New Dimensions and Landmark Practice Advances in Hypertension and Heart Disease Focus on Optimizing...

New Dimensions and Landmark New Dimensions and Landmark Practice Advances inPractice Advances in

Hypertension and Heart DiseaseHypertension and Heart Disease

New Dimensions and Landmark New Dimensions and Landmark Practice Advances inPractice Advances in

Hypertension and Heart DiseaseHypertension and Heart Disease

Focus on Optimizing the Use of Novel, Cardioselectve Focus on Optimizing the Use of Novel, Cardioselectve Beta-Blockers—From Evidence to PracticeBeta-Blockers—From Evidence to Practice

Focus on Optimizing the Use of Novel, Cardioselectve Focus on Optimizing the Use of Novel, Cardioselectve Beta-Blockers—From Evidence to PracticeBeta-Blockers—From Evidence to Practice

Investigation Investigation ●● Innovation ● Application Innovation ● Application

Ken Jamerson, MD, FACCKen Jamerson, MD, FACCProgram ChairmanProgram Chairman

Professor of MedicineProfessor of MedicineDivision of Cardiovascular MedicineDivision of Cardiovascular Medicine

University of Michigan Health SystemUniversity of Michigan Health SystemAnn Arbor, MichiganAnn Arbor, Michigan

President, Board of TrusteesPresident, Board of TrusteesInternational Society on Hypertension in Blacks (ISHIB)International Society on Hypertension in Blacks (ISHIB)

Ken Jamerson, MD, FACCKen Jamerson, MD, FACCProgram ChairmanProgram Chairman

Professor of MedicineProfessor of MedicineDivision of Cardiovascular MedicineDivision of Cardiovascular Medicine

University of Michigan Health SystemUniversity of Michigan Health SystemAnn Arbor, MichiganAnn Arbor, Michigan

President, Board of TrusteesPresident, Board of TrusteesInternational Society on Hypertension in Blacks (ISHIB)International Society on Hypertension in Blacks (ISHIB)

CME-accredited symposiumCME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Forest Laboratoriesfrom Forest Laboratories

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

CME-accredited symposiumCME-accredited symposium jointly sponsored by the University of jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from Forest Laboratoriesfrom Forest Laboratories

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this educational activity, physicians will learn:As a result of this educational activity, physicians 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.

▶ About the complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors.

▶ How to manage complicated patients with high blood pressure, including those with ischemic heart disease and/or heart failure.

▶ The importance of early treatment of patients with high blood pressure, markers to look for, and the importance of treating both systolic and diastolic blood pressure abnormalities.

▶ 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.

As a result of this educational activity, physicians will learn:As a result of this educational activity, physicians 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.

▶ About the complications linked to healthcare disparities observed in specific patient populations, and the importance of providing access, treatment, and monitoring of patients with multiple risk CV risk factors.

▶ How to manage complicated patients with high blood pressure, including those with ischemic heart disease and/or heart failure.

▶ The importance of early treatment of patients with high blood pressure, markers to look for, and the importance of treating both systolic and diastolic blood pressure abnormalities.

▶ 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 FacultyProgram FacultyProgram FacultyProgram Faculty

Program ChairmanProgram ChairmanKenneth A. Jamerson – Program ChairmanKenneth A. Jamerson – Program ChairmanProfessor of Internal MedicineProfessor of Internal MedicineCardiovascular MedicineCardiovascular MedicineUniversity of Michigan Medical SchoolUniversity of Michigan Medical SchoolMedical Director, Program of Multi-Cultural HealthMedical Director, Program of Multi-Cultural HealthUniversity of MichiganUniversity of MichiganAnn Arbor, MIAnn Arbor, MI

Henry R. Black, MDHenry R. Black, MDClinical Professor of MedicineClinical Professor of MedicineNew York University Medical CenterNew York University Medical CenterNew York, NYNew York, NY

L. Michael Prisant, MD, FACP, FACC, FAHAL. Michael Prisant, MD, FACP, FACC, FAHAProfessor of MedicineProfessor of MedicineMedical College of GeorgiaMedical College of GeorgiaDirector of Hypertension & Lipid ClinicDirector of Hypertension & Lipid ClinicAugusta, GAAugusta, GA

Faculty COI DisclosuresFaculty COI Disclosures Faculty COI DisclosuresFaculty COI Disclosures

Kenneth A. Jamerson – Program ChairmanKenneth A. Jamerson – Program ChairmanGrant/Research:Grant/Research: NIH, NHLBI, NIDDK, Novartis, King NIH, NHLBI, NIDDK, Novartis, KingConsultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventisConsultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventisSpeaker’s Bureau:Speaker’s Bureau: BMS, Merck, Novartis BMS, Merck, NovartisOther: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) Other: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) as president, to obtain industry supportas president, to obtain industry support

Henry R. Black, MDHenry R. Black, MDGrant/Research:Grant/Research: Pfizer PfizerConsultant:Consultant: Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, Myogen Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, MyogenSpeaker’s Bureau:Speaker’s Bureau: Sankyo, BI, Novartis, Pfizer Sankyo, BI, Novartis, Pfizer

L. Michael Prisant, MD, FACP, FACC, FAHAL. Michael Prisant, MD, FACP, FACC, FAHAGrant/Research:Grant/Research: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, Novartis Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, NovartisConsultant:Consultant: Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Reliant, Schwarz, SunTech MedicalReliant, Schwarz, SunTech MedicalSpeaker’s Bureau:Speaker’s Bureau: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Merck, Merck-Schering-Plough, ReliantMerck, Merck-Schering-Plough, Reliant

Kenneth A. Jamerson – Program ChairmanKenneth A. Jamerson – Program ChairmanGrant/Research:Grant/Research: NIH, NHLBI, NIDDK, Novartis, King NIH, NHLBI, NIDDK, Novartis, KingConsultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventisConsultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventisSpeaker’s Bureau:Speaker’s Bureau: BMS, Merck, Novartis BMS, Merck, NovartisOther: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) Other: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) as president, to obtain industry supportas president, to obtain industry support

Henry R. Black, MDHenry R. Black, MDGrant/Research:Grant/Research: Pfizer PfizerConsultant:Consultant: Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, Myogen Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, MyogenSpeaker’s Bureau:Speaker’s Bureau: Sankyo, BI, Novartis, Pfizer Sankyo, BI, Novartis, Pfizer

L. Michael Prisant, MD, FACP, FACC, FAHAL. Michael Prisant, MD, FACP, FACC, FAHAGrant/Research:Grant/Research: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, Novartis Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, NovartisConsultant:Consultant: Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Reliant, Schwarz, SunTech MedicalReliant, Schwarz, SunTech MedicalSpeaker’s Bureau:Speaker’s Bureau: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Merck, Merck-Schering-Plough, ReliantMerck, Merck-Schering-Plough, Reliant

Global Disease Mortality 2002Global Disease Mortality 2002

0 5 10 15 20Mortality (millions)Mortality (millions)

World Health Organization. World Health Organization. The World Health Report 2003: Shaping the Future.The World Health Report 2003: Shaping the Future. 2003 2003

Cardiovascular diseaseCardiovascular disease

Malignant neoplasmsMalignant neoplasms

InjuriesInjuries

Respiratory infectionsRespiratory infections

COPD and asthmaCOPD and asthma

HIV/AIDSHIV/AIDS

Perinatal conditionsPerinatal conditions

Digestive diseasesDigestive diseases

Diarrhoeal diseasesDiarrhoeal diseases

TuberculosisTuberculosis

Childhood diseasesChildhood diseases

MalariaMalaria

DiabetesDiabetes

Prevalence of Conventional Risk Factors in Prevalence of Conventional Risk Factors in Patients with Coronary Heart DiseasePatients with Coronary Heart Disease

19.4 %19.4 %

43.0 %

27.8 %27.8 %

8.9 %8.9 %

4 Risk Factors4 Risk Factors (< 1 %)(< 1 %)

No Risk FactorsNo Risk Factors

1 Risk Factor1 Risk Factor

2 Risk Factors2 Risk Factors

3 Risk Factors3 Risk Factors

62.4 %62.4 %

Khot U et al, JAMA 2003;290:898-904Khot U et al, JAMA 2003;290:898-904

RISK FACTORSRISK FACTORSSmokingSmokingHTNHTNCholesterolCholesterolDMDM

(N = 87,869)(N = 87,869)(N = 87,869)(N = 87,869)

Update on Hypertension ManagementUpdate on Hypertension ManagementRecent Advances – Focus on Combination Recent Advances – Focus on Combination

Therapy, Guideline Modifications, and Therapy, Guideline Modifications, and Comprehensive Cardiovascular ProtectionComprehensive Cardiovascular Protection

Primary Care SummitPrimary Care SummitIn Cardiovascular MedicineIn Cardiovascular Medicine

Henry R. Black, MDHenry R. Black, MDClinical Professor of MedicineClinical Professor of Medicine

NYU Center for the Prevention of Cardiovascular Disease Medical Center NYU Center for the Prevention of Cardiovascular Disease Medical Center New York, NY New York, NY

Henry R. Black, MDHenry R. Black, MDClinical Professor of MedicineClinical Professor of Medicine

NYU Center for the Prevention of Cardiovascular Disease Medical Center NYU Center for the Prevention of Cardiovascular Disease Medical Center New York, NY New York, NY

Achievements in Public Health, 20Achievements in Public Health, 20 thth Century Century

Age-adjusted to the 2000 US population.; Sources: NHLBI, Morbidity and Mortality Chart Book 2000 Age-adjusted to the 2000 US population.; Sources: NHLBI, Morbidity and Mortality Chart Book 2000 CDC, Health, United States 2001CDC, Health, United States 2001

0

100

200

300

400

500

600

700

800

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1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

Year

De

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0

100

200

300

400

500

600

700

800

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1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

Year

De

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Total cardiovascular diseasesTotal cardiovascular diseases

Diseases of the heartDiseases of the heart

Coronary heart diseaseCoronary heart disease

StrokeStroke

Leading Causes of Death for All Ages Leading Causes of Death for All Ages United StatesUnited States

CLRD=chronic lower respiratory diseases. 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, Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/nchs/data/hus/ hus05.pdf. Accessed July 4, 2006.2006.

19501950 19601960 19701970 19801980 19851985 19901990 19951995 20022002

100100

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Unintentional injuriesUnintentional injuries

StrokeStroke

CancerCancer

CLRDCLRD

Heart diseaseHeart disease

All causesAll causes

SGRSGR

VA STUDYVA STUDYDIURETICSDIURETICS

STATINSSTATINS

Impact of Cardiovascular DiseaseImpact of Cardiovascular Disease

► CVD No 1 killer in US: $403.1 billion CVD No 1 killer in US: $403.1 billion

► 2500 CVD deaths each day: ~ 1 death every 35 seconds2500 CVD deaths each day: ~ 1 death every 35 seconds

► CVD claims more lives each year than the next 3 leading causes of CVD claims more lives each year than the next 3 leading causes of death combineddeath combined

► CVD No 1 killer in US: $403.1 billion CVD No 1 killer in US: $403.1 billion

► 2500 CVD deaths each day: ~ 1 death every 35 seconds2500 CVD deaths each day: ~ 1 death every 35 seconds

► CVD claims more lives each year than the next 3 leading causes of CVD claims more lives each year than the next 3 leading causes of death combineddeath combined

AHA Statistics Committee and Stroke Statistics Subcommittee. AHA Statistics Committee and Stroke Statistics Subcommittee. CirculationCirculation. 2006;1-69. 2006;1-69

00

5050

100100

150150

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250250

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CancerCancer

Respiratory Respiratory DiseaseDisease TraumaTrauma

Global Mortality 2000: Global Mortality 2000: Impact of HypertensionImpact of Hypertension

Lower mortality, Lower mortality, developing regiondeveloping region

Attributable Mortality (in thousands; total 55,861,000)Attributable Mortality (in thousands; total 55,861,000)

00 8000800070007000600060005000500040004000300030002000200010001000

High blood pressureHigh blood pressure

TobaccoTobacco

High cholesterolHigh cholesterol

Unsafe sexUnsafe sex

High BMIHigh BMI

Physical inactivityPhysical inactivity

AlcoholAlcohol

UnderweightUnderweightHigh mortality, High mortality, developing regiondeveloping region

Developed regionDeveloped region

BMI = body mass index.BMI = body mass index.Adapted with permission from Ezzati M, et al. Adapted with permission from Ezzati M, et al. Lancet.Lancet. 2002;360:1347-1360. 2002;360:1347-1360.

Residual Lifetime Risk of HypertensionResidual Lifetime Risk of Hypertensionin Women and Men Aged 65 Yearsin Women and Men Aged 65 Years

Vasan RS et al. Vasan RS et al. JAMA.JAMA. 2002;287:1003-1010. 2002;287:1003-1010.

100100

6060

2020

00

8080

4040

Risk of Risk of hypertensionhypertension

(%)(%)

Follow-up (y)Follow-up (y)

MenMen

00 1212 202022 161644 66 88 1010 1414 1818

WomenWomen

Consequences of Hypertension: Consequences of Hypertension: Organ DamageOrgan Damage

CHF=congestive heart failure; CHD=coronary heart disease; LVH=left ventricular hypertrophy.CHF=congestive heart failure; CHD=coronary heart disease; LVH=left ventricular hypertrophy.

Chobanian AV et al. Chobanian AV et al. JAMA.JAMA. 2003;289:2560-2572. 2003;289:2560-2572.

HypertensionHypertension

LVH, CHD, CHFLVH, CHD, CHF

Chronic kidney diseaseChronic kidney diseaseRetinopathyRetinopathy

Transient ischemic Transient ischemic attack, strokeattack, stroke

PeripheralPeripheralarterialarterialdiseasedisease

Risk Factors:Diabetes

Hypertension

Vascular Dysfunction

Vascular Disease

Tissue Injury(MI, Stroke)

PathologicalRemodeling

Target OrganDysfunction (HF, Renal)

End-stageOrgan Failure

Death

Oxidative Stress / Oxidative Stress / EndothelialEndothelialDysfunctionDysfunction

Target OrganTarget Organ DamageDamage

Adapted from Dzau et al. Adapted from Dzau et al. Circulation. Circulation. 2006;114:2850-2870.2006;114:2850-2870.

The Cardiovascular ContinuumThe Cardiovascular Continuum

MI: Myocardial infarctionMI: Myocardial infarctionHF: Heart failureHF: Heart failure

Jackson R et al. Jackson R et al. Lancet.Lancet. 2005;365:434-441. 2005;365:434-441.

Synergistic Interaction of Multiple Synergistic Interaction of Multiple CV Risk FactorsCV Risk Factors

00ReferenceReference

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SmokerSmoker HDL-C = HDL-C = 39 mg/dL39 mg/dL

MaleMale DiabetesDiabetes Aged 60 Aged 60 YearsYears

1010

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3030

4040

505044%44%

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6%6%3%3%

110110

SBP (mm Hg)SBP (mm Hg)

120120130130140140

150150160160170170180180

Additive Risk FactorsAdditive Risk Factors

Trends in CV Risk Factors, US Adults Aged 20-74 Years Trends in CV Risk Factors, US Adults Aged 20-74 Years (NHES: 1960-1962; NHANES:1971-1975 to 1999-2000)(NHES: 1960-1962; NHANES:1971-1975 to 1999-2000)

Gregg EW, et al. Gregg EW, et al. JAMAJAMA. 2005;293:1868-1874. . 2005;293:1868-1874.

High total cholesterol was defined as High total cholesterol was defined as ≥≥240 mg/dL; hypertension was defined as ≥140/90 mm Hg. 240 mg/dL; hypertension was defined as ≥140/90 mm Hg. NHES=National Health Examination Survey.NHES=National Health Examination Survey.

