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REVISITING the ROLE of BETA-BLOCKERSin the MANAGEMENT of HYPERTENSION:
A C L O S E R L O O K A T C O M P L I C A T E D C A S E S
ATLANTA, GEORGIA • DECEMBER 2, 2008
Educational partner:
Session 5
Session 5: Revisiting the Role of Beta-Blockers in the Management of Hypertension: A Closer Look at Complicated Cases Learning Objectives
• Identify/discuss clinical considerations involved in the management of patients with complicated hypertension. • Describe at least one of the latest clinical trial results on beta-blockers and its effects on metabolic parameters.
Faculty Shawna D. Nesbitt, MD Associate Professor, Department of Internal Medicine University of Texas at Southwestern Medical Center at Dallas Dallas, Texas Shawna D. Nesbitt, MD, is associate professor of internal medicine at the University of Texas at Southwestern Medical Center at Dallas. Dr Nesbitt received her medical degree from Hahnemann University School of Medicine, Philadelphia, Pennsylvania. She completed a medical internship and residency in internal medicine at Allegheny General Hospital, Pittsburgh, Pennsylvania. Dr Nesbitt completed her medical training with a fellowship in hypertension at the University of Michigan Medical Center, Ann Arbor. Dr Nesbitt is a manuscript reviewer for American Journal of Hypertension, Ethnicity and Disease, Journal of the National Medical Association, and Hypertension. She has authored or coauthored more than 40 articles published in numerous peer-reviewed journals, including American Journal of Hypertension, Journal of Hypertension, and Journal of CardioMetabolic Syndrome. Dr Nesbitt has authored several chapters in books focusing on hypertension. She is a member of various professional societies including the Association of Black Cardiologists, American Society of Hypertension, and the International Society on Hypertension in Blacks. Dr Nesbitt has given numerous international and national lectures with a focus on hypertension over the last 15 years. Matthew J. Sorrentino, MD, FACC Associate Professor of Medicine University of Chicago Pritzker School of Medicine Department of Medicine Section of Cardiology Chicago, Illinois Matthew J. Sorrentino, MD, FACC, is associate professor of medicine at the University of Chicago Pritzker School of Medicine. Dr Sorrentino is a preventive cardiologist with clinical and research interests in hyperlipidemia and hypertension. He is an American Society of Hypertension hypertension specialist. Dr Sorrentino received his medical degree from the University of Chicago Pritzker School of Medicine. He completed his internship and residency in Internal Medicine and a fellowship in Cardiovascular Disease at the University of Chicago Hospitals. Dr Sorrentino is an abstract reviewer for the American College of Cardiology and the American Diabetes Association. He is a host on ReachMD, a satellite radio station for Medical Professionals. Dr Sorrentino has written numerous book chapters and over 70 articles published in journals such as The American Journal of Medicine, Journal of the American College of Cardiology and Journal of Geriatric Cardiology. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Nesbitt receives honoraria for serving as a consultant/speaker from Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb; and Novartis Pharmaceuticals Corporations. Dr Nesbitt receives research support from AstraZeneca Pharmaceuticals LP and Pfizer Inc.
Session 5
Dr Sorrentino receives speaking honoraria from Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; and Takeda Pharmaceuticals Corporations. Education Partner Financial Disclosure Statements The content collaborators at The France Foundation have reported the following: The content collaborators at The France Foundation have nothing to disclose. Drug List Generic Trade acebutolol Sectral atenolol Tenormin bisoprolol Zebeta carvedilol Coreg labetalol Normodyne, Trandate lisinopril Prinivil, Zestril Investigational bucindolol celiprolol dilevalol
Generic Trade metoprolol Lopressor, Toprol-XL nebivolol Bystolic pindolol Visken propranolol InnoPran-XL, Inderal timolol Betimol, Blocadren, Istalol valsartan Diovan
Suggested Reading List Bell DS. Beta-adrenergic blocking agents in patients with diabetes–friend and foe. Endocr Pract. 1999;5(1):51-53.
Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101(5):558-569.
Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med. 1999;341(15):1097-1105.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.
Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359.
Greenlund KJ, Zheng ZJ, Keenan NL, et al. Trends in self-reported multiple cardiovascular disease risk factors among adults in the United States, 1991-1999. Arch Intern Med. 2004;164(2):181-188.
Jackson R, Lawes CM, Bennett DA, et al. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual’s absolute cardiovascular risk. Lancet. 2005;365(9457):434-441.
Lewington S, Clarke R, Qizilbash N, et al; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-1913.
Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366(9496):1545-1553.
McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab. 2001;86(2):713-718.
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289(1):76-79.
Savage PD, Banzer JA, Balady GJ, Ades PA. Prevalence of metabolic syndrome in cardiac rehabilitation/secondary prevention programs. Am Heart J. 2005;149(4):627-631.
Siani A, Cappuccio FP, Barba G, et al. The relationship of waist circumference to blood pressure: the Olivetti Heart Study. Am J Hypertens. 2002;15(9):780-786.
