeneity =0.5
Eur Heart J 2008; 29: 2669-2680.
Favors
Other
1.0
Risk ratio
2.0
Major Cardiovascular Events
First listed
relatively more
effective in older
First listed
relatively more
effective in younger
P value
ACE-I vs. Placebo
0.09
CA vs. Placebo
0.7
More vs. Less
0.3
ACE-I vs. D/BB
0.8
CA vs. D/BB
0.3
ACE-I vs. CA
0.2
0.5
1.0
Risk ratio
BMJ 2008;336:1121-1123.
2.0
2004 Meta-Analysis of Outcomes: Atenolol vs.
Other Antihypertensive Treatments
►
Analysis of 5 studies: Atenolol versus other antihypertensive therapy
►
17,671 patients included, with a mean follow-up of 4.6 years
►
No differences in BP lowering
Risk Reduction
(95% CI)
All-Cause Mortality
1.13
(1.02–1.25)
CV Mortality
1.16
(1.00–1.34)
Myocardial Infarction
1.04
(.89–1.20)
Stroke
1.30
(1.12–1.50)
Trials included in meta-analysis: MRC Old (Medical Research Council Trial of Treatment of Hypertension in Older Adults);
UKPDS (United Kingdom Prospective Diabetes Study); ELSA (European Lacidipine Study of Atherosclerosis); HAPPHY (The
Heart Attack Primary Prevention in Hypertension Trial); LIFE (The Losartan Intervention for Endpoint Reduction Study).
Carlberg B. Lancet. 2004;364:1684–1689.
Atenolol vs. Other Antihypertensive Treatments:
Outcomes
Endpoint
-blocker
n/N
Other
Drug n/N
RR
(95% CI)
Stroke
1019/28132
810/28169
1.26
(1.15-1.38)
Myocardial
Infarction
1216/28132
1167/28169
1.05
(0.91-1.21)
Mortality for
All Causes
2387/28132
2216/28169
1.08
(1.02-1.14)
Lindholm LH, et al. Lancet. 2005;366:1545-1552.
Follow-up 2006 Meta-Analysis:
Atenolol vs Other Treatments
2006 Meta-analysis
End Point
Summary OR
(95% CI)
Death
1.10 (1.03-1.16)
P=0.003
CV Death
1.13 (1.04-1.22)
(P=0.005)
MI
1.05 (0.97-1.14)
P=0.19
Stroke
1.26 (1.15-1.38)
P=0.0000006
Elliott WJ. JACC. 2006;47 (Suppl):361A.
All β-Blockers vs Placebo or
No Treatment: Outcomes
End Point
β-Blocker
n/N
Placebo
n/N
RR
(95% CI)
Stroke
325/11025
518/16408
0.81
(0.71-0.93)
Myocardial
infarction
413/11025
639/16408
0.93
(0.83-1.05)
Mortality for
all causes
606/11025
932/16408
0.95
(0.86-1.04)
Lindholm LH et al. Lancet. 2005;366:1545-1553.
Beta-Blockers vs. Other Antihypertensive
Drugs: Composite Outcome*
Study
Population
-blocker
n/N
Other Drugs
n/N
RR
(95% CI)
Participants
<60 yrs
745/15136
770/15276
0.97
(0.88-1.07)
Participants
≥60 yrs
3588/39010
3817/40765
1.06
(1.01-1.10)
*Death, stroke or MI
Khan N, et al. CMAJ. 2006;174:1737-1742.
Major Cardiovascular Events
Younger (<65) vs. Older (≥65)
ACE-I vs D/BB
Age <65
Patients
(N)
Δ BP
Favors
Favors
st
(mm Hg) 1 listed 2nd listed RR (95% CI)
21,460
1.3/0.1
2.0/0.5
1.05 (0.96 to 1.14)
1.01 (0.95 to 1.06)
1.06 (0.98 to 1.14)
1.02 (0.97 to 1.06)
Age ≥65
25,212
Ca vs D/BB
Age <65
43,594
Age ≥65
46,185
1.1/-0.2
0.5/-0.4
10,049
0.9/0.6
0.91 (0.78 to 1.06)
16,310
1.0/1.0
0.98 (0.92 to 1.05)
ACE-I vs Ca
Age <65
Age ≥65
All p homogeneity >0.3
BMJ 2008;336:1121-1123.
0.5
1.0
Risk ratio
2.0
Major Cardiovascular Events
Younger (<65) vs. Older (≥65)
Patients
(N)
ACE-I vs placebo
19,154
Age <65
15,923
Age ≥65
Δ BP
Favors
(mm Hg) active
Favors
control RR (95% CI)
-4.6/-2.1
0.76 (0.66 to 0.88)
-4.2/-2.0
0.83 (0.74 to 0.94)
Ca vs placebo
Age <65
2,597
-7.2/-2.9
Age ≥65
4,354
-9.3/-3.8
0.84 (0.54 to 1.31)
0.74 (0.59 to 0.92)
14,385
-3.9/-3.6
0.88 (0.75 to 1.04)
-3.3/-3.3
1.03 (0.85 to 1.24)
More vs less
Age <65
Age ≥65
6,449
All p homogeneity >0.2
BMJ 2008;336:1121-1123.