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HTN Commonly Clusters HTN Commonly Clusters with Other Risk Factorswith Other Risk Factors

44

39

314

HTN + 1 other risk factorHTN + 1 other risk factor

HTN + 3 otherHTN + 3 other risk factorsrisk factors

HTN + 2 otherHTN + 2 other risk factorsrisk factors

HTN onlyHTN only

*Body mass index *Body mass index >>30 kg/m30 kg/m22

Kaiser Permanente Northwest database;Kaiser Permanente Northwest database;N=57,573 aged N=57,573 aged >> 35 years with HTN and no CVD 35 years with HTN and no CVD

Weycker D et al. Weycker D et al. Am J HypertensAm J Hypertens. 2007;20:599-607. 2007;20:599-607

Other risk factors: obesity,* hyperlipidemia, and diabetes

► % of patients with BP >140/90 mm Hg:% of patients with BP >140/90 mm Hg:

● 69% of patients with 169% of patients with 1stst MI MI

● 77% of patients with 177% of patients with 1stst stroke stroke

● 74% of patients with HF74% of patients with HF

► Hypertension precedes HF in 91% of casesHypertension precedes HF in 91% of cases

► Hypertension is associated with a 2- to 3-times higher Hypertension is associated with a 2- to 3-times higher risk for HFrisk for HF

► % of patients with BP >140/90 mm Hg:% of patients with BP >140/90 mm Hg:

● 69% of patients with 169% of patients with 1stst MI MI

● 77% of patients with 177% of patients with 1stst stroke stroke

● 74% of patients with HF74% of patients with HF

► Hypertension precedes HF in 91% of casesHypertension precedes HF in 91% of cases

► Hypertension is associated with a 2- to 3-times higher Hypertension is associated with a 2- to 3-times higher risk for HFrisk for HF

Hypertension Co-MorbiditiesHypertension Co-Morbidities

BP, blood pressure; HF, heart failure; MI, myocardial infarction.BP, blood pressure; HF, heart failure; MI, myocardial infarction.Thom T et al. Thom T et al. CirculationCirculation. 2006;113:e85-e151.. 2006;113:e85-e151.

120

120

150

MEN WOMENNon-smoker

mmol/l 4 5 6 7 8

mg/dl 200 250 300

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

Cholesterol

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

Cholesterol

180

160

140

120

180

160

140

180

160

140

120

180

160

140

120

180

160

140

Smoker

age

70

age

60

age

50

age

40

age

30

120

120

150

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mmol/l 4 5 6 7 8

mg/dl 200 250 300

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

Cholesterol

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

180

160

140

120

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

150

mmol/l 4 5 6 7 8

mg/dl 200 250 300

Cholesterol

180

160

140

120

180

160

140

180

160

140

120

180

160

140

120

180

160

140

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age

70

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60

age

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10 Year Risk Level

SB

P (

mm

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)

SB

P (

mm

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Coronary Heart Disease Risk ChartCoronary Heart Disease Risk Chart

ATP III: The Metabolic SyndromeATP III: The Metabolic Syndrome((3 risk factors are required for diagnosis)3 risk factors are required for diagnosis)

Modifications as of 10/2005Modifications as of 10/2005

<40 mg/dL or Rx<40 mg/dL or Rx<50 mg/dL or Rx<50 mg/dL or Rx

MenMenWomenWomen

>40 in (37-39 gen. predisp; 35 for As. Am)>40 in (37-39 gen. predisp; 35 for As. Am)>35 in (31-35 gen. predisp; 31 for As. Am)>35 in (31-35 gen. predisp; 31 for As. Am)

MenMenWomenWomen

100 mg/dL100 mg/dLFasting glucoseFasting glucose

130 or 130 or 85 mm Hg or Rx for 85 mm Hg or Rx for BPBPBlood pressureBlood pressure

HDL-CHDL-C

150 mg/dL or Rx150 mg/dL or RxTGTG

Abdominal obesity Abdominal obesity (Waist circumference(Waist circumference**))

Defining LevelDefining LevelRisk FactorRisk Factor

Grundy SM et al. Grundy SM et al. CirculationCirculation. 2005;28:2289-2304.. 2005;28:2289-2304.

Visceral obesityVisceral obesity

Insulin resistanceInsulin resistance

Raised blood pressure Raised blood pressure

Atherogenic dyslipidemiaAtherogenic dyslipidemia

Proinflammatory stateProinflammatory state

Prothrombotic stateProthrombotic state

The Metabolic Syndrome andThe Metabolic Syndrome andits Consequencesits Consequences

Type 2 DiabetesType 2 Diabetes CardiovascularCardiovascularDiseaseDisease

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMAJAMA. 2001;285:2486-2497. . 2001;285:2486-2497.

Lakka et al. JAMA 2002;288:2709-2716Lakka et al. JAMA 2002;288:2709-2716

1515

1010

55

00

00 22 44 66 88 1010 1212

Cardiovascular Disease MortalityCardiovascular Disease Mortality

RR (95% Cl), 3.55 (1.98-6.43)RR (95% Cl), 3.55 (1.98-6.43)

Metabolic SyndromeMetabolic SyndromeYesYesNoNo

Cum

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Haz

ard,

%C

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Follow-up, yFollow-up, y

Adverse Cardiovascular Prognosis in Metabolic SyndromeAdverse Cardiovascular Prognosis in Metabolic SyndromePopulation-Based Observational Study in 1209 MenPopulation-Based Observational Study in 1209 Men

8080

8585

9090

9595

100100

105105

110110

115115

120120

125125

130130

JNC IJNC I JNC IIJNC II JNC IIIJNC III JNC IVJNC IV JNC V JNC V JNC VIJNC VI

ConsiderConsidertherapytherapy

Hyper-Hyper-tensivetensive

MildMild MildMild MildMild

Stage 1Stage 1 Stage 1Stage 1

ModerateModerate ModerateModerate ModerateModerate

Stage 2Stage 2

SevereSevere SevereSevere SevereSevereStage 3Stage 3 Stage 3Stage 3

Stage 2Stage 2

Stage 4Stage 4

High-High-normalnormal




NormalNormal NormalNormal NormalNormal NormalNormal

OptimalOptimal

DBPDBP(mm Hg)(mm Hg)

OptimalOptimal

JNC 7JNC 7

Stage 1Stage 1

Stage 2Stage 2

Prehyper-Prehyper-tensiontension

NormalNormal

JNC IV.JNC IV. Arch Intern Med. Arch Intern Med. 1988;148:1023 1988;148:1023--1038.1038.JNC V.JNC V. Arch Intern Med. Arch Intern Med. 1993;153:154 1993;153:154--183.183.JNC VI.JNC VI. Arch Intern Med. Arch Intern Med. 1997;157:2413 1997;157:2413--2446.2446.Chobanian AV et al. Chobanian AV et al. JAMA.JAMA. 2003;289:2560-2572. 2003;289:2560-2572.

JNC I.JNC I. JAMA. JAMA. 1977;237:255-261. 1977;237:255-261.JNC II.JNC II. Arch Intern Med. Arch Intern Med. 1980;140:1280-1285. 1980;140:1280-1285.JNC III.JNC III. Arch Intern Med. Arch Intern Med. 1984;144:1045-1057. 1984;144:1045-1057.

Hypertension Hypertension JNC BP Classifications: DBPJNC BP Classifications: DBP

JNC V JNC V

OptimalOptimal110110

120120

130130

140140

150150

160160

170170

180180

190190

200200

210210

220220

JNC IV.JNC IV. Arch Intern Med. Arch Intern Med. 1988;148:1023 1988;148:1023--1038.1038.JNC V.JNC V. Arch Intern Med. Arch Intern Med. 1993;153:154 1993;153:154--183.183.JNC VI.JNC VI. Arch Intern Med. Arch Intern Med. 1997;157:2413 1997;157:2413--2446.2446.Chobanian AV et al. Chobanian AV et al. JAMA.JAMA. 2003;289:2560-2572. 2003;289:2560-2572.

JNC IJNC I JNC IIJNC II JNC IIIJNC III JNC IVJNC IV JNC VIJNC VI

Border- Border- lineline

ISHISH

Stage 1Stage 1 Stage 1Stage 1

Stage 2Stage 2

Stage 3Stage 3



NormalNormal NormalNormal

OptimalOptimal

SBPSBP(mm Hg)(mm Hg)

NormalNormal

Border- Border- lineline

ISHISH

Stage 4Stage 4

No recommendations No recommendations for SBP in JNC Ifor SBP in JNC I

or JNC IIor JNC II

JNC 7JNC 7

Stage 1Stage 1

Prehyper-Prehyper-tensiontension

NormalNormal

Stage 3Stage 3

Stage 2Stage 2

JNC I.JNC I. JAMA. JAMA. 1977;237:255-261. 1977;237:255-261.JNC II.JNC II. Arch Intern Med. Arch Intern Med. 1980;140:1280-1285. 1980;140:1280-1285.JNC III.JNC III. Arch Intern Med. Arch Intern Med. 1984;144:1045-1057. 1984;144:1045-1057.

HypertensionHypertensionJNC BP Classifications: SBPJNC BP Classifications: SBP

Stage 2Stage 2

Mortality According to Blood Pressure Mortality According to Blood Pressure in Men Age 50 to 69in Men Age 50 to 69

0

50

100

150

200

250

158-167 148-157 138-147 128-137 98-127

98-10293-97

88-9283-87

68-82

Society of Actuaries. Blood Pressure Study, 1939.Society of Actuaries. Blood Pressure Study, 1939.

Ra

tio (

%)

of a

ctu

al t

o

Ra

tio (

%)

of a

ctu

al t

o

exp

ect

ed

mor

talit

ye

xpe

cte

d m

orta

lity

Systolic blood pressure (mmHg)Systolic blood pressure (mmHg)Dias

tolic

bloo

d

Diasto

lic b

lood

pres

sure

(mm

Hg)

pres

sure

(mm

Hg)

Hypertension JNC 7Hypertension JNC 7

Blood Pressure (mm Hg)Blood Pressure (mm Hg) CategoryCategory

SystolicSystolic DiastolicDiastolic

<120<120 and <80and <80 NormalNormal

120-139120-139 or 80-89or 80-89 Prehypertension Prehypertension

140-159140-159 or 90-99or 90-99 Stage 1 hypertension Stage 1 hypertension

≥≥160160 or or ≥100≥100 Stage 2 hypertension Stage 2 hypertension

Chobanian AV, et al. Chobanian AV, et al. Hypertension.Hypertension. 2003;42:1206-52. 2003;42:1206-52.

JNC 7: Seventh Report of the Joint National Committee on Prevention, Detection,JNC 7: Seventh Report of the Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure.Evaluation, and Treatment of High Blood Pressure.

Life Time Risk of StrokeLife Time Risk of StrokeFraminghamFramingham

Adapted from Lloyd-Jones, Hypertension Primer, Fourth Edition, 2007Adapted from Lloyd-Jones, Hypertension Primer, Fourth Edition, 2007

Stroke and Ischemic Heart Disease Mortality vs Stroke and Ischemic Heart Disease Mortality vs Usual Systolic BP by AgeUsual Systolic BP by Age

Mor

talit

yM

orta

lity

(Flo

atin

g ab

solu

te r

isk

and

95%

CI)

(Flo

atin

g ab

solu

te r

isk

and

95%

CI)

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

50-59 years50-59 years




StrokeStroke

Age at risk:Age at risk:

256256

128128

6464

3232

1616

88

44

22

11

00

120120 140140 160160 180180

Ischemic Heart DiseaseIschemic Heart Disease

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





Age at risk:Age at risk:


256256

128128

6464

3232

1616

88

44

22

11

00

120120 140140 160160 180180

Lancet. 2002;360:1903-1913Lancet. 2002;360:1903-1913

BP Reductions as Small as 2 mmHg Reduce BP Reductions as Small as 2 mmHg Reduce the Risk of CV Events by Up to 10%the Risk of CV Events by Up to 10%

▶ Meta-analysis of 61 prospective, observational Meta-analysis of 61 prospective, observational studiesstudies

▶ 1 million adults1 million adults

▶ 12.7 million person-years12.7 million person-years

Prospective Studies Collaboration. Prospective Studies Collaboration. Lancet.Lancet. 2002;360:1903-1913 2002;360:1903-1913

2 mmHg2 mmHgdecrease in decrease in mean SBPmean SBP

10%10% reduction in reduction in risk of stroke risk of stroke mortalitymortality

7%7% reduction in reduction in risk of ischemic risk of ischemic heart disease heart disease mortalitymortality

CV

Mor

talit

y R

isk

CV

Mor

talit

y R

isk

Systolic/Diastolic Blood Pressure (mmHg)Systolic/Diastolic Blood Pressure (mmHg)

0

1

2

3

4

5

6

7

8

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

Cardiovascular Mortality Risk Doubles with Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg BP Increment*Each 20/10 mmHg BP Increment*

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

* Individuals aged 40-69 years, starting at BP 115/75 mm Hg* Individuals aged 40-69 years, starting at BP 115/75 mm Hg

Prospective Studies CollaborationProspective Studies Collaboration

““Throughout middle and old age, usual blood Throughout middle and old age, usual blood pressure is strongly and directly related to pressure is strongly and directly related to

vascular (and overall) mortality, without any vascular (and overall) mortality, without any evidence of a threshold down to at least evidence of a threshold down to at least

115/75 mmHg115/75 mmHg.”.”

““Throughout middle and old age, usual blood Throughout middle and old age, usual blood pressure is strongly and directly related to pressure is strongly and directly related to

vascular (and overall) mortality, without any vascular (and overall) mortality, without any evidence of a threshold down to at least evidence of a threshold down to at least

115/75 mmHg115/75 mmHg.”.”

Lancet.Lancet. 2002;360:1903 2002;360:1903–1913.–1913.

The Spectrum of HypertensionThe Spectrum of Hypertensionin Americain America

PRE-HTN

HTN AT GOAL

HT

H N

OT

AT

GO

AL

HT

H N

OT

AT

GO

AL

NO

T R

ES

IST

AN

T

NO

T R

ES

IST

AN

T

HT

N N

OT

AT

GO

AL

HT

N N

OT

AT

GO

AL

RE

SIS

TA

NT

RE

SIS

TA

NT

40-4540-45 MILLIONMILLION

60-70 MILLION60-70 MILLION(37% at GOAL)(37% at GOAL)

3-11 3-11 MILLIONMILLION

*BP ≥ 140/90 mm Hg *BP ≥ 140/90 mm Hg

Prevalence of Hypertension* in US Adults:Prevalence of Hypertension* in US Adults: NHANES 2005–2006NHANES 2005–2006

Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Data Brief no. 3; National Health and Nutrition Examination Survey. 2008.

SBP=systolic blood pressure DBP=diastolic blood pressure

18-3918-39

PercentPercent

0 20 40 60 80 100

40-5940-59

60 years and over60 years and over

MenMen

WomenWomen

Mexican AmericanMexican American

Non-Hispanic WhiteNon-Hispanic White

Non-Hispanic BlackNon-Hispanic Black

0 20 40 60 80 100

Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Data Brief no. 3; National Health and Nutrition Examination Survey. 2008.

SBP=systolic blood pressure DBP=diastolic blood pressure

Prevalence of Hypertension* in US Adults:Prevalence of Hypertension* in US Adults: NHANES 2005–2006NHANES 2005–2006

*SBP = 120-139 mm Hg*SBP = 120-139 mm HgDBP = 80-89 mm Hg DBP = 80-89 mm Hg

18-3918-39

PercentPercent

40-5940-59

60 years and over60 years and over

MenMen

WomenWomen




Algorithm for Treatment of HypertensionAlgorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)(<130/80 mmHg for those with diabetes or chronic kidney disease)

Not at Goal Blood Pressure (<140/90 mmHg) Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug ChoicesInitial Drug ChoicesInitial Drug ChoicesInitial Drug Choices

Drug(s) for the compelling Drug(s) for the compelling indications indications

Other antihypertensive drugs Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) (diuretics, ACEI, ARB, BB, CCB)

as needed. as needed.

Drug(s) for the compelling Drug(s) for the compelling indications indications

Other antihypertensive drugs Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) (diuretics, ACEI, ARB, BB, CCB)

as needed. as needed.

With Compelling With Compelling IndicationsIndications

With Compelling With Compelling IndicationsIndications

Lifestyle ModificationsLifestyle ModificationsLifestyle ModificationsLifestyle Modifications

Not at Goal Not at Goal Blood PressureBlood Pressure

Not at Goal Not at Goal Blood PressureBlood Pressure

Optimize dosages or add additional drugs Optimize dosages or add additional drugs until goal blood pressure is achieved.until goal blood pressure is achieved.

Consider Consider consultation with hypertension specialist.consultation with hypertension specialist.

Optimize dosages or add additional drugs Optimize dosages or add additional drugs until goal blood pressure is achieved.until goal blood pressure is achieved.

Consider Consider consultation with hypertension specialist.consultation with hypertension specialist.

Stage 2 Hypertension Stage 2 Hypertension (SBP (SBP >>160 or DBP 160 or DBP >>100 m100 mmHg) mHg)

2-drug combination for most (usually 2-drug combination for most (usually thiazide-type diuretic and thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)ACEI, or ARB, or BB, or CCB)

Stage 2 Hypertension Stage 2 Hypertension (SBP (SBP >>160 or DBP 160 or DBP >>100 m100 mmHg) mHg)

2-drug combination for most (usually 2-drug combination for most (usually thiazide-type diuretic and thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)ACEI, or ARB, or BB, or CCB)

Stage 1 HypertensionStage 1 Hypertension(SBP 140(SBP 140–159 or DBP 90–99 mmHg)–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, May consider ACEI, ARB, BB, CCB, or combination.or combination.