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1
Hypertension Progression with Age and Related Risk Factors
Shawna D. Nesbitt, MD
Associate Professor, Department of Internal MedicineUniversity of Texas at Southwestern Medical Center at Dallas
Dallas, Texas
Traditional CVD Risk Factors
• Family history • Older age• Male gender• Smoking• Physical inactivity• Overweight/obesity• Total-C/LDL-C/HDL-C/TG • Hypertension • Hyperglycemia
Adapted from Stampfer MJ, et al. Circulation. 2004;109(25suppl 1):IV3-IV5.
Prevalence of CVD Risk Factors in US Adults 1961–2004
010203040506070
1960 1970 1980 1990 2000
Overweight Hypertension Smoking High Cholesterol
Perc
ent o
f Pop
ulat
ion
Year
• Hypertension: SBP > 140, DBP > 90 mm Hg, or medicated for HT• High cholesterol: > 240 mg/dl. • Overweight: BMI > 25 kg/m2
Source: NHIS for smoking, ages > 18 and NHANES for the other risk factors, ages 35–74.
Percentage of Adults With ≥ 2 Self-Reported CV Risk Factors
High BP, High Cholesterol, Diabetes, Obesity, Smoking, Physical Inactivity (2003)
Percentage of population with ≥ 2 risk factors
Greenlund KJ, et al. Arch Intern Med. 2004;164(2):181-188; Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2005;54(5):113-117.
NA25.0% to 29.9%22.0% to 24.9%< 22% ≥ 30%
20031991
Ischemic Heart Disease Risk Increases with SBP, DBP, and Age
CI, confidence interval; IHD, ischemic heart disease. Lewington S, et al. Lancet. 2002;360(9349):1903-1913.
Systolic Blood Pressure
40-49 years
50-59 years
60-69 years
70-79 years
80-89 yearsAge at risk:
IHD mortality(floatingabsolute risk and 95% CI)
25612864
32168421
120 140 160 180Usual SBP (mm Hg)
Diastolic Blood Pressure
25612864
3216
8421
70 80 90 100 110Usual DBP (mm Hg)
Age at risk:
40-49 years
50-59 years
60-69 years
70-79 years
80-89 years
Lower Is Better!Jackson R, et al. Lancet. 2005(9457);365:434-441.
Synergistic Interaction of Traditional Multiple Risk Factors on CVD Risk
0Reference
5-year CVD risk per 100 people
TC = 270
mg/dL
Smoker HDL = 39 mg/dL
Male Diabetes 60 yearsof age
10
20
30
40
5044%
33%
24%
18%
12%
6%3%
110
SBP (mm Hg)
120130140
150160170180
<1%
TC = total cholesterolAdditive Risk Factors
2
Protective Factor
INTERHEART: Risk of AMI Associated With Risk Factors in the Overall Population
0.91 (0.82, 1.02)24.024.5Alcohol intake
0.86 (0.76, 0.97)14.319.3Exercise
0.70 (0.62, 0.79) 35.842.4Vegetable/fruit daily
2.67 (2.21, 3.22)――Psychosocial
1.62 (1.45, 1.80)46.333.3Abdominal obesity*
1.91 (1.74, 2.10)39.021.9Hypertension
2.37 (2.07, 2.71) 18.47.5Diabetes
2.87 (2.58, 3.19)45.226.8Current smoking
3.25 (2,81, 3.76)33.520.0Apo B/Apo A
OR (99% CI) Adj. for All% Cases% ControlRisk Factor
*Upper tertile of waist circumference.Adapted from Yusuf S, et al. Lancet. 2004;364(9438):937-952.
1998
Obesity Trends Among U.S. Adults BRFSS
2006
1990
No Data < 10% 10%–14 15%–19% 20%–24% 25%–29% ≥ 30%
BMI ≥ 30
http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm
Overweight
Elevated BMI Increases the Risk of Cardiovascular Disease Mortality
Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment.
Calle EE, et al. N Engl J Med. 1999;341(15):1097-1105.
Normal weight Obese
Rel
ativ
e R
isk
of
CVD
Mor
talit
y
0.6
3.0
2.6
2.2
1.8
1.4
1.0
> 18 25 30 ≥40
BMI, kg/m2
WomenMen
Waist Circumference Correlates With BP and Insulin Resistance
768 men with fasting glucose ≤ 126 mg/dL (≤ 7 mmol/L)
Siani A, et al. Am J Hypertens. 2002;15(9):780-786.
P < 0.001 for trend in each parameter.
50
40
30
20
10
0I II III IV V
50
40
30
20
10
0I II III IV V
High blood pressure Insulin resistance
Quintiles of Waist Circumference
%
Hypertension Is Associated With Insulin Resistance
Adapted from Ferrannini E, et al. N Engl J Med 1987;317(6):350-357.
P < 0.001
n = 11 n = 13
Error bars = SE
0
1
2
3
4
5
6
7
8
Normotensive Hypertensive
Insu
lin S
ensi
tivity
(mg/
min
/kg)
Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286:10.
Diabetes Among US Adults
1990 1995
2001
No Data <4% 4%-6% 6%-8% 8%-10% >10%
• Includes Gestational Diabetes • BRFSS
3
EPIC-Norfolk Study: Every 1% Increase in HbA1c Increased CV Risk
1% Increase in HbA1c Above 5% 1% Increase in HbA1c Above 7%
*Multivariate regression: adjusted for age and risk factor; †Multivariate regression: adjusted for age, sex, and risk factor.EPIC-Norfolk: The European Prospective Investigation into Cancer in Norfolk was a prospective population study of 4662 men and 5570 women aged 45-79 years. Average follow-up time was 6.3 years.