0.5
1.0
Risk ratio
2.0
Major Cardiovascular Events
Younger (<65) vs. Older (≥65)
ARB vs. other
Age <65
Age ≥65
Patients
(N)
Δ BP
Favors
(mm Hg) ARB
1,464
-1.7/-0.3
0.89 (0.75 to 1.05)
6,338
-2.0/-1.2
0.91 (0.81 to 1.02)
0.5
p homogeneity =0.8
BMJ 2008;336:1121-1123.
Favors
Other
1.0
Risk ratio
RR (95% CI)
2.0
Major Cardiovascular Events
Proportionate
First listed
relatively more increase in relative
risk for every extra
effective in
10 year of age
younger
(95% CI)
First listed
relatively more
effective in
older
P value
ACE-I vs. Placebo
1.09 ( 1.00-1.20)
0.09
CA vs. Placebo
0.90 (0.52 -1.54)
0.7
More vs. Less
1.12 (0.91 -1.37)
0.3
ACE-I vs. D/BB
0.99 (0.92 -1.06)
0.8
CA vs. D/BB
0.95 (0.87 -1.04)
0.3
ACE-I vs. CA
1.06 (0.98 -1.15)
0.2
0.5
1.0
Risk ratio
BMJ 2008;336:1121-1123.
2.0
-blocker Evidence: Secondary Prevention
Summary of Secondary Prevention Trials of b-blocker Therapy
Phase of
Treatment
Total #
Patients
RR (95% CI)
Acute
treatment
28,970
0.87 (0.77-0.98)
Secondary
prevention
24,298
0.77 (0.70-0.84)
Overall
53,268
0.81 (0.75-0.87)
0.5
1.0
2.0
RR of death
b-blocker
Placebo better
better
CI=Confidence interval, RR=Relative risk
Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A
textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
Risk Reduction With β-Blockers
in Post-MI Patients
15 Trials (n =18,995)
0%
Sudden
Overall
cardiac
mortality death
Nonsudden
death
Nonfatal MI
–20%
–20%
–10%
–20%
–30%
–22%
–33%
–40%
Hanes DS et al. J Clin Hypertens (Greenwich). 2001;3(4):236-243.
-Blocker Trials in Heart Failure: Overview
Annual Mortality
Mean Follow-up
RR
24 months
10%
P Value
% Patients
BEST
placebo 17%
bucindolol 15%
CIBIS-II
15 months
34% P=.0001
12 months
placebo 11.0%
metoprolol succinate 7.2%
34% P=.0062
placebo 13.2%
bisoprolol 8.8%
MERIT-HF
COPERNICUS
10.4 months
placebo 18.5%
carvedilol 11.4%
0
0.25 0.5
0.75
1.0
1.25
P=.10
1.5
1.75
35%
P=.0014
2.0
Relative Risk and 95% Confidence Intervals
Lancet. 1999:353:2001-2007; CIBIS II Investigator and Committees. Lancet. 1999;353:9-13; Packer M et al. N Engl J Med.
2001;344:1651-1658; Beta-blockers Evaluation Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667.
-Blockers as Initial Agents
Initial Therapy for Hypertension?
In my opinion:
►
►
►
►
-BLOCKERS should be not be used for initial
treatment unless the patient has a compelling or
specific indication.
Diuretics, ACE-I/ARBs and CCBs should be
considered as “TIER 1” drugs and used before BLOCKERS in other patients.
-BLOCKERS should be considered as a common
additional agent to those patients resistant to
properly selected TIER 1 agents.
But…
-Blockers as Initial Therapy for Hypertension?
In my opinion:
►
… we still do not know whether this approach will also apply to
newer cardioselective, vasodilatory -BLOCKERS.
►
Their potential is unknown since they:
►
●
Reduce blood pressure by a more pathophysiologically appropriate
mechanism (maintainance of cardiac output and reduction of total
peripheral resistance) than traditional do traditional -BLOCKERS .
●
Are not likely to have untoward metabolic effects.
●
Increase NO production which has beneficial effects on the
endothelium.
Conclusions: The clinical, hemodynamic and metabolic effects of the
new generation agents are promising. Outcome trials are needed to
clarify how and why our approaches to these agents might be different.
JNC 8 (VIII) ????
►
Should Tinker Further With
Our Classification System?
►
Should We Recommend
Treating Prehypertensives
With Drugs?
►
►
Should Beta Blockers
Become A 4th Line Drug For
Hypertension, As Have
Alpha Blockers?
Should We No Longer
Recommend That All Two
Drug Combinations Include
A Diuretic?
►
Is It Really About Only
Blood Pressure Or Might It
Really Be “Beyond Blood
Pressure”?
►
How Should New Clinical
Trials Be Integrated Into
Guidelines?
►
How Fast Should Bp Be
Lowered?
►
Where And How Should We
Measure Blood Pressure?
►
Should Cost Considerations
Be Part Of The Document?
The Ages Of Man
The View Of Those Who Pay For Care
Infants:
Cheap to produce & easy to replace
Young Adults:
Expensive to raise & educate and have not yet
returned investment
Adult - Age 50:
Benefit of Prevention = Cost of Survival
Adult > Age 65:
Successful prevention adds economically
unproductive & potentially “costly”
individuals to population
THE CHEAPEST PATIENT IS THE DEAD PATIENT
Adapted from: GA Rose, The Strategy of Preventive Medicine, 1992.