Stage 1 HypertensionStage 1 Hypertension(SBP 140(SBP 140–159 or DBP 90–99 mmHg)–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, May consider ACEI, ARB, BB, CCB, or combination.or combination.

Without Compelling Without Compelling IndicationsIndications

Without Compelling Without Compelling IndicationsIndications

Goal Of Antihypertensive TherapyGoal Of Antihypertensive Therapy

► < 140 mm Hg < 140 mm Hg andand < 90 mm Hg for most < 90 mm Hg for most

patientspatients

► < 130 mm Hg < 130 mm Hg andand < < 8080 mm Hg for mm Hg for diabeticsdiabetics, ,

patients with HF and those with patients with HF and those with CRFCRF and and

any day now for those with any day now for those with CADCAD

Goal is not dependent on age, gender or co-morbidityGoal is not dependent on age, gender or co-morbidity

THE GOAL IS THE CEILING, NOT THE THE GOAL IS THE CEILING, NOT THE

FLOOR.FLOOR.

► < 140 mm Hg < 140 mm Hg andand < 90 mm Hg for most < 90 mm Hg for most

patientspatients

► < 130 mm Hg < 130 mm Hg andand < < 8080 mm Hg for mm Hg for diabeticsdiabetics, ,

patients with HF and those with patients with HF and those with CRFCRF and and

any day now for those with any day now for those with CADCAD

Goal is not dependent on age, gender or co-morbidityGoal is not dependent on age, gender or co-morbidity

THE GOAL IS THE CEILING, NOT THE THE GOAL IS THE CEILING, NOT THE

FLOOR.FLOOR.

HF of Ischemic EtiologyHF of Ischemic Etiology

ACS - STEMIACS - STEMI

ACS – UA and NSTEMIACS – UA and NSTEMI

CAD and Stable AnginaCAD and Stable Angina

Primary PreventionPrimary Prevention

DiagnosisDiagnosis

Rosendorff et al. Rosendorff et al. Circulation.Circulation. 2007;115:2761-2788. 2007;115:2761-2788.

ASC: acute coronary syndrome, UA: Unstable angina, NSTEMI: Non-ST segment elevation myocardial infarction, STEMI: ST segment elevation myocardial infarction, HF: Heart failure

<130/80, but consider <120/70<130/80, but consider <120/70

<130/80<130/80

<130/80 <130/80

Diabetes, Chronic Kidney Disease, CAD, Diabetes, Chronic Kidney Disease, CAD, CAD Equivalents, or Framingham Risk Score CAD Equivalents, or Framingham Risk Score

≥10%≥10%

Target BP (mm Hg)Target BP (mm Hg)

<140/90<140/90

AHA Scientific Statement—Treatment of Hypertension in the AHA Scientific Statement—Treatment of Hypertension in the Prevention and Management of Ischemic Heart DiseasePrevention and Management of Ischemic Heart Disease

AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; ββB, B, ßß-blocker; CCB, -blocker; CCB, calcium channel blocker; MI, myocardial infarction; calcium channel blocker; MI, myocardial infarction; CAD, coronary artery disease.CAD, coronary artery disease.Chobanian AV, et al. Chobanian AV, et al. JAMA.JAMA. 2003;289(19):2560-2572. 2003;289(19):2560-2572.

The Seventh Report of The Seventh Report of the Joint National Committeethe Joint National Committee

Compelling Compelling IndicationsIndications DiureticDiuretic ßßBB ACEIACEI ARBARB CCBCCB AAAA

Heart failureHeart failure

Post-MIPost-MI

High CAD riskHigh CAD risk

DiabetesDiabetes Chronic kidneyChronic kidney

diseasedisease

RecurrentRecurrent stroke strokepreventionprevention

JNC 7: Combination TherapyJNC 7: Combination Therapy

► ““When BP is more than 20 mmHg above When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic systolic goal or 10 mmHg above diastolic goal, consideration should be given to goal, consideration should be given to initiate therapy with 2 drugs, either as initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose separate prescriptions or in fixed-dose combinations.”combinations.”

► ““When BP is more than 20 mmHg above When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic systolic goal or 10 mmHg above diastolic goal, consideration should be given to goal, consideration should be given to initiate therapy with 2 drugs, either as initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose separate prescriptions or in fixed-dose combinations.”combinations.”

HypertensionHypertension, 2003;42:1221b, 2003;42:1221b

18-5918-59

60 years and over 60 years and over




PercentPercent

Awareness of Hypertension in US Adults:Awareness of Hypertension in US Adults:NHANES 2005–2006NHANES 2005–2006

Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Data Brief no. Data Brief no. 3; National Health and Nutrition Examination Survey.3; National Health and Nutrition Examination Survey. 2008. 2008.

0 20 40 60 80 100

TotalTotal

MenMenWomenWomen

TotalTotalMenMen

WomenWomen


Pharmacological Treatment of Hypertensive Pharmacological Treatment of Hypertensive Adults in the US: NHAMES 2005-2006Adults in the US: NHAMES 2005-2006

18-5918-59




PercentPercent

0 20 40 60 80 100

TotalTotal

MenMenWomenWomen

TotalTotalMenMen

WomenWomen



Treated Hypertensive Adults at Goal BP; Treated Hypertensive Adults at Goal BP; NHANES 2005-2006NHANES 2005-2006

18-5918-59




PercentPercent

0 20 40 60 80

TotalTotal

MenMenWomenWomen

TotalTotalMenMen

WomenWomen


Percentage of Patients Requiring Percentage of Patients Requiring ≥ 2 ≥ 2 Antihypertensive DrugsAntihypertensive Drugs to Reach BP Targets to Reach BP Targets

Per

cent

Per

cent

1. HOT: Hansson et al. 1. HOT: Hansson et al. Lancet. Lancet. 1998;351:1755–62.1998;351:1755–62.2. LIFE: Dahlöf et al. 2. LIFE: Dahlöf et al. LancetLancet. 2002;359:995-1003.. 2002;359:995-1003.3. ALLHAT: Cushman et al. 3. ALLHAT: Cushman et al. J Clin Hypertens.J Clin Hypertens. 2002;4:393–404.2002;4:393–404.

4. CONVINCE: Black et al. 4. CONVINCE: Black et al. JAMA.JAMA. 2003;289:2073-2082. 2003;289:2073-2082.5. ASCOT: Dahlöf et al. 5. ASCOT: Dahlöf et al. Lancet.Lancet. 2005;366:895-906. 2005;366:895-906.

HOTHOT LIFELIFE ALLHATALLHAT CONVINCECONVINCE ASCOTASCOT00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

6060

9090

6363

73737878

Position Statement: MonotherapyPosition Statement: MonotherapyVersus Combination Therapy ESC/ESHVersus Combination Therapy ESC/ESH

► Regardless of the drug employed, Regardless of the drug employed, monotherapy allows to achieve BP monotherapy allows to achieve BP target in only a limited number of hypertensive patients.target in only a limited number of hypertensive patients.

► Use of more than one agent is necessary to achieve target BP in the Use of more than one agent is necessary to achieve target BP in the majority of patientsmajority of patients.. A vast array of effective and well tolerated A vast array of effective and well tolerated combinations is available.combinations is available.

► Initial treatment can make use of monotherapy or combination of two Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or drugs at low doses with a subsequent increase in drug doses or number, if needed.number, if needed.

► Monotherapy could be the initial treatment for a mild BP elevation with Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when 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 initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high.high or very high.

► Fixed combinations of two drugs can simplify treatment schedule and Fixed combinations of two drugs can simplify treatment schedule and favor compliance.favor compliance.

► Regardless of the drug employed, Regardless of the drug employed, monotherapy allows to achieve BP monotherapy allows to achieve BP target in only a limited number of hypertensive patients.target in only a limited number of hypertensive patients.

► Use of more than one agent is necessary to achieve target BP in the Use of more than one agent is necessary to achieve target BP in the majority of patientsmajority of patients.. A vast array of effective and well tolerated A vast array of effective and well tolerated combinations is available.combinations is available.

► Initial treatment can make use of monotherapy or combination of two Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or drugs at low doses with a subsequent increase in drug doses or number, if needed.number, if needed.

► Monotherapy could be the initial treatment for a mild BP elevation with Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when 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 initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high.high or very high.

► Fixed combinations of two drugs can simplify treatment schedule and Fixed combinations of two drugs can simplify treatment schedule and favor compliance.favor compliance.

Advantages of Multidrug Therapy in HypertensionAdvantages of Multidrug Therapy in Hypertension

► Increased efficacy of each drug Increased efficacy of each drug compared to either as compared to either as monotherapymonotherapy

► More prompt achievement of More prompt achievement of goalgoal

► Reduced side effects, clinical Reduced side effects, clinical and metabolicand metabolic

► Alterations in Alterations in pharmacodynamics allowing pharmacodynamics allowing longer duration of action longer duration of action

► Broader spectrum of responseBroader spectrum of response

► Increased efficacy of each drug Increased efficacy of each drug compared to either as compared to either as monotherapymonotherapy

► More prompt achievement of More prompt achievement of goalgoal

► Reduced side effects, clinical Reduced side effects, clinical and metabolicand metabolic

► Alterations in Alterations in pharmacodynamics allowing pharmacodynamics allowing longer duration of action longer duration of action



► Complementary mechanisms of Complementary mechanisms of actionaction

► Fewer pills should mean better Fewer pills should mean better adherenceadherence

► Fewer co-pays if given as a Fewer co-pays if given as a fixed dose combination and fixed dose combination and often cheaper than buying each often cheaper than buying each individuallyindividually


► Complementary mechanisms of Complementary mechanisms of actionaction

► Fewer pills should mean better Fewer pills should mean better adherenceadherence

► Fewer co-pays if given as a Fewer co-pays if given as a fixed dose combination and fixed dose combination and often cheaper than buying each often cheaper than buying each individuallyindividually

Adapted and updated from Black HR. Adapted and updated from Black HR. Patient CarePatient Care, 1997., 1997.

ESH 2003: Possible Combinations of Different ESH 2003: Possible Combinations of Different Classes of Antihypertensive AgentsClasses of Antihypertensive Agents

-blockers-blockers

-blockers-blockersCalciumCalcium

antagonistsantagonists

ATAT11-receptor-receptorblockersblockers

DiureticsDiuretics

ACE inhibitorsACE inhibitors

The The most effective and well toleratedmost effective and well tolerated combinations are shown as combinations are shown as solid linessolid lines

ESH Guidelines. ESH Guidelines. J Hypertens.J Hypertens. 2007;25:1105-1087. 2007;25:1105-1087. ESH= European Society of Hypertension ESH= European Society of Hypertension

2006 Revision 2006 Revision -Blockers Removed-Blockers Removed

<55 Years<55 Years≥≥55 years or Black 55 years or Black Patients at any AgePatients at any Age

A*A* C or DC or D Step 1Step 1

A* + C or A* + D Step 2

A* + C + D Step 3

Step 4Add:• further diuretic therapy or• alpha-blocker or• beta-blockerConsider seeking specialist advice

HR, heart rate; BP, blood pressure.HR, heart rate; BP, blood pressure.1. Tse WY et al. 1. Tse WY et al. Diabet MedDiabet Med. 1994;11(2):137-144. . 1994;11(2):137-144. 2. Fonarow GC. 2. Fonarow GC. Am J MedAm J Med. 2004;116(Suppl 5A):76S-88S. . 2004;116(Suppl 5A):76S-88S. 3. Bell DS. 3. Bell DS. The EndocrinologistThe Endocrinologist. 2003;13:116-123.. 2003;13:116-123.

Potential Cardiac Benefits of Potential Cardiac Benefits of ββ--BlockadeBlockadein Patients With Hypertensionin Patients With Hypertension

►AntiatherogenicAntiatherogenic—reduces inflammation, —reduces inflammation, shear stress, endothelial dysfunction, and shear stress, endothelial dysfunction, and risk for plaque rupturerisk for plaque rupture1,2,31,2,3

►AntiarrhythmicAntiarrhythmic11

● decreases HRdecreases HR22

● decreases sympathetic activitydecreases sympathetic activity11

● increases cardiac vagal toneincreases cardiac vagal tone11

►Anti-ischemicAnti-ischemic11

● decreases HR and BPdecreases HR and BP22

● prolongs diastole (filling coronary arteries)prolongs diastole (filling coronary arteries)22

►Reverses cardiac remodelingReverses cardiac remodeling22

►AntiatherogenicAntiatherogenic—reduces inflammation, —reduces inflammation, shear stress, endothelial dysfunction, and shear stress, endothelial dysfunction, and risk for plaque rupturerisk for plaque rupture1,2,31,2,3

►AntiarrhythmicAntiarrhythmic11

● decreases HRdecreases HR22

● decreases sympathetic activitydecreases sympathetic activity11

● increases cardiac vagal toneincreases cardiac vagal tone11

►Anti-ischemicAnti-ischemic11

● decreases HR and BPdecreases HR and BP22

● prolongs diastole (filling coronary arteries)prolongs diastole (filling coronary arteries)22

►Reverses cardiac remodelingReverses cardiac remodeling22

Phase of Phase of TreatmentTreatment

Acute Acute treatmenttreatment

SecondarySecondarypreventionprevention

OverallOverall

Total #Total #PatientsPatients

28,97028,970

24,29824,298

53,26853,268

0.50.5 1.01.0 2.02.0RR of deathRR of death

b-blocker betterb-blocker better

RR (95% CI)RR (95% CI)

Placebo betterPlacebo better

0.87 (0.77-0.98)0.87 (0.77-0.98)

0.77 (0.70-0.84)0.77 (0.70-0.84)

0.81 (0.75-0.87)0.81 (0.75-0.87)

-blocker Evidence: Secondary Prevention-blocker Evidence: Secondary Prevention

Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A 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.textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.

Summary of Secondary Prevention Trials of b-blocker TherapySummary of Secondary Prevention Trials of b-blocker Therapy

CI=Confidence interval, RR=Relative riskCI=Confidence interval, RR=Relative risk

––22%22% ––20%20% ––20%20%

Hanes DS et al. Hanes DS et al. J Clin Hypertens (Greenwich).J Clin Hypertens (Greenwich). 2001;3(4):236-243. 2001;3(4):236-243.

Risk Reduction With Risk Reduction With ββ-Blockers-Blockersin Post-MI Patients in Post-MI Patients

––30%30%

––40%40%

––20%20%

––10%10%

0%0%

––33%33%

OverallOverallmortalitymortality

SuddenSuddencardiaccardiacdeathdeath

Non-suddenNon-suddendeathdeath Nonfatal MINonfatal MI

15 Trials (n =18,995)15 Trials (n =18,995)

-Blocker Trials in Heart Failure: Overview-Blocker Trials in Heart Failure: Overview

Relative Risk and 95% Confidence IntervalsRelative Risk and 95% Confidence Intervals

Annual MortalityAnnual Mortality

BESTBEST 24 months24 monthsplacebo 17%placebo 17%bucindolol 15%bucindolol 15%

CIBIS-II CIBIS-II 15 months15 monthsplacebo 13.2%placebo 13.2%bisoprolol 8.8%bisoprolol 8.8%

MERIT-HFMERIT-HF 12 months12 monthsplacebo 11.0%placebo 11.0%metoprolol succinate 7.2%metoprolol succinate 7.2%

COPERNICUSCOPERNICUS 10.4 months10.4 monthsplacebo 18.5%placebo 18.5%carvedilol 11.4%carvedilol 11.4%

00 0.250.25 0.50.5 0.750.75 1.01.0 1.251.25 1.51.5 1.751.75 2.02.0

% Patients% Patients

PP=.0001=.0001

PP=.0062=.0062

PP=.0014=.0014

RRRR

34%34%

35%35%

34%34%

PP=.10=.1010%10%

P ValueP Value

LancetLancet. 1999:353:2001-2007; CIBIS II Investigator and Committees. . 1999:353:2001-2007; CIBIS II Investigator and Committees. LancetLancet. 1999;353:9-13; Packer M . 1999;353:9-13; Packer M et al. et al. N Engl J MedN Engl J Med. 2001;344:1651-1658; Beta-blockers Evaluation Survival Trial Investigators. . 2001;344:1651-1658; Beta-blockers Evaluation Survival Trial Investigators. N Engl N Engl J MedJ Med. 2001;344:1659-1667.. 2001;344:1659-1667.