CHD CVD Totalmortality
Incr
ease
in R
elat
ive
Ris
k (%
)*
Incr
ease
in R
elat
ive
Ris
k (%
)†
0
10
20
30
40↑ 40%
↑ 16%
↑ 26%
Men
0
5
10
15
20
25
30
Total mortality
CHD CVD
↑ 21%↑ 24%↑ 25%
Total mortality
CHD CVD
Women
↑ 21%
↑ 28%
↑ 20%
Khaw KT, et al. Ann Intern Med. 2004;141:(6)413-420.
Diagnose by presence of 3 or more risk factorsAdapted with permission from Grundy SM, et al. Circulation. 2004;109:433-438.Ford ES, et al. JAMA. 2002;287(3):356-359.
AHA/NHLBI-Modified ATP III Criteria for Metabolic Syndrome
Risk Factor Defining Level Prevalence
Abdominal obesity Waist* 39%Men > 40 inWomen > 35 in
Triglycerides, mg/dL ≥ 150 30%HDL-C, mg/dL 37%
Men < 40Women < 50
BP, mm Hg ≥ 130/≥ 85 34%**Fasting glucose, mg/dL ≥ 100 (NCEP ≥ 110) 13%**
*Lower cutpoints for Asian Americans.**Or medication use
Metabolic Syndrome: Prevalence Increases With Age
Prev
a len
ce, %
Age, yrNCEP criteria.Adapted from Ford ES, et al. JAMA. 2002(3);287:356-359.
47 million US adults (23%) have metabolic syndrome
05
1015202530354045
20-29 30-39 40-49 50-59 60-69 ≥ 70
Men (n = 4265)Women (n = 4559)
Follow-up, Years
Cum
ulat
ive
Haz
ard,
%
121086420
RR = 3.55 (95% CI, 1.96-6.43)
0
5
10
15
866288
852279
834234
292100
YesNo
Metabolic Syndrome?
Metabolic Syndrome
Controls
Reproduced with permission from Lakka HM, et al. JAMA. 2002;288(21):2709-2716.
Cardiovascular Disease Mortality and Metabolic Syndrome
Savage PD, et al. Am Heart J. 2005;149(4):627-631.Milani RV, Lavie CJ. Am J Cardiol. 2003;92(1):50-54.Curran PJ, et al. J Am Coll Cardiol. 2004;43(suppl A):249A.
Over Half of Patients Referred to Cardiologists Have Metabolic Syndrome
Cardiac Rehabilitation
N = 1912Savage, 2005
Patie
nts
With
Met
abol
ic
Synd
rom
e (%
)
5058 59
0
20
40
60
N = 235Milani, 2003
N = 85Curran, 2004
Acute MI
0 1 2 3 4 50
2
4
6
8
C-r
eact
ive
Prot
ein,
mg/
L
Components of Metabolic Syndrome, No.
Inflammation in Metabolic Syndrome
Women’s Health Study (N = 14,719)
Reproduced with permission from Ridker P, et al. Circulation. 2003;107(3):391-397.
(N = 4086)
(N = 3152)
(N = 2292)
(N = 1135)
(N = 170)
(N = 3884)
4
Effects of Weight Loss* on Inflammatory Biomarkers
Baseline12 months
ICAM = intercellular adhesion molecule; IL-6 = interleukin 6; TNF = tumor necrosis factor; VCAM=vascular cell adhesion molecule.
Adapted from Ziccardi P, et al. Circulation. 2002;105(7):804-809.
pg/m
L
0
1
2
3
4
5
6
TNF-α IL-6
P < 0.01
P < 0.01
ng/m
L
0
100
200
300
400
500
600
700
800
P-selectin ICAM-1 VCAM-1
P < 0.01
P < 0.02
P < 0.02
*Mean decrease of 9.8+1.5 kg. 0 2 4 6 8
0.95
0.96
0.97
0.98
0.99
1.00
hsCRP < 3, No Metabolic Syndrome
hsCRP ≥ 3, No Metabolic Syndrome
hsCRP < 3, Yes Metabolic Syndrome
hsCRP ≥ 3, Yes Metabolic Syndrome
hsCRP Adds Prognostic Information to the ATP III Definition of Metabolic Syndrome
CVD
Eve
nt-F
ree
Surv
ival
Pro
babi
lity
Years of Follow-up
N = 14,719
Ridker PM, et al. Circulation. 2003;107(3):391-397.
hsCRP = high-sensitivity CRP
Association of Insulin Resistance With Cardiovascular Risk Factors and Atherosclerosis
Obesity
Glucose intolerance
• AGEsHypertension Endothelial
dysfunction• ↑ VCAM,E-selectin
• ↓ NO Impaired
thrombolysis• ↑ PAI-1• ↓ tPA
Atherosclerosis
Inflammation• ↑ CRP• ↑ IL-6
Insulin resistance
Dyslipidemia• Low HDL
• Small, dense LDL particles
• Hyper-triglyceridemia
McFarlane SI, et al. J Clin Endocrinol Metab. 2001;86(2):713-718.