Mean Follow-upMean Follow-up

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII -blocker in all patients following MI or ACS-blocker in all patients following MI or ACS

-blocker in all patients with LVSD-blocker in all patients with LVSD

-blocker in those with other forms of CV disease or -blocker in those with other forms of CV disease or DM, unless contraindicatedDM, unless contraindicated

*Relative contraindications include asthma, chronic obstructive pulmonary *Relative contraindications include asthma, chronic obstructive pulmonary disease, insulin dependent diabetes mellitus, severe peripheral arterial disease, insulin dependent diabetes mellitus, severe peripheral arterial disease, and a PR interval >0.24 secondsdisease, and a PR interval >0.24 seconds

ACS=Acute coronary syndrome, CV=Cardiovascular, DM=Diabetes mellitus, ACS=Acute coronary syndrome, CV=Cardiovascular, DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarctionLVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction

-blocker Recommendations*-blocker Recommendations*

Secondary PreventionSecondary Prevention

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Timeline of Timeline of ββ-Blocker Introduction -Blocker Introduction in the USin the US

1980 20101960

PropanololPropanolol

1990 20001970

MetoprololMetoprololtartratetartrate

NadololNadolol

AtenololAtenolol

TimololTimolol

PindololPindolol

AcebutololAcebutolol

LabetalolLabetalol

PenbutololPenbutolol

CarteololCarteolol

BetaxololBetaxolol

MetoprololMetoprololSuccinateSuccinate

BisoprololBisoprolol

CarvedilolCarvedilol NebivololNebivolol

NonselectiveNonselective

VasodilatingVasodilatingSelectiveSelective

Hemodynamic Effects of Nebivolol and Atenolol Hemodynamic Effects of Nebivolol and Atenolol in Patients with Hypertension*in Patients with Hypertension*

Left ventricularLeft ventricularend-diastolic volume (mL)end-diastolic volume (mL)

Left ventricular endLeft ventricular end systolic systolic volume (mL)volume (mL)

Stroke volume (mL)Stroke volume (mL)

Heart rate (beats/min)Heart rate (beats/min)

Cardiac output (L/min)Cardiac output (L/min)

Peripheral resistance Peripheral resistance (dyne/cm-5)(dyne/cm-5)

-40 -30 -20 -10 0 10 20 30

Percent change vs baseline

-13.25.8

7.1

-10.8-28.2

20.6

-1.49.2

10.65.7

Ejection fraction (%)Ejection fraction (%)7.8

-2.1

3.6

-24.0

Atenolol Atenolol (100 mg/qd)(100 mg/qd)

NebivololNebivolol(5 mg/qd)(5 mg/qd)

Kamp et al. Am J Cardiol. 2003;92:344

*At 2 weeks *At 2 weeks

Incident Diabetes in Clinical Trials of Incident Diabetes in Clinical Trials of Antihypertensive Drugs – A Network Meta-analysisAntihypertensive Drugs – A Network Meta-analysis

Odds ratio of incident diabetesOdds ratio of incident diabetes Incoherence=0.000017Incoherence=0.000017

ARBsARBs

ACE InhibitorsACE Inhibitors

CCBsCCBs

PlaceboPlacebo

ΒΒ blockersblockers

DiureticsDiuretics ReferentReferent

0.90 (0.75-1.09) p=0.300.90 (0.75-1.09) p=0.30

0.77 (0.63-0.94) p=0.0090.77 (0.63-0.94) p=0.009

0.75 (0.62-0.90) p=0.0020.75 (0.62-0.90) p=0.002

0.67 (0.56-0.80) p<0.00010.67 (0.56-0.80) p<0.0001

0.57 (0.46-0.72) p<0.00010.57 (0.46-0.72) p<0.0001

0.500.50 0.700.70 0.900.90 1.261.26

Elliott WJ, Meyer PM. Elliott WJ, Meyer PM. Lancet.Lancet. 2007;369:201–207. 2007;369:201–207.

Effect of Effect of -Blockers on Insulin Sensitivity in -Blockers on Insulin Sensitivity in Hypertensive PatientsHypertensive Patients

-40 -20 0 20 40

PropranololPropranolol

MetoprololMetoprolol

AtenololAtenolol

PindololPindolol

DilevalolDilevalol

CarvedilolCarvedilol

CeliprololCeliprolol

% Change Above Baseline% Change Above Baseline

Jacob S et al. Jacob S et al. AmAm J Hypertens.J Hypertens. 1998;11:1258-1265. 1998;11:1258-1265.

Between these agents, the difference

on IS is ~25-45%, which is similar to

the metabolic effects

of the insulin-sensitizers

2004 Meta-Analysis of Outcomes: Atenolol vs. 2004 Meta-Analysis of Outcomes: Atenolol vs. Other Antihypertensive TreatmentsOther Antihypertensive Treatments

► Analysis of 5 studies: Atenolol versus other antihypertensive therapyAnalysis of 5 studies: Atenolol versus other antihypertensive therapy

► 17,671 patients included, with a mean follow-up of 4.6 years17,671 patients included, with a mean follow-up of 4.6 years

► No differences in BP loweringNo differences in BP lowering

► Analysis of 5 studies: Atenolol versus other antihypertensive therapyAnalysis of 5 studies: Atenolol versus other antihypertensive therapy

► 17,671 patients included, with a mean follow-up of 4.6 years17,671 patients included, with a mean follow-up of 4.6 years

► No differences in BP loweringNo differences in BP lowering

Trials included in meta-analysis: MRC Old (Medical Research Council Trial of Treatment of Hypertension in Older Adults); 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 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).(The Heart Attack Primary Prevention in Hypertension Trial); LIFE (The Losartan Intervention for Endpoint Reduction Study).

Risk ReductionRisk Reduction(95% CI)(95% CI)

All-Cause MortalityAll-Cause Mortality 1.131.13(1.02–1.25)(1.02–1.25)

CV MortalityCV Mortality 1.161.16(1.00–1.34)(1.00–1.34)

Myocardial InfarctionMyocardial Infarction 1.041.04(.89–1.20)(.89–1.20)

Stroke Stroke 1.301.30(1.12–1.50)(1.12–1.50)

Carlberg B. Carlberg B. LancetLancet. 2004;364:1684–1689. 2004;364:1684–1689Carlberg B. Carlberg B. LancetLancet. 2004;364:1684–1689. 2004;364:1684–1689

All All ββ-Blocker-Blockers vs Placebo or s vs Placebo or No Treatment: OutcomesNo Treatment: Outcomes

Lindholm LH et al. Lindholm LH et al. Lancet. Lancet. 2005;366:1545-1553.2005;366:1545-1553.

End PointEnd Point ββ-Blocker-Blockern/Nn/N

PlaceboPlacebon/Nn/N

RRRR(95% CI)(95% CI)

StrokeStroke 325/11025325/11025 518/16408518/16408 0.810.81(0.71-0.93)(0.71-0.93)

Myocardial infarctionMyocardial infarction 413/11025413/11025 639/16408639/16408 0.930.93(0.83-1.05)(0.83-1.05)

Mortality forMortality forall causesall causes 606/11025606/11025 932/16408932/16408 0.950.95

(0.86-1.04)(0.86-1.04)

Atenolol vs. Other Antihypertensive Treatments: Atenolol vs. Other Antihypertensive Treatments: OutcomesOutcomes

EndpointEndpoint -blocker-blockern/Nn/N

Other Other Drug n/NDrug n/N


StrokeStroke 1019/281321019/28132 810/28169810/28169 1.261.26(1.15-1.38)(1.15-1.38)

Myocardial Myocardial InfarctionInfarction 1216/281321216/28132 1167/281691167/28169 1.051.05

(0.91-1.21)(0.91-1.21)

Mortality forMortality forAll CausesAll Causes 2387/281322387/28132 2216/281692216/28169 1.081.08

(1.02-1.14)(1.02-1.14)

Lindholm LH, et al. Lancet. 2005;366:1545-1552

Follow-up 2006 Meta-Analysis:Follow-up 2006 Meta-Analysis:Atenolol vs Other TreatmentsAtenolol vs Other Treatments

2006 Meta-analysis2006 Meta-analysis

End PointEnd Point Summary ORSummary OR(95% CI)(95% CI)

DeathDeath 1.10 (1.03-1.16)1.10 (1.03-1.16)P=P=0.0030.003

CV DeathCV Death 1.13 (1.04-1.22)1.13 (1.04-1.22)((P=P=0.005)0.005)

MIMI 1.05 (0.97-1.14)1.05 (0.97-1.14)P=P=0.190.19

StrokeStroke 1.26 (1.15-1.38)1.26 (1.15-1.38)P=P=0.00000060.0000006

Elliott WJ. Elliott WJ. JACC. JACC. 2006;47 (Suppl):361A.2006;47 (Suppl):361A.

Study PopulationStudy Population blockerblocker n/N n/N

Other DrugsOther Drugsn/Nn/N


ParticipantsParticipants<60 yrs<60 yrs 745/15136745/15136 770/15276770/15276 0.970.97

(0.88-1.07)(0.88-1.07)

ParticipantsParticipants≥60 yrs≥60 yrs 3588/390103588/39010 3817/407653817/40765 1.061.06

(1.01-1.10)(1.01-1.10)

Beta-Blockers vs. Other Antihypertensive Drugs: Beta-Blockers vs. Other Antihypertensive Drugs: Composite Outcome*Composite Outcome*

*Death, stroke or MI*Death, stroke or MI

Khan N, et al. CMAJ. 2006;174:1737-1742

Why they SHOULD be dropped:Why they SHOULD be dropped:▶ There are more effective alternatives. There are more effective alternatives. TRUETRUE▶ They are not effective antihypertensives in older They are not effective antihypertensives in older

and African American patients. and African American patients. NEITHER ARE NEITHER ARE ACE-I or ARBs.ACE-I or ARBs.

▶ They reduce BP (by reducing cardiac output) in a They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. way that is unphysiologic for most patients. TRUETRUE

▶ They do not reduce systolic BP as well as other They do not reduce systolic BP as well as other agents. agents. TRUETRUE

▶ There are safer alternatives. There are safer alternatives. BLOCKERS BLOCKERS MAY BE SAFE, BUT THERE ARE NO MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS.THESE AGENTS.

Why they SHOULD be dropped:Why they SHOULD be dropped:▶ There are more effective alternatives. There are more effective alternatives. TRUETRUE▶ They are not effective antihypertensives in older They are not effective antihypertensives in older

and African American patients. and African American patients. NEITHER ARE NEITHER ARE ACE-I or ARBs.ACE-I or ARBs.

▶ They reduce BP (by reducing cardiac output) in a They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. way that is unphysiologic for most patients. TRUETRUE

▶ They do not reduce systolic BP as well as other They do not reduce systolic BP as well as other agents. agents. TRUETRUE

▶ There are safer alternatives. There are safer alternatives. BLOCKERS BLOCKERS MAY BE SAFE, BUT THERE ARE NO MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS.THESE AGENTS.

ShouldShould ßß-Blockers-Blockers be Dropped as be Dropped as Initial Therapy for Hypertension?Initial Therapy for Hypertension?

Why they should NOT be dropped:Why they should NOT be dropped:

▶ They have been used successfully as initial therapy in They have been used successfully as initial therapy in trials since the 1970s. trials since the 1970s. BUT SO HAVE OTHER BUT SO HAVE OTHER CLASSESCLASSES

▶ Doctors are very familiar with how to use them. Doctors are very familiar with how to use them. BUT BUT THEY KNOW HOW TO USE OTHER CLASSES AS THEY KNOW HOW TO USE OTHER CLASSES AS WELLWELL

▶ They have important additional properties and They have important additional properties and indications. indications. BUT SO DO OTHER CLASSES BUT SO DO OTHER CLASSES

▶ They are widely available and generic. They are widely available and generic. BUT SO ARE BUT SO ARE OTHER CLASSESOTHER CLASSES

Why they should NOT be dropped:Why they should NOT be dropped:

▶ They have been used successfully as initial therapy in They have been used successfully as initial therapy in trials since the 1970s. trials since the 1970s. BUT SO HAVE OTHER BUT SO HAVE OTHER CLASSESCLASSES

▶ Doctors are very familiar with how to use them. Doctors are very familiar with how to use them. BUT BUT THEY KNOW HOW TO USE OTHER CLASSES AS THEY KNOW HOW TO USE OTHER CLASSES AS WELLWELL

▶ They have important additional properties and They have important additional properties and indications. indications. BUT SO DO OTHER CLASSES BUT SO DO OTHER CLASSES

▶ They are widely available and generic. They are widely available and generic. BUT SO ARE BUT SO ARE OTHER CLASSESOTHER CLASSES

So ShouldSo Should ßß-Blockers-Blockers be Dropped as be Dropped as Initial Therapy for Hypertension?Initial Therapy for Hypertension?

So ShouldSo Should -Blockers-Blockers be Dropped as be Dropped as Initial Therapy for Hypertension?Initial Therapy for Hypertension?

In my opinion:In my opinion:

► -BLOCKERS -BLOCKERS should be not be used for initial should be not be used for initial treatment unless the patient has a compelling or treatment unless the patient has a compelling or specific indication.specific indication.

► Diuretics, ACE-I/ARBs and CCBs should be Diuretics, ACE-I/ARBs and CCBs should be considered as “TIER 1” drugs and used before considered as “TIER 1” drugs and used before --BLOCKERSBLOCKERS in other patients. in other patients.

► -BLOCKERS-BLOCKERS should be considered as a common should be considered as a common additional agent to those patients resistant to additional agent to those patients resistant to properly selected TIER 1 agents.properly selected TIER 1 agents.

In my opinion:In my opinion:

► -BLOCKERS -BLOCKERS should be not be used for initial should be not be used for initial treatment unless the patient has a compelling or treatment unless the patient has a compelling or specific indication.specific indication.

► Diuretics, ACE-I/ARBs and CCBs should be Diuretics, ACE-I/ARBs and CCBs should be considered as “TIER 1” drugs and used before considered as “TIER 1” drugs and used before --BLOCKERSBLOCKERS in other patients. in other patients.

► -BLOCKERS-BLOCKERS should be considered as a common should be considered as a common additional agent to those patients resistant to additional agent to those patients resistant to properly selected TIER 1 agents.properly selected TIER 1 agents.

Current Role of Vasodilatory Current Role of Vasodilatory 11-Blockers for -Blockers for Hypertension ManagementHypertension Management

L. Michael Prisant, MD, FACCL. Michael Prisant, MD, FACCCardiologistCardiologist

Professor of MedicineProfessor of MedicineMedical College of GeorgiaMedical College of Georgia

Augusta, GeorgiaAugusta, Georgia

L. Michael Prisant, MD, FACCL. Michael Prisant, MD, FACCCardiologistCardiologist

Professor of MedicineProfessor of MedicineMedical College of GeorgiaMedical College of Georgia

Augusta, GeorgiaAugusta, Georgia

Novel Mechanisms of Action, Hemodynamic Effects, Novel Mechanisms of Action, Hemodynamic Effects, Cardiometabolic Profiles, and Clinical Efficacy Across Cardiometabolic Profiles, and Clinical Efficacy Across

the Cardiovascular Risk Spectrumthe Cardiovascular Risk Spectrum

Novel Mechanisms of Action, Hemodynamic Effects, Novel Mechanisms of Action, Hemodynamic Effects, Cardiometabolic Profiles, and Clinical Efficacy Across Cardiometabolic Profiles, and Clinical Efficacy Across

the Cardiovascular Risk Spectrumthe Cardiovascular Risk Spectrum

The Heart in HypertensionThe Heart in HypertensionThe Heart in HypertensionThe Heart in Hypertension

Coronary IschemiaCoronary Ischemia

Heart FailureHeart Failure

Atrial FibrillationAtrial Fibrillation

DiastolicDiastolicHeart Heart FailureFailure

DiastolicDiastolicHeart Heart FailureFailure

SystolicSystolicHeartHeartFailureFailure

SystolicSystolicHeartHeartFailureFailure

Ventricular Ectopy, Ventricular Fibrillation, Sudden Cardiac DeathVentricular Ectopy, Ventricular Fibrillation, Sudden Cardiac Death

-blockers:-blockers:Compelling IndicationsCompelling Indications

Modified from Chobanian AV, et al. JAMA 2003;289:2560-2572.

DiureticDiuretic -blocker-blocker ACE ACE InhibitorInhibitor

Angiotensin Angiotensin II BlockerII Blocker

Calcium Calcium AntagonistsAntagonists

Aldosterone Aldosterone AntagonistAntagonist


Post Heart AttackPost Heart Attack

High CAD RiskHigh CAD Risk

Diabetes MellitusDiabetes Mellitus

Chronic Renal Chronic Renal DiseaseDisease

Recurrent StrokeRecurrent Stroke

New studies

-blocker History-blocker History

First GenerationNonselectivePropranolol

Timolol

Second Generation

SelectiveAtenolol

MetoprololBisoprolol

Third Generation

VasodilatoryLabetalolCarvedilolNebivolol

First GenerationNonselectivePropranolol

Timolol

Second Generation

SelectiveAtenolol

MetoprololBisoprolol

Third Generation

VasodilatoryLabetalolCarvedilolNebivolol

-blockers Approved in the -blockers Approved in the United StatesUnited States

Source: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu

1980198019801980 20102010201020101960196019601960 1990199019901990 20002000200020001970197019701970

NadololNadolol19791979

TimololTimolol19811981

LabetalolLabetalol19841984

LabetalolLabetalol19841984

PropranololPropranolol19671967

AcebutololAcebutolol19841984

AcebutololAcebutolol19841984

MetoprololMetoprololTartrateTartrate

19781978

SotalolSotalol19921992

Bisoprolol Bisoprolol 19921992

Carvedilol 1995Carvedilol 1995Carvedilol 1995Carvedilol 1995Carvedilol CRCarvedilol CR

20062006Carvedilol CRCarvedilol CR

20062006Betaxolol

1989

PenbutololPenbutolol19871987

PenbutololPenbutolol19871987

NebivololNebivolol20072007

NebivololNebivolol20072007

Propranolol XL Propranolol XL 20032003

Vasodilating Vasodilating -blockers are yellow-blockers are yellow

Date of New Drug Application ApprovalDate of New Drug Application ApprovalDate of New Drug Application ApprovalDate of New Drug Application Approval

LM Prisant 2008

PindololPindolol19821982

PindololPindolol19821982

Propranolol LAPropranolol LA19831983

Propranolol LAPropranolol LA19831983

EsmololEsmolol19861986

EsmololEsmolol19861986

CarteololCarteolol19881988

CarteololCarteolol19881988

MetoprololMetoprololSuccinate Succinate

19921992

MetoprololMetoprololSuccinate Succinate

19921992

AtenololAtenolol19811981

AtenololAtenolol19811981

Effects Mediated by Effects Mediated by 11- and - and 22-adrenoceptors-adrenoceptors

TissueTissue ReceptorReceptor EffectEffectHeartHeart

SA nodeSA node 11, , 22 heart rate heart rateAV nodeAV node 11, , 22 conduction velocity conduction velocityAtriaAtria 11, , 22 contractility contractility

VentriclesVentricles 11, , 22 contractility, conduction velocity & contractility, conduction velocity & automaticity of idioventricular pacemakersautomaticity of idioventricular pacemakers

ArteriesArteries 22 VasodilationVasodilationVeinsVeins 22 VasodilationVasodilation

Skeletal muscleSkeletal muscle 22 Vasodilation, Vasodilation, contractility contractilityGlycogenolysis, K+ uptakeGlycogenolysis, K+ uptake

Liver Liver 22 Glycogenolysis and gluconeogenesisGlycogenolysis and gluconeogenesis

Pancreas (Pancreas ( cells) cells) 22 Insulin and glucagon secretionInsulin and glucagon secretionParathyroid glandsParathyroid glands 11, , 22 Parathormone secretionParathormone secretionThyroid glandThyroid gland 22 T4T4T3 conversionT3 conversionFat cellsFat cells 11 LipolysisLipolysis

BronchiBronchi 22 BronchodilationBronchodilation

KidneyKidney 11 Renin releaseRenin releaseUrinary bladder detrusor Urinary bladder detrusor 22 RelaxationRelaxation

Gallbladder and ducts Gallbladder and ducts 22 RelaxationRelaxationGastrointestinalGastrointestinal 22 RelaxationRelaxation

UterusUterus 22 RelaxationRelaxation

Nerve terminals Nerve terminals 22 Promotes noradrenaline releasePromotes noradrenaline releaseLópez-Sendón J, et al. Eur Heart J 2004;25:1341-1362.

-blockers: -blockers: Targets and Receptor SelectivityTargets and Receptor Selectivity

MM22

aa11

bb22

bb22

aa22

aa22 aa22

NENE

AChACh

Sympathetic Sympathetic Nerve TerminalNerve Terminal

++++++

__

NENE NENE

++

__ __

HeartHeart Blood VesselBlood Vessel

InotropyInotropy

ChronotropyChronotropy

DromotropyDromotropy

VasoconstrictionVasoconstriction

VasoconstrictionVasoconstriction

VasodilationVasodilation

VasodilationVasodilation

• 11-selective blocker-selective blocker

• -nonselective blocker-nonselective blocker

• -nonselective blocker with -nonselective blocker with 11--

blocking activity blocking activity

aa=alpha receptor, Ach=acetylcholine,=alpha receptor, Ach=acetylcholine, b b=beta receptor, M=muscarinic receptor, NE=Norepinephrine=beta receptor, M=muscarinic receptor, NE=Norepinephrine

MM22

Klabunde RE (ed). Klabunde RE (ed). Cardiovascular Physiology ConceptsCardiovascular Physiology Concepts LWW 2001 LWW 2001

Parasympathetic Parasympathetic Nerve TerminalNerve Terminal

Sympathetic Cholinergic Nerve Sympathetic Cholinergic Nerve TerminalTerminal

aa11

MM22

bb22

bb11

––

ßß-blockers:-blockers:Heterogenous Drug ClassHeterogenous Drug Class

ßß11//ßß22

SelectivitySelectivityßß11//ßß22

SelectivitySelectivity

ßß-blockers-blockers

MetabolicMetabolicProfileProfile

MetabolicMetabolicProfileProfile

SideSideEffectsEffectsSideSide

EffectsEffects

VasodilatoryVasodilatoryPropertiesProperties

VasodilatoryVasodilatoryPropertiesProperties

OutcomesOutcomesTrialsTrials

OutcomesOutcomesTrialsTrials

--blockersblockers

Which One?Which One?

Why There is No Class Effect: Why There is No Class Effect: Characteristics of Characteristics of -blockers-blockers

Selectivity for the -receptor

Lipophilicity (vs hydrophilicity)

Route of elimination

Partial agonist activity

Affinity for the postsynaptic 1-receptor

Membrane stabilizing activity

Selectivity for the -receptor

Lipophilicity (vs hydrophilicity)

Route of elimination

Partial agonist activity

Affinity for the postsynaptic 1-receptor

Membrane stabilizing activity

Selectivity for the Selectivity for the -receptors:-receptors:• Non-selective:Non-selective: Produce a competitive blockade of both Produce a competitive blockade of both 11- and - and 22--

adrenergic receptors:adrenergic receptors:

• CarteololCarteolol• NadololNadolol• PenbutololPenbutolol• PindololPindolol• PropranololPropranolol• Sotalol (not indicated for hypertension)Sotalol (not indicated for hypertension)• TimololTimolol

1.1. 11-selective:-selective: higher affinity for the higher affinity for the 11- than for the - than for the 22-receptors-receptors

Selectivity for the Selectivity for the -receptors:-receptors:• Non-selective:Non-selective: Produce a competitive blockade of both Produce a competitive blockade of both 11- and - and 22--

adrenergic receptors:adrenergic receptors:

• CarteololCarteolol• NadololNadolol• PenbutololPenbutolol• PindololPindolol• PropranololPropranolol• Sotalol (not indicated for hypertension)Sotalol (not indicated for hypertension)• TimololTimolol

1.1. 11-selective:-selective: higher affinity for the higher affinity for the 11- than for the - than for the 22-receptors-receptors

-blocker Characteristics-blocker Characteristics

Raynaud’s

11-Selectivity-Selectivity

40.7

15.6

4.230.73 0.49

05

101520253035404550

Nebivolol Bisoprolol Carvedilol Metoprolol Bucindolol

Ki

2/Ki

1

Brixius K, et al. Br J Pharmacol 2002;133:1330-1338.


Lipophilic (vs hydrophilic) -blockers

• Extensively metabolized in the gut wall and liver (first pass effect) oral bioavailability (10–30%)

• Drugs may accumulate in patients with reduced hepatic blood flow:

1. Elderly2. Heart failure3. Liver cirrhosis

• Easily enter the central nervous system, which may account for a greater incidence of central side-effects (sedation)

• Also crosses placenta fetal bradycardia

Lipophilic (vs hydrophilic) -blockers

• Extensively metabolized in the gut wall and liver (first pass effect) oral bioavailability (10–30%)

• Drugs may accumulate in patients with reduced hepatic blood flow:

1. Elderly2. Heart failure3. Liver cirrhosis

• Easily enter the central nervous system, which may account for a greater incidence of central side-effects (sedation)

• Also crosses placenta fetal bradycardia

Route of EliminationRoute of Elimination

100%100% 50%50% 0%0%

0%0% 20%20% 40%40% 60%60% 80%80% 100%100%

Liver EliminationLiver Elimination

PropranololPropranololMetoprololMetoprololLabetalolLabetalolBetaxololBetaxolol

PenbutololPenbutololCarvedilolCarvedilolNebivololNebivolol

TimololTimolol


PindololPindolol


Diacetolol ‡Diacetolol ‡

AtenololAtenololNadololNadololSotalol *Sotalol *

Carteolol †Carteolol †

Adapted from Meier J. Adapted from Meier J. CardiologyCardiology 1979;64 (Suppl 1):1-13. 1979;64 (Suppl 1):1-13.

Renal EliminationRenal Elimination

** Antiarrhythmic agentAntiarrhythmic agent†† No longer available in US for hypertensionNo longer available in US for hypertension‡‡ Metabolite of acebutololMetabolite of acebutolol


Partial Agonist Activity:Partial Agonist Activity:

● Also called Also called intrinsic sympathomimetic activityintrinsic sympathomimetic activity (ISA) (ISA)

● Stimulate and block the Stimulate and block the -receptor-receptor

● Act as partial Act as partial -agonists, but:-agonists, but:

1.1. Still blocks Still blocks the the more significant agonist effects more significant agonist effects of of endogenous catecholaminesendogenous catecholamines

2.2. Tends to slow the heart rate lessTends to slow the heart rate less

● Associated with more adverse cardiac eventsAssociated with more adverse cardiac events

Partial Agonist Activity:Partial Agonist Activity:

● Also called Also called intrinsic sympathomimetic activityintrinsic sympathomimetic activity (ISA) (ISA)

● Stimulate and block the Stimulate and block the -receptor-receptor

● Act as partial Act as partial -agonists, but:-agonists, but:

1.1. Still blocks Still blocks the the more significant agonist effects more significant agonist effects of of endogenous catecholaminesendogenous catecholamines

2.2. Tends to slow the heart rate lessTends to slow the heart rate less

● Associated with more adverse cardiac eventsAssociated with more adverse cardiac events

CharacteristicsCharacteristics

** Membrane Stabilizing ActivityMembrane Stabilizing Activity†† AntioxidantAntioxidant‡‡ Nitric oxide-mediated vasodilationNitric oxide-mediated vasodilation¶¶ Class III antiarrhythmicClass III antiarrhythmic

No No -blocker is cardioselective in large doses-blocker is cardioselective in large doses22-blockade is needed for tremor and migraines-blockade is needed for tremor and migraines

11-blockers are better for bronchospasm & insulin-requiring diabetes-blockers are better for bronchospasm & insulin-requiring diabetes

ISA-Nadolol

Propranolol*TimololSotalol¶

ISA-Nadolol

Propranolol*TimololSotalol¶

ISA+PindololCarteolol

Penbutolol

ISA+PindololCarteolol

Penbutolol

ISA-AtenololEsmolol

MetoprololNebivolol‡BisoprololBetaxolol*

ISA-AtenololEsmolol

MetoprololNebivolol‡BisoprololBetaxolol*

ISA+Acebutolol*

ISA+Acebutolol*

NonselectiveNonselective SelectiveSelective1-blocker1-blocker

Labetalol 1:4-7*Carvedilol 1:10*†Labetalol 1:4-7*

Carvedilol 1:10*†

-adrenoceptor Blockers-adrenoceptor Blockers

Modified from Kaplan NM. Clinical Hypertension (8ed). 2002;262.

Mechanisms of Mechanisms of -blockers-blockers

Perc

enta

ge o

f C

ontr

ol Peripheral Resistance

Arterial Pressure

Cardiac Output

Central Activity

Renin Activity

Week YearMonthDay

Man in’t Veld AJ, Schalekamp MADH. Br J Clin Pharmacol 1982;13(suppl 2):245S-257S.

-blockers:-blockers:Long-Term Hemodynamic EffectsLong-Term Hemodynamic Effects

Vasc

ula

r R

esi

stance

(%

)V

asc

ula

r R

esi

stance

(%

)

Cardiac Output (%)

TimololTimolol

Man in’t Veld AJ, Schalekamp MADH. Br J Clin Pharmacol. 1982;13(suppl 2):245S-257S.

PropranololPropranololMetoprololMetoprolol

AtenololAtenololPenbutololPenbutolol


AlprenololAlprenolol OxprenololOxprenolol

PractololPractolol

PindololPindolol

Pretreatment ValuesPretreatment Values

70

80

90

100

110

120

70 80 90 100 110

-blockers:-blockers:Peripheral Vasodilating ActivityPeripheral Vasodilating Activity

Several MechanismsSeveral Mechanisms

BucindololBucindolol (not marketed because of BEST) (not marketed because of BEST)• Produces vasodilatation by ? cGMP-dependent mechanism Produces vasodilatation by ? cGMP-dependent mechanism

Carvedilol, labetalol:Carvedilol, labetalol: due to due to 11-blockade-blockade

Celiprolol:Celiprolol: due to due to 22-adrenergic receptor agonism (not marketed in -adrenergic receptor agonism (not marketed in

US, due to hepatic dysfunction)US, due to hepatic dysfunction)

NebivololNebivolol• LipophilicLipophilic• Racemic mixtureRacemic mixture• Nitric oxide (NO)-mediated vasodilator propertiesNitric oxide (NO)-mediated vasodilator properties

BucindololBucindolol (not marketed because of BEST) (not marketed because of BEST)• Produces vasodilatation by ? cGMP-dependent mechanism Produces vasodilatation by ? cGMP-dependent mechanism

Carvedilol, labetalol:Carvedilol, labetalol: due to due to 11-blockade-blockade

Celiprolol:Celiprolol: due to due to 22-adrenergic receptor agonism (not marketed in -adrenergic receptor agonism (not marketed in

US, due to hepatic dysfunction)US, due to hepatic dysfunction)

NebivololNebivolol• LipophilicLipophilic• Racemic mixtureRacemic mixture• Nitric oxide (NO)-mediated vasodilator propertiesNitric oxide (NO)-mediated vasodilator properties

Nebivolol: Nebivolol: Ultraselective, Vasodilating Ultraselective, Vasodilating 11-blocker-blocker

OHOH

F

HN

O

O F

ll-nebivolol-nebivolol dd-nebivolol-nebivolol

VasorelaxantVasorelaxant 11-blocker-blocker

Racemic MixtureRacemic Mixture

Prisant LM. J Clin Pharmacol 2008; 48:225-239.

Vascular Relaxation via theVascular Relaxation via theL-arginineL-arginine–Nitric-Oxide Pathway–Nitric-Oxide Pathway

Veverka A, et al. Veverka A, et al. Am Pharmacother Am Pharmacother 2006;40:1353-1360.2006;40:1353-1360.

L-arginineL-arginine

Nitric Nitric oxideoxide

(diffuses into smooth muscle)(diffuses into smooth muscle)

EndothelialEndothelialNOSNOS

Guanylyl CyclaseGuanylyl Cyclase

Activated Guanylyl CyclaseActivated Guanylyl Cyclase

cGMPcGMPGTPGTP

Vascular Smooth Muscle RelaxationVascular Smooth Muscle Relaxation

––

Nebivolol: Nitric Oxide Mediates Stimulation of Nebivolol: Nitric Oxide Mediates Stimulation of Endothelium-Dependent VenodilationEndothelium-Dependent Venodilation

Bowman AJ, et al. Br J Clin Pharmacol 1994;38:199-204.

Nebivolol Dose (mol min-1)

10-12 10-11 10-10 10-9 10-8 10-7

100

80

60

40

20

0

-20

Ven

odila

tion

(%)

Without NO Inhibitor

With NO Inhibitor

Time (s)Time (s) Time (s)Time (s) Time (s)Time (s)

Calcium ionophoreCalcium ionophore Calcium ionophoreCalcium ionophore Calcium ionophoreCalcium ionophore

WhiteWhite African AmericanAfrican AmericanAfrican AmericanAfrican American

+ Nebivolol+ Nebivolol

300

mM

300

mM

30 m

M3

0 m

M

30 m

M3

0 m

MRelease of Nitric Oxide from Release of Nitric Oxide from

Human Endothelium: White vs BlacksHuman Endothelium: White vs Blacks

Mason RP, et al. Mason RP, et al. CirculationCirculation 2005;112:3795-3801. 2005;112:3795-3801.