Hypertension Writing GroupDefinition of Hypertension
Compared with JNC 7
SBP, systolic blood pressure; DBP diastolic blood pressure; HWG, Hypertension Writing Group.Giles TD, et al. J Clin Hypertens. 2005;7(9):505-512.
DBP(mm Hg)
JNC 7 HWG JNC 7 HWG100
120
140
160
180
200
80
100
130SBP
(mm Hg)
Normal Normal Normal Normal
Pre-hyper-tension
Stage 1or
Normal
Stage 1 or Normal
Pre-hyper-tension
Stage 2or
Stage 1Stage 1
Stage 2 Stage 3
Stage 1
Stage 2 Stage 3
Stage 2 orStage 1 90
150
†CVD designation is determined by the constellation of risk factors, early disease markers, and target-organ disease. CVD, cardiovascular disease.
Hypertension Writing Group Definition and Classification of Hypertension
Overtly present with or without CVD events
Early signs present
NoneNoneTarget-organ Disease
Overtly present with progression
Overtly presentUsually presentNone Early Disease Markers
ManyManySeveralNone or fewCardiovascular Risk Factors
Marked and sustained BP
elevationsOR
Advanced CVD†
Sustained BPelevations
ORProgressive
CVD†
Occasional or intermittent BP
elevationsOR
Early CVD†
Normal BP or rare BP elevations
ANDNo identifiable
CVD†
Descriptive Category
Stage 3 hypertension
Stage 2 hypertension
Stage 1 hypertension
NormalClassification
Giles TD, et al. J Clin Hypertens. 2005;7(9):505-512.
Summary
• The prevalence of obesity and diabetes is increasing
• Metabolic syndrome, a precursor to CVD and diabetes, is also on the rise
• Aggressive management of diabetes and other CVD risk factors is essential
• Primary care physicians are instrumental in addressing the therapeutic challenges faced by their patients with cardiometabolic risk factors
5
Evolution of Beta-Blockade and the Management of
Complicated Hypertension
Matthew J. Sorrentino, MD, FACC
Associate Professor of MedicineUniversity of Chicago Pritzker School of Medicine
Department of MedicineSection of Cardiology
Chicago, Illinois
The Seventh Report of the The Seventh Report of the Joint National CommitteeJoint National Committee
Chobanian AV, et al. JAMA. 2003;289(19):2560-2572.
oror
oror
or
andand
≥≥ 100100≥≥ 160160Stage 2 hypertensionStage 2 hypertension
9090––9999140140––159159Stage 1 hypertensionStage 1 hypertension
80–89120–139Prehypertension
< 80< 80< 120< 120NormalNormal
Diastolic BP(mm Hg)
Systolic BP(mm Hg)
BP Classification
Resistant hypertension is the failure to reach goal BP in patients who are adhering to full doses of an appropriate 3-drug regimen that includes a diuretic.
• Caucasians 68%• African-Americans 52%• Mexican-Americans 57%• Patients ≥ 60 years old 44%• Patients with diabetes 25%
Ong KL, et al. Hypertension. 2007;49:69-75.
Percentage of Treated Patients With Percentage of Treated Patients With Hypertension at Goal 2003Hypertension at Goal 2003––20042004
Awareness, Treatment, and Control of Awareness, Treatment, and Control of Hypertension in the US Hypertension in the US
14,653 patients from NHANES database.14,653 patients from NHANES database.*P < 0.05 for the difference between 1999-2000 and 2003-2004.
6558 6057
697671
50 54
3732
30
24
3735
1020304050607080
1999-2000 2001-2002 2003-2004
Years
Control Control target for target for Healthy Healthy PeoplePeople20002000(now 2010)(now 2010)
AwarenessAwareness
Control (All)Control (All)
Control (Treated)Control (Treated)
Control (Treated, with diabetes)Control (Treated, with diabetes)
TreatmentTreatment
% (S
E)
*
**
Ong KL, et al. Hypertension. 2007;49(1):69-75.
Perceived Barriers to Optimizing Perceived Barriers to Optimizing ββ--Blocker TreatmentBlocker Treatment
•• Negative effects on lipid Negative effects on lipid metabolismmetabolism
•• Negative effects on Negative effects on glucose metabolismglucose metabolism
•• Negative effects on renal Negative effects on renal blood flowblood flow
•• Masked hypoglycemiaMasked hypoglycemia
•• FatigueFatigue•• ImpotenceImpotence•• Weight increaseWeight increase•• Peripheral Peripheral
vasoconstriction vasoconstriction (cold extremities)(cold extremities)
•• DepressionDepression*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.