Nitric Oxide: NO

Superoxide Anion: O2-

Peroxynitrite: ONOO-

Hemodynamic Effects of Nebivolol and Atenolol Hemodynamic Effects of Nebivolol and Atenolol in Hypertensive Patients*in Hypertensive Patients*

Left ventricularend-diastolic volume (mL)

Left ventricular end systolic volume (mL)

Stroke volume (mL)

Heart rate (beats/min)

Cardiac output (L/min)

Peripheral resistance (dyne/cm-5)

-40 -30 -20 -10 0 10 20 30Percent change vs baseline

-13.2

5.8

7.1

-10.8

-28.2

20.6

-1.4

9.2

10.6

5.7

Ejection fraction (%)7.8

-2.1

3.6

-24.0

Atenolol (100 mg/qd)

Nebivolol(5 mg/qd)

Kamp, et al. Am J Cardiol 2003;92:344

*At 2 weeks *At 2 weeks

Insulin ResistanceInsulin Resistance

Berne C, Pollare T, Lithell H. Berne C, Pollare T, Lithell H. Diabetes CareDiabetes Care 1991 (Suppl 4);39-47 1991 (Suppl 4);39-47Prisant LM, Carr AA. Prisant LM, Carr AA. Am J HypertensAm J Hypertens 1992;775-777 1992;775-777White WB, Prisant LM, Wright JT White WB, Prisant LM, Wright JT Am J MedAm J Med 2000;108:238-245 2000;108:238-245

-33.2-33.2

-26-26-23.4-23.4

-20-20-17.1-17.1 -16.3-16.3

-9.5-9.5

-5-5-2.4-2.4

2.22.2

17.217.219.119.1

24.324.3



AtenololAtenolol

SpironolactoneSpironolactone

PindololPindolol

HCTZHCTZ

IsradipineIsradipine

VerapamilVerapamil

FurosemideFurosemide

DiltiazemDiltiazem

CaptoprilCaptopril

PrazosinPrazosin

DoxazosinDoxazosin

Effects of 3–6 Months of Antihypertensive Monotherapy on Effects of 3–6 Months of Antihypertensive Monotherapy on Insulin Sensitivity IndexInsulin Sensitivity Index

% C

ha

ng

e%

Ch

an

ge

% C

ha

ng

e%

Ch

an

ge

Objective:Objective:Compare effects of Compare effects of -blockers with different -blockers with different pharmacologic properties on glycemic and metabolic control pharmacologic properties on glycemic and metabolic control in patients with diabetes in patients with diabetes and hypertension receiving RAAS blockadeand hypertension receiving RAAS blockade

Participants:Participants:1235 patients 1235 patients

Treatment:Treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or Carvedilol 6.25 mg to 25 mg bid (n = 498) or Metoprolol tartrate 50 mg to 200 mg bid (n = 737)Metoprolol tartrate 50 mg to 200 mg bid (n = 737)

Follow-up:Follow-up:35 weeks35 weeks

Objective:Objective:Compare effects of Compare effects of -blockers with different -blockers with different pharmacologic properties on glycemic and metabolic control pharmacologic properties on glycemic and metabolic control in patients with diabetes in patients with diabetes and hypertension receiving RAAS blockadeand hypertension receiving RAAS blockade

Participants:Participants:1235 patients 1235 patients

Treatment:Treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or Carvedilol 6.25 mg to 25 mg bid (n = 498) or Metoprolol tartrate 50 mg to 200 mg bid (n = 737)Metoprolol tartrate 50 mg to 200 mg bid (n = 737)

Follow-up:Follow-up:35 weeks35 weeks

GGlycemic lycemic EEffects in diabetes ffects in diabetes MMellitus: carvedilol-metoprolol comparison ellitus: carvedilol-metoprolol comparison ININ hypertensives studyhypertensives study

Bakris GL, et al. JAMA 2004;292:2227-2236.

GEMINIGEMINI

GEMINI: GEMINI: Blood Pressure and Heart RateBlood Pressure and Heart Rate

Mean Systolic BPMean Systolic BP Mean Diastolic BPMean Diastolic BP Mean Heart RateMean Heart Rate(mm Hg)(mm Hg) (mm Hg)(mm Hg) (beats/minute)(beats/minute)

Carvedilol (n = 454)Carvedilol (n = 454) Metoprolol (n = 636)Metoprolol (n = 636)

Bakris GL, et al. JAMA 2004;292:2227-2236.

Treatment DifferenceTreatment Difference(Carvedilol vs Metoprolol)(Carvedilol vs Metoprolol) (95% CI)(95% CI) PP Value Value

SBP, mm HgSBP, mm Hg22 ––1.0 (–2.60, –0.58)1.0 (–2.60, –0.58) 0.210.21

DBP, mm HgDBP, mm Hg22 0.29 (–0.61, 1.20)0.29 (–0.61, 1.20) 0.530.53

HR, beats/minHR, beats/min22 1.6 (0.70, 2.58)1.6 (0.70, 2.58) < 0.001< 0.001

00

2020

4040

6060

8080

100100

120120

140140

160160

BaselineBaseline Month 5Month 5 BaselineBaseline Month 5Month 5 BaselineBaseline Month 5Month 5

Metoprolol tartrate Metoprolol tartrate CarvedilolCarvedilol

% (SD)% (SD) PP % (SD)% (SD) PP

HbAHbA1c1c 0.15 (0.04)0.15 (0.04) <0.001<0.001 0.02 (0.04)0.02 (0.04) 0.650.65

Insulin Insulin sensitivitysensitivity ––2.02.0 0.480.48 ––9.19.1 0.0040.004

GEMINI: Change inGEMINI: Change inHbAHbA1c1c and Insulin Sensitivity and Insulin Sensitivity

EndpointEndpoint(mean (mean ))

Bakris GL, et al.Bakris GL, et al. JAMA JAMA 2004;292:2227-36. 2004;292:2227-36.

Insulin ResistanceInsulin Resistance

-12.2

-21.6-25

-20

-15

-10

-5

0

5

Nebivolol2.5-5 mg QD

Atenolol50-100 mg QD

Perc

enta

ge C

hange

p<0.01p<0.01

Poirer L, et al. Poirer L, et al. J Hypertens J Hypertens 2001;19:1429-1435.2001;19:1429-1435.

Insulin Sensitivity IndexInsulin Sensitivity Index

36-week Randomized, Double-blind Crossover Design36-week Randomized, Double-blind Crossover Design(n = 25)(n = 25)

Post Myocardial InfarctionPost Myocardial Infarction

DiureticDiuretic -blocker-blockerACE ACE

InhibitorInhibitor ARBARBCalcium Calcium

AntagonistAntagonistAldosterone Aldosterone AntagonistAntagonist

Post-Myocardial Post-Myocardial InfarctionInfarction

Myocardial Infarction: Myocardial Infarction: Is there a Class Effect for Is there a Class Effect for -blockers?-blockers?

Freemantle N, et al. Freemantle N, et al. BMJ BMJ 1999;318:1730-7.1999;318:1730-7.Freemantle N, et al. Freemantle N, et al. BMJ BMJ 1999;318:1730-7.1999;318:1730-7.

Total Mortality Reduction after Myocardial InfarctionTotal Mortality Reduction after Myocardial InfarctionTotal Mortality Reduction after Myocardial InfarctionTotal Mortality Reduction after Myocardial Infarction

AcebutololAcebutololAcebutololAcebutolol

AlprenololAlprenololAlprenololAlprenolol

AtenololAtenololAtenololAtenolol

Carvedilol *Carvedilol *Carvedilol *Carvedilol *

MetoprololMetoprololMetoprololMetoprolol

OxprenololOxprenololOxprenololOxprenolol

PindololPindololPindololPindolol

PractololPractololPractololPractolol

PropranololPropranololPropranololPropranolol

SotalolSotalolSotalolSotalol

TimololTimololTimololTimolol

XamoterolXamoterolXamoterolXamoterol||00||00

||11||11

||22||22

||33||33

||44||44

||55||55

||66||66

Odd Ratio of DeathOdd Ratio of DeathOdd Ratio of DeathOdd Ratio of Death

n = 54,234n = 54,234n = 54,234n = 54,234

** Meta-analysis did NOT include CAPRICORN Trial Meta-analysis did NOT include CAPRICORN Trial (Lancet 2001;357:1385-90), which showed 23%(Lancet 2001;357:1385-90), which showed 23% in all- in all-cause mortality (Hazard ratio = 0.77 [95% Confidence cause mortality (Hazard ratio = 0.77 [95% Confidence interval = 0.60-0.98], p=0.03) interval = 0.60-0.98], p=0.03)

** Meta-analysis did NOT include CAPRICORN Trial Meta-analysis did NOT include CAPRICORN Trial (Lancet 2001;357:1385-90), which showed 23%(Lancet 2001;357:1385-90), which showed 23% in all- in all-cause mortality (Hazard ratio = 0.77 [95% Confidence cause mortality (Hazard ratio = 0.77 [95% Confidence interval = 0.60-0.98], p=0.03) interval = 0.60-0.98], p=0.03)

••••••••

••••

••••

••••

••••

••••

••••

••••

••••••••

••••

CAPRICORN CAPRICORN Study DesignStudy Design

Dargie HJ, et al. Eur J Heart Fail 2000;2:325-332.

PlaceboPlacebo

6.25 mg BID6.25 mg BID

BaselineBaseline

12.5 mg BID12.5 mg BID

3–10 3–10 DaysDays

3–10 3–10 DaysDays

633633EventsEvents

Visits Every 3–4 Visits Every 3–4 MonthsMonths

CarvedilolCarvedilol25 mg BID25 mg BID

► Encouraged adjunctive therapyEncouraged adjunctive therapy

► Receiving ACE inhibitor Receiving ACE inhibitor 48 hrs48 hrs

► Clinically stable, but may have had pulmonary edema or cardiogenic Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarctionshock during index infarction

► Encouraged adjunctive therapyEncouraged adjunctive therapy

► Receiving ACE inhibitor Receiving ACE inhibitor 48 hrs48 hrs

► Clinically stable, but may have had pulmonary edema or cardiogenic Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarctionshock during index infarction

CAPRICORN:CAPRICORN:All-Cause MortalityAll-Cause Mortality

The CAPRICORN Investigators.The CAPRICORN Investigators. Lancet Lancet 2001;357:1385-1390.2001;357:1385-1390.

► 6,644 patients with LVEF<40% after a MI with or without HF randomized to 6,644 patients with LVEF<40% after a MI with or without HF randomized to carvedilol or placebo for 24 monthscarvedilol or placebo for 24 months

0.70.7

0.750.75

0.80.8

0.850.85

0.90.9

0.950.95

11

00 0.50.5 11 1.51.5 22 2.52.5


PlaceboPlacebo

YearsYears

Pro

port

ion

Eve

nt-f

ree

Pro

port

ion

Eve

nt-f

ree

n=975n=975

n=984n=984

Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN)Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN)

HR = 0.77 (0.60-0.98)HR = 0.77 (0.60-0.98)p = 0.031p = 0.031

Expansion of InfarctHours to Days

Initial Infarct

Ventricular Remodeling After Ventricular Remodeling After Myocardial InfarctionMyocardial Infarction

Jessup M, Brozena S. Jessup M, Brozena S. N Engl J Med N Engl J Med 2003;348:2007:2007-18.2003;348:2007:2007-18.

Global RemodelingDays to Months


QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.

DiureticDiuretic -blocker-blockerACE ACE

InhibitorInhibitor ARBARBCalcium Calcium

AntagonistAntagonistAldosterone Aldosterone AntagonistAntagonist


Heart Failure: Is There Heart Failure: Is There Class Effect for Class Effect for -blockers?-blockers?

MERIT-HF. MERIT-HF. LancetLancet 1999;353:2001-2007; CIBIS-II. 1999;353:2001-2007; CIBIS-II. LancetLancet 1999;353:9-13; Packer M, et al. 1999;353:9-13; Packer M, et al. N Engl J Med N Engl J Med 2001;344:1651-1658; BEST. 2001;344:1651-1658; BEST. N Engl J MedN Engl J Med 2001;344:1659-1667. 2001;344:1659-1667.MERIT-HF. MERIT-HF. LancetLancet 1999;353:2001-2007; CIBIS-II. 1999;353:2001-2007; CIBIS-II. LancetLancet 1999;353:9-13; Packer M, et al. 1999;353:9-13; Packer M, et al. N Engl J Med N Engl J Med 2001;344:1651-1658; BEST. 2001;344:1651-1658; BEST. N Engl J MedN Engl J Med 2001;344:1659-1667. 2001;344:1659-1667.

Relative risk and 95% confidence intervalsRelative risk and 95% confidence intervalsRelative risk and 95% confidence intervalsRelative risk and 95% confidence intervals

AnnualAnnualMortalityMortalityAnnualAnnual

MortalityMortality

BEST BEST (n=2708)(n=2708)PlaceboPlacebo 17.0%17.0%BucindololBucindolol 15.0%15.0%

CIBIS-II CIBIS-II (n=2647)(n=2647) PlaceboPlacebo 13.2%13.2%BisoprololBisoprolol 8.8%8.8%

MERIT-HF MERIT-HF (n=3991)(n=3991)PlaceboPlacebo 11.0%11.0%Metoprolol succinateMetoprolol succinate 7.2%7.2%

COPERNICUS COPERNICUS (n=2289)(n=2289)PlaceboPlacebo 18.5%18.5%CarvedilolCarvedilol 11.4%11.4%

BEST BEST (n=2708)(n=2708)PlaceboPlacebo 17.0%17.0%BucindololBucindolol 15.0%15.0%

CIBIS-II CIBIS-II (n=2647)(n=2647) PlaceboPlacebo 13.2%13.2%BisoprololBisoprolol 8.8%8.8%

MERIT-HF MERIT-HF (n=3991)(n=3991)PlaceboPlacebo 11.0%11.0%Metoprolol succinateMetoprolol succinate 7.2%7.2%

COPERNICUS COPERNICUS (n=2289)(n=2289)PlaceboPlacebo 18.5%18.5%CarvedilolCarvedilol 11.4%11.4%

0000 0.250.250.250.25 0.50.50.50.5 0.750.750.750.75 1.01.01.01.0 1.251.251.251.25 1.51.51.51.5 1.751.751.751.75 2.02.02.02.0

MeanMean RiskRisk PPFollow-upFollow-up Reduction Reduction ValueValue

MeanMean RiskRisk PPFollow-upFollow-up Reduction Reduction ValueValue

10.4 mo10.4 mo 35%35% p =.0014p =.001410.4 mo10.4 mo 35%35% p =.0014p =.0014

12 mo12 mo 34%34% p =.0062p =.006212 mo12 mo 34%34% p =.0062p =.0062

15 mo15 mo 34%34% p =.0001p =.000115 mo15 mo 34%34% p =.0001p =.0001

24 mo24 mo 10%10% p =. 10p =. 1024 mo24 mo 10%10% p =. 10p =. 10

SENIORS StudySENIORS Study

100100

9090

8080

7070

6060

5050

100100

9090

8080

7070

6060

505000 66 1212 1818 2424 3030 00 66 1212 1818 2424 3030

HR 0.86 (0.74–0.99) HR 0.86 (0.74–0.99) P = 0.039P = 0.039

Time (months)Time (months)

All-cause Mortality or CV Hospital Admission All-cause Mortality or CV Hospital Admission (Primary Outcome)(Primary Outcome)

NebivololNebivolol

Time (months)Time (months)

All-cause Mortality All-cause Mortality (Main Secondary Outcome)(Main Secondary Outcome)

HR 0.88 (0.71–1.08) HR 0.88 (0.71–1.08) P = 0.214P = 0.214

PlaceboPlacebo

Event- Event- free free

survival survival (%)(%)

NebivololNebivolol

PlaceboPlacebo

Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart FailureSeniors with Heart Failure

Flather MD, et al. Flather MD, et al. Eur Heart J Eur Heart J 2005; 26:215-225.2005; 26:215-225.