Metabolic Concerns* Tolerability Concerns
Evolution of Beta-Blockade
First Generation Second Generation Third Generation Next Generation
Propranolol AtenololMetoprolol
Carvedilol Labetalol Nebivolol
Non-Selective Selective VasodilatingNon-
Selective
VasodilatingSelective
6
ββ--Blockers Are HeterogeneousBlockers Are Heterogeneousβ-Blocker ISA Selectivity Vasodilation Dosage
Acebutolol ++ CardioselectiveCardioselective NoNo qdqd/bid/bid
Atenolol -- CardioselectiveCardioselective NoNo qdqd/bid/bid
Bisoprolol -- CardioselectiveCardioselective NoNo qdqd
Bucindolol ++ NonselectiveNonselective Likely via Likely via αα1 1 blockadeblockade bidbid
Carvedilol -- NonselectiveNonselective αα1 1 blockade blockade qdqd/bid/bid
Labetalol ++ NonselectiveNonselective αα1 1 blockadeblockade bidbid
Metoprolol -- CardioselectiveCardioselective NoNo qdqd/bid/bid
Nebivolol -- CardioselectiveCardioselective LL--arginine/NO pathwayarginine/NO pathway qdqd
Pindolol ++++ NonselectiveNonselective NoNo bidbid
Propranolol -- NonselectiveNonselective NoNo bidbid
Timolol -- NonselectiveNonselective NoNo bidbid
Adapted from López-Sendón J, et al. Eur Heart J. 2004;25(15):1341-1362.Bristow MR. Circulation. 2000;101(5):558-569.
ISA: intrinsic sympathomimetic activity
Responses Mediated byβ-Adrenergic Receptors in the Heart
β1 β2Positive chronotropic response
α1cVasoconstriction
β1 β2 α1cProarrhythmia
β1Myocyte apoptosis
Harmful effects
Beneficial effects Receptor Subtype
β1Fetal gene induction
β1 > β2 α1cMyocyte damage/myopathy
β2Fibroblast hyperplasia
β1 > β2 >> α1cCardiac myocyte growth
β1 β2Vasodilation
β1 β2 >> α1cPositive inotropic response
Adapted from Mann DL, et al. Circulation. 2005;111:2837-2849.
0
50
100
150
200
250
300
350
Nebivolol Bisoprolol Metoprolol Bucindolol Propranolol Carvedilol
β 1/β
2Se
lect
ivity
β1/β2-Receptor SelectivityAmong β-Blockers
Bristow MR, et al. Am J Hypertens. 2005;18(pt 2):51A-52A. Abstract P-121.
The Vasodilating β-Blockers
stimulation causes release/activity of NO, and vasodilation
stimulation causes vasodilation
antagonism causes vasodilation
Effect
receptors located in smooth muscle, heart
carvedilollabetalolbucindolol
α1-receptor antagonism
pathways located in blood vessel walls
nebivololL-arginine/nitric oxide pathways
receptors located in bronchi, blood vessels, gut
dilevalolceliprolol
β2-agonism
Site of ActivityAgent(s)Mechanisms
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.
0 1 2
Atenolol Increases the Risk of Stroke and All-Cause Mortality
1.26 (1.15-1.38)
1.05 (0.91-1.21)
1.08 (1.02-1.14)
Stroke
MI
All-cause mortality
Lindholm LH, et al. Lancet. 2005;366:1545-1553.
Favors OtherAntihypertensivesFavors Atenolol
Non-Atenolol β-Blockers Do Not Increase Stroke, MI, or Mortality
Lindholm LH, et al. Lancet. 2005;366:1545-1553.
1.20 (0.30-4.71)
0.86 (0.67-1.11)
0.89 (0.70-1.12)
Stroke
MI
All-cause mortality
0 1 2 3 4 5
Favors OtherAntihypertensives
Favors Non-Atenolol β-Blockers
7
β-Blockers vs Diuretics: Elderly HTN
Messerli FH, et al. JAMA. 1998;279:1903-1907.
Cerebrovascular eventsDiuretics 8 222/5876 412/6661β-blockers 2 79/1521 178/2678
Stroke mortalityDiuretics 7 69/5838 122/6618β-blockers 2 25/1521 57/2678
Coronary heart diseaseDiuretics 8 365/5876 531/6661β-blockers 2 115/1521 197/2678
Cardiovascular mortalityDiuretics 7 332/5838 510/6618β-blockers 2 130/1521 230/2678
All-cause mortalityDiuretics 7 681/5838 907/6618β-blockers 2 227/1521 384/2678
0.4 0.6 0.8 1.0 1.2 1.4
Active Control events/Outcome No. of treatment events/ No. of Odds ratio andfirst drug trials No. of patients patients 95% confidence interval
β-blocker: pindolol, metoprolol, or atenolol
Diuretics
β-blockers
Clinical Outcomes With β-BlockerTherapy in Diabetes: UKPDS Study
UKPDS Group. BMJ. 1998;317:713-720.
Any diabetes-related endpoint
Diabetes-related deaths
All-cause mortality
Myocardial infarction
Stroke
Microvascular disease
1.10
1.27
1.14
1.20
1.12
1.29
Relative Risk and 95% CI0.5 1 2
FavorsACE
inhibitor
Favorsβ-blocker
RR P
.43
.28
.44
.35
.74
.30
GEMINI: Effect on Blood Pressure GEMINI: Effect on Blood Pressure and Heart Rateand Heart Rate
020406080
100120140160
Baseline Month 5 Baseline Month 5 Baseline Month 5
Carvedilol (n = 454)
Metoprolol (n = 636)
Bakris GL, et al. JAMA. 2004;292:2227-2236.