2128 patients ≥ 70 years 2128 patients ≥ 70 years heart failure historyheart failure history (admission < 1 year or known EF ≤35%) to (admission < 1 year or known EF ≤35%) to nebivolol, titrated to 10 mg QD, or placebonebivolol, titrated to 10 mg QD, or placebo

Median 21 monthsMedian 21 months

2005 ACC/AHA Heart Failure Guidelines2005 ACC/AHA Heart Failure Guidelines

► Within drug classes, agents may differ pharmacologicallyWithin drug classes, agents may differ pharmacologically

► These pharmacological differences may translate into differences in clinical These pharmacological differences may translate into differences in clinical outcomesoutcomes

► When multiple agents within a class produce discordant results on clinical When multiple agents within a class produce discordant results on clinical outcomes, class effect cannot be presumed (eg, outcomes, class effect cannot be presumed (eg, -blockers)-blockers)

Use of 1 of the 3 Use of 1 of the 3 ββ--blockers proven to reduce mortality blockers proven to reduce mortality (ie, bisoprolol, carvedilol, and metoprolol succinate) is (ie, bisoprolol, carvedilol, and metoprolol succinate) is recommendedrecommended for all stable patients with current or for all stable patients with current or prior symptoms of HF and reduced LVEF, unless prior symptoms of HF and reduced LVEF, unless contraindicatedcontraindicated

I IIa IIb III

Hunt SA, et al. Hunt SA, et al. Circulation Circulation 2005;112:1825–1852.2005;112:1825–1852.

Other FDA Indications of AvailableOther FDA Indications of AvailableOral Oral -blockers for Hypertension-blockers for Hypertension

LVLVMIMI DysfunctionDysfunction HeartHeart AtrialAtrial VentricularVentricular

DrugDrug HTNHTN AnginaAngina ProphylaxisProphylaxis Post-MIPost-MI FailureFailure FibrillationFibrillation ArrhythmiasArrhythmias

AcebutololAcebutolol AtenololAtenolol **BetaxololBetaxolol BisoprololBisoprolol CarvedilolCarvedilol Carvedilol CRCarvedilol CR LabetalolLabetalol Metoprolol tartrateMetoprolol tartrate ††Metoprolol succinateMetoprolol succinate NadololNadolol NebivololNebivolol PenbutololPenbutolol PindololPindolol Propranolol Propranolol §, ¶§, ¶ ‡‡ Propranolol LA Propranolol LA §, ¶§, ¶ Propranolol XLPropranolol XL Timolol ¶Timolol ¶ ‡‡

LVLVMIMI DysfunctionDysfunction HeartHeart AtrialAtrial VentricularVentricular

DrugDrug HTNHTN AnginaAngina ProphylaxisProphylaxis Post-MIPost-MI FailureFailure FibrillationFibrillation ArrhythmiasArrhythmias

AcebutololAcebutolol AtenololAtenolol **BetaxololBetaxolol BisoprololBisoprolol CarvedilolCarvedilol Carvedilol CRCarvedilol CR LabetalolLabetalol Metoprolol tartrateMetoprolol tartrate ††Metoprolol succinateMetoprolol succinate NadololNadolol NebivololNebivolol PenbutololPenbutolol PindololPindolol Propranolol Propranolol §, ¶§, ¶ ‡‡ Propranolol LA Propranolol LA §, ¶§, ¶ Propranolol XLPropranolol XL Timolol ¶Timolol ¶ ‡‡

** Acute MI only (0-7 days)Acute MI only (0-7 days)†† Acute MI and for up to 3 monthsAcute MI and for up to 3 months‡‡ Stable survivors of acute MI to reduce CV mortalityStable survivors of acute MI to reduce CV mortality§§ Hypertrophic subaortic stenosis, essential tremorHypertrophic subaortic stenosis, essential tremor¶¶ Migraine prophylaxisMigraine prophylaxis

FDA indicationFDA indication Trial data support an indicationTrial data support an indication

Intravenous formulation availableIntravenous formulation available

SummarySummary

-blockers are a diverse class of drugs-blockers are a diverse class of drugs

They differ in their indications and their effectiveness for They differ in their indications and their effectiveness for various disordersvarious disorders

Selective, vasodilatory Selective, vasodilatory -blockers are: -blockers are:

● Indicated for hypertensionIndicated for hypertension

● Proven for heart failure and myocardial infarctionProven for heart failure and myocardial infarction

● Offer advantages in patients with diabetes mellitusOffer advantages in patients with diabetes mellitus

● Are well toleratedAre well tolerated

-blockers are a diverse class of drugs-blockers are a diverse class of drugs

They differ in their indications and their effectiveness for They differ in their indications and their effectiveness for various disordersvarious disorders

Selective, vasodilatory Selective, vasodilatory -blockers are: -blockers are:

● Indicated for hypertensionIndicated for hypertension

● Proven for heart failure and myocardial infarctionProven for heart failure and myocardial infarction

● Offer advantages in patients with diabetes mellitusOffer advantages in patients with diabetes mellitus

● Are well toleratedAre well tolerated

Clinical Utility of Cardio-Selective Clinical Utility of Cardio-Selective Beta Blockade in Special PopulationsBeta Blockade in Special Populations

Kenneth A. Jamerson, MDKenneth A. Jamerson, MDProfessor of Internal Medicine, Medical SchoolProfessor of Internal Medicine, Medical School

University of MichiganUniversity of MichiganMedical Director, Program of Multi-Cultural HealthMedical Director, Program of Multi-Cultural Health

University of Michigan University of Michigan Ann Arbor, MIAnn Arbor, MI

Kenneth A. Jamerson, MDKenneth A. Jamerson, MDProfessor of Internal Medicine, Medical SchoolProfessor of Internal Medicine, Medical School

University of MichiganUniversity of MichiganMedical Director, Program of Multi-Cultural HealthMedical Director, Program of Multi-Cultural Health

University of Michigan University of Michigan Ann Arbor, MIAnn Arbor, MI


Key Points of this PresentationKey Points of this Presentation

► Most hypertensive patients who are receiving treatment Most hypertensive patients who are receiving treatment may not be optimally controlledmay not be optimally controlled

► To achieve recommended blood pressure goals, it is often To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive necessary to combine two or more antihypertensive agents. agents.

► High Risk Sub-groups deserve special considerationHigh Risk Sub-groups deserve special consideration

► Most hypertensive patients who are receiving treatment Most hypertensive patients who are receiving treatment may not be optimally controlledmay not be optimally controlled

► To achieve recommended blood pressure goals, it is often To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive necessary to combine two or more antihypertensive agents. agents.

► High Risk Sub-groups deserve special considerationHigh Risk Sub-groups deserve special consideration

Obesity Trends* Among US AdultsObesity Trends* Among US Adults

(*BMI (*BMI 30 kg/m30 kg/m22, or about 30 lb overweight for 5, or about 30 lb overweight for 544 person) person)

2004200419961996

15% to 19%15% to 19%10%-14%10%-14%<10%<10% 20%-24%20%-24% No dataNo data25%25%

Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/obesity_trends_ 2004.ppt#1. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/obesity_trends_ 2004.ppt#1. Accessed May 31, 2006Accessed May 31, 2006

BRFSS: 1996 and 2004BRFSS: 1996 and 2004BRFSS: 1996 and 2004BRFSS: 1996 and 2004

The ProblemThe Problem

Adding Fat Inflames the Fat: Adding Fat Inflames the Fat: Adipose Tissue AngiotensinAdipose Tissue Angiotensin

Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112:1785-8.

Angiotensinogen

ACE

Ventricular RemodelingVentricular Remodeling

Vascular RemodelingVascular Remodeling

Energetic FailureEnergetic Failure

Neurohormonal Activation Across Neurohormonal Activation Across the CV Spectrumthe CV Spectrum

RAAS=renin angiotensin-aldosterone system;SNS=sympathetic nervous system

Diabetes andHypertension

Post-MILV Dysfunction

End-StageCardiomyopathy

RAAS + SNS

The Tecumseh Blood Pressure StudyThe Tecumseh Blood Pressure Study

A prospective epidemiological study of the antecedents of hypertension and A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and womencardiovascular disease in 1,100 young men and women

A prospective epidemiological study of the antecedents of hypertension and A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and womencardiovascular disease in 1,100 young men and women

Ann ArborAnn ArborAnn ArborAnn Arbor

TecumsehTecumsehTecumsehTecumseh

HematocritHematocritHematocritHematocrit

CholesterolCholesterolCholesterolCholesterol

OverweightOverweightOverweightOverweight

Heart RateHeart RateHeart RateHeart Rate

InsulinInsulinInsulinInsulin

TriglyceridesTriglyceridesTriglyceridesTriglycerides

DBPDBPDBPDBP

N=124 (aged 18-28 years)N=124 (aged 18-28 years)Adapted from Julius et al. JAMA 1990;264:354-358Adapted from Julius et al. JAMA 1990;264:354-358N=124 (aged 18-28 years)N=124 (aged 18-28 years)Adapted from Julius et al. JAMA 1990;264:354-358Adapted from Julius et al. JAMA 1990;264:354-358

P<0.001P<0.001

P<0.01P<0.01

P<0.05P<0.05

P<0.001P<0.001

P<0.01P<0.01

P<0.05P<0.05

Tecumseh BP Study: Association of DBP and Tecumseh BP Study: Association of DBP and Other CHD Risk FactorsOther CHD Risk Factors

S. Julius, et al: JAMA 264:354-358, 1990S. Julius, et al: JAMA 264:354-358, 1990

Blood Pressure Trends inBlood Pressure Trends inTecumseh, MITecumseh, MI

HypertensiveHypertensiveNormotensiveNormotensive

**

** **

**

****

** P< .01P< .01

**** P<.001P<.001

**

6060

7070

8080

9090

100100

110110

120120

130130

140140

6.46.4 21.521.5 31.331.3

Hypertensive and Normotensive at 31 Years of AgeHypertensive and Normotensive at 31 Years of Age

Blo

od

Pre

ssu

re m

mH

gB

loo

d P

ress

ure

mm

Hg

Insulin Resistance SyndromeInsulin Resistance Syndrome

InsulinInsulinresistanceresistance

Inherited Inherited genetic genetic defectdefect

ObesityObesity

Excessive Excessive caloric caloric intakeintake

NDDMNDDM

HyperinsulinemiaHyperinsulinemia

HypertensionHypertension AtherosclerosisAtherosclerosis

HypertriglyceridemiaHypertriglyceridemiaHypercholesterolemiaHypercholesterolemia

Decreased HDL-CDecreased HDL-CDiabetes CareDiabetes Care 1991;14:173-194 1991;14:173-194

Thigh Cuff Inflation to Elicit a Physiologic Thigh Cuff Inflation to Elicit a Physiologic Increase in Sympathetic ToneIncrease in Sympathetic Tone

Inflate Thigh Cuffs

Decrease Venous Return

Cardio-Pulmonary Receptors

Decrease Right Atrial Pressure

Forearm Vasoconstriction

Decrease Forearm Blood

Flow

VasomotorCenter

Increased Sympathetic

Outflow

-

-+

Effect of Insulin and Reflex Sympathetic Activation on Glucose Effect of Insulin and Reflex Sympathetic Activation on Glucose and Oxygen Extraction in the Forearm of 14 Healthy Volunteersand Oxygen Extraction in the Forearm of 14 Healthy Volunteers

The Effects of Pressers on Glucose Metabolism The Effects of Pressers on Glucose Metabolism in Skeletal Musclein Skeletal Muscle

-50

-40

-30

-20

-10

0

10

20

REFLEX ANG II

FLOW

A-V GLUC

GLUC UTIL

-50

-40

-30

-20

-10

0

10

20

REFLEX ANG II

FLOW

A-V GLUC

GLUC UTIL

NOR EPI PROP+NOR EPI

Sympathetic Nerve Activity in Patients With Sympathetic Nerve Activity in Patients With HTN, Diabetes, or BothHTN, Diabetes, or Both

► Sympathetic nerve activity is significantly Sympathetic nerve activity is significantly higher in:higher in:● Patients with essential HTN compared with normotensive Patients with essential HTN compared with normotensive

patients (patients (PP<.01)<.01)● Patients with diabetes compared with normotensive patients Patients with diabetes compared with normotensive patients

((PP<.001)<.001)

► Sympathetic nerve activity is higher in patients with both Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes patients with either essential HTN or type 2 diabetes ((PP<.001)<.001)

► Sympathetic nerve activity is significantly Sympathetic nerve activity is significantly higher in:higher in:● Patients with essential HTN compared with normotensive Patients with essential HTN compared with normotensive

patients (patients (PP<.01)<.01)● Patients with diabetes compared with normotensive patients Patients with diabetes compared with normotensive patients

((PP<.001)<.001)

► Sympathetic nerve activity is higher in patients with both Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes patients with either essential HTN or type 2 diabetes ((PP<.001)<.001)

Huggett RJ. Circulation. 2003;108:3097-3101.

Data derived from 68 closely matched subjects with n=17 for all groups compared

Effect of Effect of -Blockers on Insulin Sensitivity in -Blockers on Insulin Sensitivity in Hypertensive PatientsHypertensive Patients

-40 -20 0 20 40



AtenololAtenolol

PindololPindolol

DilevalolDilevalol


CeliprololCeliprolol

% Change Above Baseline% Change Above Baseline

Jacob S et al. Am J Hypertens. 1998;11:1258-1265

The Pathobiology of Obesity:The Pathobiology of Obesity:A Syndrome of Risk Factors for CVDA Syndrome of Risk Factors for CVD

MyocardialMyocardial InfarctionInfarction

StrokeStroke

HeartHeartFailureFailure

AtherosclerosisAtherosclerosis

ObesityObesity HypertensionHypertension

Dyslipidemia

ClinicalClinicalDiabetesDiabetes

Gibbons 2004

Obesity-Related Cardiovascular Disease: Obesity-Related Cardiovascular Disease: Pro-Inflammatory Adipokines as Mediators Pro-Inflammatory Adipokines as Mediators

Adiponectin O2- IL-6 TNF-α CRPAng II

Oxidative Stress Inflammation Hypertension

Obesity

AtherosclerosisAtherosclerosis DiabetesDiabetes

Endothelial Dysfunction Insulin Resistance

The ProblemThe Problem

Does Being African American Does Being African American Modify the Problem?Modify the Problem?

International Society of International Society of Hypertension in BlacksHypertension in Blacks

IMPACT CampaignIMPACT Campaign

Science Guidelines Behavioral ChangeScience Guidelines Behavioral Change

““ RaceRace””is a crudeis a crudeproxy.proxy.

DISEASEDISEASE

IndividualIndividual--biologybiology--genotypegenotype

EnvironmentEnvironment--diet, lifestylediet, lifestyle--SES, exposuresSES, exposures

““ RaceRace””is a crudeis a crudeproxy.proxy.

DISEASEDISEASE



DISEASEDISEASE



Models to Explain Health DisparitiesModels to Explain Health Disparities

▶ Racial Genetic ModelRacial Genetic Model● Cause of HD: population differences in the distribution of Cause of HD: population differences in the distribution of

genetic variants genetic variants

▶ Health-behavior ModelHealth-behavior Model● Cause of HD: differences between R/E groups in the Cause of HD: differences between R/E groups in the

distribution of individual behaviors related to health such as distribution of individual behaviors related to health such as diet, exercise, and tobacco use diet, exercise, and tobacco use

▶ SES ModelSES Model● Cause of HD: over-representation of some R/E groups within Cause of HD: over-representation of some R/E groups within

lower SESlower SES

▶ Psychosocial Stress ModelPsychosocial Stress Model● Cause of HD: stresses associated with minority group status, Cause of HD: stresses associated with minority group status,

especially the experience of racism and discriminationespecially the experience of racism and discrimination

▶ Racial Genetic ModelRacial Genetic Model● Cause of HD: population differences in the distribution of Cause of HD: population differences in the distribution of

genetic variants genetic variants

▶ Health-behavior ModelHealth-behavior Model● Cause of HD: differences between R/E groups in the Cause of HD: differences between R/E groups in the

distribution of individual behaviors related to health such as distribution of individual behaviors related to health such as diet, exercise, and tobacco use diet, exercise, and tobacco use

▶ SES ModelSES Model● Cause of HD: over-representation of some R/E groups within Cause of HD: over-representation of some R/E groups within

lower SESlower SES

▶ Psychosocial Stress ModelPsychosocial Stress Model● Cause of HD: stresses associated with minority group status, Cause of HD: stresses associated with minority group status,

especially the experience of racism and discriminationespecially the experience of racism and discrimination

Although much genetic variation (85-90%) is shared Although much genetic variation (85-90%) is shared among all human populations, about 5% of SNPs among all human populations, about 5% of SNPs have high levels of allele frequency differential have high levels of allele frequency differential ((>50%). We call these markers Ancestry >50%). We call these markers Ancestry Informative Markers (AIMs).Informative Markers (AIMs).