SBPSBP(mm Hg, mean)(mm Hg, mean)
Heart rateHeart rateminute, meanminute, mean
DBPDBP(mm Hg, mean)(mm Hg, mean)
Metoprolol group had higher rate of bradycardia
(4.1% vs 1.4%, P = 0.007)
`
Carvedilol(n = 454)
P P = 0.65= 0.65
P P < 0.001< 0.001M
ean
HbA
Mea
n H
bA1c
1c
(%)
(%) Treatment Treatment
DifferenceDifference
Carvedilol Carvedilol vsvs
MetoprololMetoprolol−−0.13%0.13%
((−−00.22, .22, −−00.04).04)P P = 0.004= 0.004
Metoprolol tartrate(n = 657)
Baseline Month 5 Baseline Month 5
Change in Hemoglobin AChange in Hemoglobin A1c 1c GEMINIGEMINI
7.67.6
7.47.4
7.27.2
7.07.0
1111 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
5.6
5.7
5.8
5.9
6.0
6.1
6.2
6.3
Treatment Difference
Carvedilolvs
Metoprolol–7.2%
(–13.8, –0.20)P = 0.004
Carvedilol(n = 371)
Metoprolol Tartrate(n = 540)
Baseline Month 5 Baseline Month 5
P P = 0.004= 0.004
P P = NS= NS
Mea
n H
OM
A in
sulin
resi
stan
ceM
ean
HO
MA
insu
lin re
sist
ance
Bakris GL, et al. JAMA. 2004;292(18):2227-2236.von Fallois J, et al. Fortschr Med Orig. 2000;118 (suppl 2):77-82.
Mea
n ch
ange
from
bas
elin
e
GlucoseGlucose TriglyceridesTriglyceridesCholesterolCholesterol
--2020--1818--1616--1414--1212--1010--88--66--44--2200
--16%16%
--9%9%
--18%18%
Change in Glucose and LipidsChange in Glucose and Lipidsin Patients With Diabetesin Patients With Diabetes
• Observational study • Nebivolol monotherapy• 1529 centers • 6376 patients with hypertension • Period of 6 weeks
8
Change in Insulin Sensitivity in Hypertensive Patients With Glucose Intolerance
N = 25. Crossover; 16-week treatments. Nebivolol 2.5-5 mg and atenolol 50-100 mg daily.*P < 0.05 vs placebo.EH, euglycemic-hyperinsulinemic; IVGTT, intravenous glucose tolerance test.
Poirier L et al. J Hypertens. 2001;19(8):1429-1435.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Placebo Nebivolol Atenolol
Glu
cose
dis
appe
aran
ce ra
te K
(min
-1)
Glu
cose
dis
posa
l rat
e M
(mg/
kg p
er m
in)
Insulin sensitivityEH clamp
IVGTT≈ 20%reduction
*
0
0.5
1
1.5
2
Placebo Nebivolol Atenolol
≈ 10%reduction
*
P < 0.01
Effect of β-Blockade on Insulin Level and Sensitivity in Hypertensive Patients
4.0
4.5
5.0
5.5
6.0
6.5
7.0
Insulin Sensitivity Index (M/I)*
Baseline After 1 yr ofmetoprololsuccinate
↓ 22%P = 0.0025
(M v
alue
/mU
/L ×
100)
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Fasting Plasma Insulin
Baseline After 1 yr of metoprololsuccinate
(mU
/L)
P = NS
24 hypertensive patients age 21-71 years were treated with 200 mg of metoprolol succinate for one year.*M = glucose uptake per minute during steady-state phase of clamp test; I = mean insulin concentration duringsteady-state phase of clamp test.
Haenni A, et al. Metabolism. 1994;43:455-461.
Differing Effects of Differing Effects of ββ--Blockers on Blockers on Hemodynamics in Hypertensive PatientsHemodynamics in Hypertensive Patients
LV end-diastolicvolume (mL)
LV end-systolicvolume (mL)
Stroke volume (mL)
Heart rate (beats/min)
Cardiac output (L/min)
Peripheral resistance(dyne/cm-5) –13.2
5.8
7.17.1
–10.8–28.2
20.6
–1.49.2
10.65.7
Ejection fraction (%) 7.8–2.1
3.6
––24.024.0
AtenololAtenolol(100 (100 mg/d)mg/d)NebivololNebivolol(5 (5 mg/dmg/d))
––4040Percent change vs Percent change vs baseline
––3030 ––2020 –10 00 1010 2020 30
At 2 weeks.
Kamp O, et al. Am J Cardiol. 2003;92(3):344-348.
Nitric Oxide Is Nitric Oxide Is VasoprotectiveVasoprotectiveand Antiand Anti--atherogenicatherogenic
eNOS, endothelium-derived nitric oxide synthase; LDL, low-density lipoprotein; NO, nitric oxide. Adapted from John S, et al. J Hypertens. 2000;18(4):363-374.
Endothelium
InhibitsInhibits
PlateletPlateletaggregationaggregation
Smooth muscleSmooth muscleproliferationproliferation
EndothelinEndothelinproductionproduction
Smooth muscleSmooth musclecontractioncontraction
Monocyte andMonocyte andplatelet adhesionplatelet adhesion
eNOSeNOS
NONO
Oxidation ofOxidation ofLDL cholesterolLDL cholesterol
Expression ofExpression ofadhesion moleculesadhesion molecules
**
Different Effects of Different Effects of ββ--Blockade Blockade on Forearm Blood Flowon Forearm Blood Flow
N = 16 healthy men.
Cockcroft JR, et al. J Pharmacol Exp Ther. 1995;274(3)1067-1071.
Increase in forearm
blood flow(%)
**
*
100
60
20
–20
0 18 88.5 177 354 (µg/min) 00 10 50.0 100 200 (µg/min)
NebivololAtenolol
Atenolol
Nebivolol*P < 0.01
Endothelial Dysfunction Predicts Endothelial Dysfunction Predicts CV Events CV Events in Hypertensive Patientsin Hypertensive Patients
Perticone F, et al. Circulation. 2001;104(2):191-196.
0
0.2
0.4
0.6
0.8
1.0
12
225 164
Follow-up (mo)24 36 48 60 72 84
132 73 52 41 27 10Patients exposed
to risk:
Even
t-fre
e su
rviv
al
P = 0.0012(Log-rank test)
3rd tertile of FBF
2nd 2nd tertiletertile of of FBF1st 1st tertile of FBFof FBF
0
FBF, forearm blood flow
9
Key Findings From Recent Key Findings From Recent LipidLipid--Lowering TrialsLowering Trials
2002 2003 2004 2005
HPSBenefit in CVD and DM regardless of baseline LDL-C
ASCOT-LLABenefit in high-
risk HTN regardless of
baseline LDL-C
CARDSBenefit in DM
TNTBenefit of
intensive vsmoderate
lipid loweringin stable CAD
ALLHAT-LLTNeutral effect in HTN
with mildlipid lowering
PROVE IT-TIMI 22Early and late benefit of intensive vs moderate lipid lowering in ACS
Primary preventionSecondary prevention (ACS)Secondary prevention (stable CAD)
4DNeutral effect
in ESRD
A to ZLate benefit of
intensive vs moderate lipid lowering in ACS
IDEALBenefit of intensive vs moderate lipid lowering
in stable CAD
Key Findings From Recent BP-Lowering Trials
2002 2003 2004 2005
ALLHATsimilar CHD outcomes for diuretic, CCB,
and ACEI; diuretic superior in preventing HF
(and stroke & CVD vs ACEI)
INVESTCCB ± ACEIequivalent to β-blocker
± diuretic in hypertension
+ CAD
VALUEARB and CCB
similar in composite 10
EP; CCB lower MI rate
ASCOT-BPLABenefit of
CCB ± ACEI vs β-blocker ± diuretic
in high-risk hypertension without CAD
CAMELOTadding CCB
reduced events in hypertension
+ CAD
β-blocker meta-analysis
Increased risk of stroke vs other
antihypertensives
Target BP (mm Hg)No. of antihypertensive agents
1Trial 2 3 4
AASK MAP < 92
UKPDS DBP < 85
ABCD DBP < 75
MDRD MAP < 92
HOT DBP < 80
IDNT SBP < 135/DBP < 85
ALLHAT SBP < 140/DBP < 90
Multiple Antihypertensive Agents Are Needed to Achieve Target BP
DBP, diastolic blood pressure; DM, diabetes mellitus; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661. Lewis EJ, et al. N Engl J Med.2001;345(12):851-860. Cushman WC, et al. J Clin Hypertens. 2002;4(6):393-404. Dahlöf B, et al. Lancet.2005;366(9489):895-906.
ASCOT < 140/90 (< 130/80 DM)
Dia
betic
CK
D
β-Blockers Associated with Sexual Dysfunction
a.No statistically significant differences in incidence of erectile dysfunction among various types of antihypertensive medications bSexual behavior in women.
Drug Incidence of Sexual Dysfunction(% of pts) Source
AtenololPlacebo
113
Wassertheil-Smoller et al. Ann Intern Med.1991;114:613.
AtenololLisinopril
173
Fogari et al.Am J Hypertens.1998;11:1244.
CarvedilolValsartan
13.50.9
Fogari et al.Am J Hypertens. 2001;14:27.
β-blockera
CCBs31.718.3
Burchardt M et al. J Urol. 2000;164(4):1188-91.
Atenololb
LisinoprilDesire (-18%)/Fantasies (-23%)Desire (+38%)/Fantasies (+51%)
Fogari et al.Am J Hypertens. 2004;17:77.
JNC 7: Algorithm for JNC 7: Algorithm for Treatment of HypertensionTreatment of Hypertension
Initial Drug Choices
Drug(s) for the compelling indications
Diuretics, ACEI, ARB, βB, or CCB as
needed.
With Compelling Indications
Stage 2 Hypertension(SBP ≥ 160 or
DBP ≥ 100 mm Hg)
2-drug combination for most. (Thiazide-type diuretic and ACEI or ARB or βB or CCB.)
Stage 1 Hypertension(SBP 140–159 or
DBP 90–99 mm Hg)
Thiazide-type diuretics for most. May consider ACEI, ARB, βB, CCB,
or combination.
Without Compelling Indications
Chobanian AV, et al. JAMA. 2003;289(19):2560-2572.
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.
Heart failure
Post-MI
High CAD risk
Diabetes
Chronic kidneydisease
Recurrent strokeprevention
ACEI ARB CCB AADiuretic βB
The Seventh Report of the Joint National Committee
Compelling Indications
10
Summary
• Some HTN studies and meta-analyses have shown inferior CV outcomes with β-blockers.
• The β-blockers are of critical importance in the management of patients with cardiovascular disease in general, and are useful in HTN.
• Vasodilating β-blockers (carvedilol, nebivolol) are associated with improved tolerability (metabolic, symptoms) and have a better hemodynamic profile.
• Future trials of newer β-blockers may clarify their role in HTN.
Case Review for Complicated Hypertension
Case: 55-Year-Old Woman With Multiple CVD Risk Factors
New patient • 55-year-old woman; smoker • Previously diagnosed with slightly elevated BP,
cholesterol, and glucose levels – Refused suggested medications
• States she is “a little overweight”– Asks to be prescribed weight loss pills
• Father died at age 62 of a heart attack • Mother, age 74, developed diabetes in her mid-50s
Case: 55-Year-Old Woman With Multiple CVD Risk Factors
• Total cholesterol: 238 mg/dL• LDL-C: 105 mg/dL• HDL-C: 32 mg/dL • Triglycerides: 350 mg/dL • Fasting glucose: 112 mg/dL• HbA1C: 7.0• Creatinine: 1.3 mg/dL• Estimated GFR (MDRD): 62
mL/min/1.73 m2
• Height: 5’5”• Weight: 196 lb• BMI: 32.6 kg/m2
• Waist: 44” (central obesity)• BP: 160/96 mm Hg• Pulse: 72 bpm• Heart: RRR without murmur
Physical exam Labs
RRR: Regular Rate and Rhythm;GFR: Glomerular Filtration Rate; MDRD: Modification of Diet in Renal Disease
ARS Question 1Assuming lifestyle intervention has beenimplemented, which of the following CV riskfactors need pharmacological treatment?
1. Blood Pressure2. Triglycerides3. Glucose4. 1 & 35. All of the Above
Patient
Patient has all 5 risk factors
Adapted with permission from Grundy SM, et al. Circulation. 2004;109:433-438.
AHA/NHLBI-Modified ATP III Criteria for Metabolic Syndrome
Risk factor Defining level
Abdominal obesity Waist circumferenceMen > 40 inWomen > 35 in
Triglycerides (mg/dL) ≥ 150HDL-C (mg/dL)
Men < 40Women < 50
BP (mm Hg) ≥ 130/≥ 85Fasting glucose (mg/dL) ≥ 100 112
44
32
350
160/96
11
Case: 55-Year-Old Woman With Multiple CVD Risk Factors
Diagnosis:• Hypertension with metabolic syndrome • Dyslipidemia• Smoker
Patient is identified as being at moderate risk for a CV event by Framingham risk score (17% 10-year risk)
ARS Question 2
In addition to low dose aspirin, she agrees to take a “couple” of pills; which of these would be most useful?
1. RAS blocker/calcium antagonist 2. Calcium antagonist with a statin plus fixed dose
of a RAS blocker/diuretic3. RAS blocker/β-Blocker plus fenofibrate4. RAS blocker/calcium antagonist plus fenofibrate5. RAS blocker/calcium antagonist plus niacin
Case: 50-Year-Old Man With T2DM and CAD
• 50-year-old man• Being seen for increased triglycerides
refractory to fibrates• Past medical history:
– Diagnosed with T2DM at age 42– 5 vessel CAD with CABG at age 47
• Family history:– Father died at age 62 with CAD– Paternal grandfather died at age 65 with CAD– Mother and maternal grandmother with T2DM
T2DM: Type 2 Diabetes Mellitus; CAD: Coronary Artery Disease; CABG: Coronary Artery Bypass Graft
Case: 50-Year-Old Man With T2DM and CAD
Medications – ASA/Warfarin– Metformin 1000 BID– Glyburide 2.5 BID– Fenofibrate 145 mg/day– Metoprolol 100 mg/day– HCTZ/triamterene 25/100 mg/d– Niacin (intermittent/noncompliant)– Fish oil x 2 grams/day– Multivitamin x 1 daily
Case: 50-Year-Old Man With T2DM and CAD
• Physical exam– 220 lbs and 71 in = BMI 30.7 kg/m2
– Central obesity– CABG scars– BP: 138/86 mm Hg– P: 56 regular
Case: 50-Year-Old Man With Type 2 DM and CAD
Lab Value Normal Range
• Fasting glucose 146 mg/dL < 100 mg/dL• HbA1C 7.8% 5% (T2DM goal < 7%)• ALT 66 IU/L ≤ 60• hsCRP 1.6 mg/L < 2.0• Insulin 28.1 uU/mL < 10• Trig 289 mg/dL < 150• LDL-C 117 mg/dL < 130• HDL-C 29.9 mg/dL ≥ 40
12
ARS Question 3
How should the meds/lifestyle be adjusted?
1. Taper the metoprolol and diuretics and substitute a vasodilating beta blocker and ACE inhibitor for BP
2. Stop fenofibrate and start (titrate) sustained-release niacin 2.5 g at bedtime
3. Low carbohydrate diet/increase exercise4. Increase glyburide to 5 mg BID5. All of the above
Case: 50-Year-Old Man With T2DM and CAD: Teaching Points
Multiple cardiovascular risk factors
– s/p CABG (secondary prevention)– Dyslipidemia (Trig/HDL-C)– Obesity (BMI > 27 with comorbidities)– Diabetes