Plot of Individual Ancestry Estimates Using Plot of Individual Ancestry Estimates Using STRUCTURE on 112 AIMsSTRUCTURE on 112 AIMs

Bamileke (Cameroon) Bamileke (Cameroon) European Americans (MD) African AmericansEuropean Americans (MD) African Americans(DC)(DC) (23.2% European ancestry)(23.2% European ancestry)

Falush et al. 2003Falush et al. 2003

Ancestry can be Estimated Across Chromosomal Regions.Ancestry can be Estimated Across Chromosomal Regions.

Seldin et al. Seldin et al. Genome Res.Genome Res. 14:1076 -1084, 2004 14:1076 -1084, 2004 Smith et al. Smith et al. AJHGAJHG 74:1001-1013, 2004 74:1001-1013, 2004

European Genetic Contribution in African-American European Genetic Contribution in African-American Populations Living in Different Geographical Areas of the USPopulations Living in Different Geographical Areas of the US

Parra et al. AJHG 1998; Parra et al. AJPA 2002; Kittles et al. unpublished

Selection (Natural and Mate) may Have Selection (Natural and Mate) may Have Driven this Modular Evolution.Driven this Modular Evolution.

Optimal phenotype for “traditional” diet/ lifestyleOptimal phenotype for “traditional” diet/ lifestyle

““Thrifty-genotype” hypothesis.. Thrifty-genotype” hypothesis..

▶ Fat storage?Fat storage? IGF and LPL related genesIGF and LPL related genes

▶ Salt sensitivity?Salt sensitivity? CYP3A, ICAM gene clustersCYP3A, ICAM gene clusters

▶ Higher testosterone?Higher testosterone? CYP3A, AR, SRD5AR, CYP3A, AR, SRD5AR, CYP17CYP17

▶ Darker skin color?Darker skin color? Vitamin D related genesVitamin D related genes

Optimal phenotype for “traditional” diet/ lifestyleOptimal phenotype for “traditional” diet/ lifestyle

““Thrifty-genotype” hypothesis.. Thrifty-genotype” hypothesis..

▶ Fat storage?Fat storage? IGF and LPL related genesIGF and LPL related genes

▶ Salt sensitivity?Salt sensitivity? CYP3A, ICAM gene clustersCYP3A, ICAM gene clusters

▶ Higher testosterone?Higher testosterone? CYP3A, AR, SRD5AR, CYP3A, AR, SRD5AR, CYP17CYP17

▶ Darker skin color?Darker skin color? Vitamin D related genesVitamin D related genes

African-American Women and Cardiometabolic African-American Women and Cardiometabolic Syndrome: A High Risk PopulationSyndrome: A High Risk Population

Obesity in Normotensive African-American WomenObesity in Normotensive African-American WomenInflammation and Oxidative StressInflammation and Oxidative Stress

CRPCRP

Biomarker Profile of ObesityBiomarker Profile of Obesity

Pemu, Ofili Gibbons 2007Pemu, Ofili Gibbons 2007

00

0.50.5

1.01.0

IsoprostanesIsoprostanes

LeanLean

ObeseObese

AdiponectinAdiponectin

The Role of The Role of 1 Cardioselective 1 Cardioselective Beta Blockers for Management of Beta Blockers for Management of

Hypertension and RelatedHypertension and RelatedCardiovascular ConditionsCardiovascular Conditions

2006 AACE Hypertension Guidelines2006 AACE Hypertension Guidelines

► ß-blocker use recommended as 2ß-blocker use recommended as 2ndnd or 3 or 3rdrd line in line in hypertensionhypertension

Because the major adverse effects of BBs may be Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the insulin resistance, the use of the new third-generation new third-generation ßß--blockers (such as nebivolol)blockers (such as nebivolol) or drugs that block both or drugs that block both αα and and ß receptors (such as carvedilol) may prove to be ß receptors (such as carvedilol) may prove to be particularly beneficial. particularly beneficial. These agents cause vasodilatation These agents cause vasodilatation and an increase in insulin sensitivity.and an increase in insulin sensitivity.

► ß-blocker use recommended as 2ß-blocker use recommended as 2ndnd or 3 or 3rdrd line in line in hypertensionhypertension

Because the major adverse effects of BBs may be Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the insulin resistance, the use of the new third-generation new third-generation ßß--blockers (such as nebivolol)blockers (such as nebivolol) or drugs that block both or drugs that block both αα and and ß receptors (such as carvedilol) may prove to be ß receptors (such as carvedilol) may prove to be particularly beneficial. particularly beneficial. These agents cause vasodilatation These agents cause vasodilatation and an increase in insulin sensitivity.and an increase in insulin sensitivity.

AACE Hypertension Task Force. Endocr Pract. 2006;12:193-222AACE Hypertension Task Force. Endocr Pract. 2006;12:193-222

The Evolution of The Evolution of ßß-Blockers-Blockers

1960s 1970s 1980s-1990s 2007

Non-Non-SelectiveSelective


VasodilatingVasodilatingVasodilating Vasodilating



Selective Selective

Propranolol AtenololMetroprolol

CarvedilolLabetalol

Nebivolol

Nebivolol: Mechanism of ActionNebivolol: Mechanism of Action

Nebivolol

Selective ß1-blockade* Vasodilation†

Additional properties:Suppression of renin activity and diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers

*Decreased heart rate, decreased myocardial contractility. In extensive metabolizes and at doses *Decreased heart rate, decreased myocardial contractility. In extensive metabolizes and at doses << 10 mg., nebivolol is 10 mg., nebivolol is preferentially preferentially ßß11 selective. selective.

††Decreased peripheral vascular resistance.Decreased peripheral vascular resistance.Nebivolol package insert. New York, NY. Forest Laboratoies, Inc.; 2007.Nebivolol package insert. New York, NY. Forest Laboratoies, Inc.; 2007.

-13.2

20.6

7.1

-15

-10

-5

0

5

10

15

20

25

Nebivolol Reduces Peripheral Vascular Nebivolol Reduces Peripheral Vascular Resistance in Patients with HypertensionResistance in Patients with Hypertension

Per

cen

t ch

ange

vs

base

line

Per

cen

t ch

ange

vs

base

line

Peripheral resistancePeripheral resistance(dyne/cm5)(dyne/cm5)

Stroke volumeStroke volume(mL)(mL)

Cardiac outputCardiac output(L/min)(L/min)

**

**

*N=25; parameters at 2 weeks*N=25; parameters at 2 weeksAt 2 weeks; *P<0.05 vs pretreatment. Change in SBP/DBP was -19/12 mm Hg for nebivololAt 2 weeks; *P<0.05 vs pretreatment. Change in SBP/DBP was -19/12 mm Hg for nebivololAdapted from Kamp O et al. Am J Cardiol. 2003;92:344-348Adapted from Kamp O et al. Am J Cardiol. 2003;92:344-348

-15

-10

-5

0

5

10

15

20

25

Heart rateHeart rate(bpm)(bpm)

Bea

ts p

er m

inut

eB

eats

per

min

ute

Nebivolol Enhances Vasodilation in Nebivolol Enhances Vasodilation in Hypertensive PatientsHypertensive Patients

NebivololNebivolol

Time (s) Time (s) Time (s)

Calcium ionophore Calcium ionophore Calcium ionophore

WhiteWhite African AmericanAfrican American African AmericanAfrican American+ Nebivolol+ Nebivolol

300

mM

30 m

M30

mM

NO

O2-

ONOO-

Release of Nitric Oxide from Human Release of Nitric Oxide from Human Endothelium: White and African AmericansEndothelium: White and African Americans

Mason RP et al. Circulation 2005;112:3795-3801

0.49 0.734.23

15.6

40.7

0

10

20

30

40

50

ßß11

sele

ctiv

ity s

elec

tivity

Human MyocardiumHuman Myocardium

BucindololBucindolol CarvedilolCarvedilol MetoprololMetoprolol BisoprololBisoprolol NebivololNebivolol

ßß11 Selectivity = K Selectivity = K11 ( (ßß22)/K)/K11(ß(ß11).).

In extensive metabolizers and at doses less than or equal to 10 mg, nebivolol is preferentially ßIn extensive metabolizers and at doses less than or equal to 10 mg, nebivolol is preferentially ß 11 selective. selective.

Brixius K et al. Brixius K et al. Br J PharmacolBr J Pharmacol. 2001;133:1330-1338. 2001;133:1330-1338

Nebivolol: Nebivolol: ßß11 Receptor Selectivity Receptor Selectivity

-17

-20

-16 -15

-25

-20

-15

-10

-5

0

Nebivolol 5 mg qd (n=73)

Metoprolol 100 mg bid (n=67)

Nebivolol and Metoprolol: Nebivolol and Metoprolol: Effect on BP at 3 MonthsEffect on BP at 3 Months

Mea

n M

ean

ΔΔ v

s ba

selin

e (m

m H

g)vs

bas

elin

e (m

m H

g)

** **

**

**

NN 7373 6767 7373 6767

Baseline BP (mmHg)Baseline BP (mmHg) 106106 107107 160160 157157

DBPDBP SBPSBP

*P<0.05 vs. baselineBP = sitting blood pressure; DBP=sitting diastolic blood pressure; SBP=sitting systolic blood pressureUhlir O et al. Drug Invest 1991;3(auppl 1):107-110

-4.4

-9.1

-10.6

-3.6

-5.9

-12

-10.3 -10.2

-14

-12

-10

-8

-6

-4

-2

0

DBP SBP

Mea

n M

ean

ΔΔ in

BP

in

BP

vs

base

line

(mm

Hg)

vs b

asel

ine

(mm

Hg)

NN 4747 4646 5151 4949Baseline DBP (mm Hg)Baseline DBP (mm Hg) 100.6100.6 99.999.9 100.3100.3 101.4101.4Baseline SBP (mm Hg)Baseline SBP (mm Hg) 151.4151.4 151.7151.7 154.2154.2 156.4156.4

Saunders E et al. J Clin Hypertens. 2007;9:866-875

Placebo DBP Placebo SBPPlacebo DBP Placebo SBP

DoseDose PlaceboPlacebo 5 mg5 mg 10 mg10 mg 20 mg20 mg

Efficacy of Nebivolol in Black Patients:Efficacy of Nebivolol in Black Patients:Diastolic and Systolic BPDiastolic and Systolic BP

-4.8

-9.3-9.9

-3.6

-9.9-10.9

-10.3 -10.7-12

-10

-8

-6

-4

-2

0

DBP SBP

Mea

n M

ean

ΔΔ in

BP

in

BP

vs

base

line

(mm

Hg)

vs b

asel

ine

(mm

Hg)

NN 9292 189189 188188 196196Baseline DBP (mm Hg)Baseline DBP (mm Hg) 100.6100.6 99.999.9 100.3100.3 101.4101.4Baseline SBP (mm Hg)Baseline SBP (mm Hg) 151.4151.4 151.7151.7 154.2154.2 156.4156.4

•Obesity defined as body mass index >30 kg/m2. •Data on file, Forest Laboratories, Inc. New York, NY

Placebo DBP Placebo SBPPlacebo DBP Placebo SBP

DoseDose PlaceboPlacebo 5 mg5 mg 10 mg10 mg 20 mg20 mg

Efficacy of Nebivolol in Obese* Patients:Efficacy of Nebivolol in Obese* Patients:Diastolic and Systolic BPDiastolic and Systolic BP

Incidence Rate (%)Incidence Rate (%) Discontinuation Rate (%)Discontinuation Rate (%)

Adverse Adverse Event (%)Event (%)

Placebo Placebo (n=205)(n=205)

Nebivolol Nebivolol 5mg-40mg 5mg-40mg

(n=1597)(n=1597)

Placebo Placebo (n=205)(n=205)

Nebivolol Nebivolol 5mg-40mg 5mg-40mg

(n=1597)(n=1597)

FatigueFatigue 1.51.5 3.63.6 0.50.5 0.00.0

DyspneaDyspnea 0.50.5 1.01.0 0.00.0 0.10.1

BradycardiaBradycardia 0.50.5 0.80.8 0.00.0 0.20.2

Erectile Erectile DysfunctionDysfunction†† 0.90.9 0.60.6 0.00.0 0.00.0

DepressionDepression 0.00.0 0.30.3 0.00.0 0.00.0

Nebivolol Profile with Respect to Side Effects Nebivolol Profile with Respect to Side Effects Commonly Associated with Commonly Associated with ßß-Blockers*-Blockers*

*Pooled data from the three monotherapy US registration trials with nebivolol.*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 mgFor erectile dysfunction n=108 for placebo and n=853 for nebivolol. 5 mg to 40 mgRegistration trials. Data on file, Forest Laboratories, Inc. New York, NYRegistration trials. Data on file, Forest Laboratories, Inc. New York, NY

Insulin Resistance: Insulin Resistance: Effect of Nebivolol vs. AtenololEffect of Nebivolol vs. Atenolol

-12.2

-21.6-25

-20

-15

-10

-5

0

5

Nebivolol2.5-5 mg QD

Atenolol50-100 mg QD

Per

cent

age

Cha

nge

p<0.01

Insulin Sensitivity IndexInsulin Sensitivity Index

36-week Randomized, Double-blind Crossover Design36-week Randomized, Double-blind Crossover Designn = 25n = 25

Poirer L, et al. J Hypertens 2001;19:1429-1435

2.792.67

2.29

2.83

0

0.5

1

1.5

2

2.5

3

Baseline Month 6Baseline Month 6Nebivolol 5 mg (n=37)Nebivolol 5 mg (n=37)

Baseline Month 6Baseline Month 6Metoprolol 100 mg (n=35)Metoprolol 100 mg (n=35)

P=0.008

P=0.003

P=NS

Effect of Nebivolol and Metoprolol Effect of Nebivolol and Metoprolol on Insulin Resistanceon Insulin Resistance

Mea

n M

ean

insu

lin r

esis

tanc

e by

HO

MA

insu

lin r

esis

tanc

e by

HO

MA

(md/

dL x

IU

/mL)

(md/

dL x

IU

/mL)

Baseline SBP/BP was 153/92 mm Hg and 155/95 mm Hg in the nebivolol and metroprolol groups, respectively. Following 6 months Baseline SBP/BP was 153/92 mm Hg and 155/95 mm Hg in the nebivolol and metroprolol groups, respectively. Following 6 months of therapy. BP was 131/79 mm Hg and 129/82 mm Hg in the nebivolol and metroprolol groups, respectively. HOMA=homeostasis of therapy. BP was 131/79 mm Hg and 129/82 mm Hg in the nebivolol and metroprolol groups, respectively. HOMA=homeostasis model assessment insulin resistance.model assessment insulin resistance.Celik T et al. Celik T et al. J HypertensJ Hypertens 2006;24:591-596 2006;24:591-596

3.7

1.7

2.8

2.4

0

0.5

1

1.5

2

2.5

3

3.5

4M

ean

Mea

n ΔΔ

fro

m b

ase

line

(mg

/dL)

from

ba

selin

e (m

g/d

L)

PlaceboPlacebo(n=196)(n=196)

NebivololNebivolol

5 mg5 mg(n=432)(n=432)

10 mg10 mg(n=435)(n=435)

20 mg20 mg(n=438)(n=438)

Nebivolol: Effect on Glucose LevelsNebivolol: Effect on Glucose Levels

Pooled Analysis of the Three Monotherapy US Registration TrialsPooled Analysis of the Three Monotherapy US Registration Trials

These laboratory parameters are among the 51 standard laboratory values that were collected from patients with mild to moderate These laboratory parameters are among the 51 standard laboratory values that were collected from patients with mild to moderate hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. Data on file, Forest Laboratories, New York, NYData on file, Forest Laboratories, New York, NY

0

50

100

150

200Baseline Endpoint

mg/

dLm

g/dL

LDL (mean)LDL (mean) HDL (mean)HDL (mean) TriglyceridesTriglycerides(median)(median)

Nebivolol: Effect on Lipid LevelsNebivolol: Effect on Lipid Levels

Pooled Analysis of the Three Monotherapy US Registration TrialsPooled Analysis of the Three Monotherapy US Registration Trials

1.1. Registration trials. Data on file, Forest Laboratories, Inc. New York, NYRegistration trials. Data on file, Forest Laboratories, Inc. New York, NY2.2. Nebivolol package insert. New York, NY. Forest Laboratories, Inc; 2007Nebivolol package insert. New York, NY. Forest Laboratories, Inc; 2007

Laboratory ParametersLaboratory Parameters

► In controlled monotherapy trials, nebivolol was In controlled monotherapy trials, nebivolol was associated with:associated with:

- An increase in BUN, uric acid, and triglycerides- An increase in BUN, uric acid, and triglycerides

- A decrease in HDL cholesterol and platelet count- A decrease in HDL cholesterol and platelet count

These laboratory parameters are among the 51 standard laboratory values that were collected from patients with mild to moderate These laboratory parameters are among the 51 standard laboratory values that were collected from patients with mild to moderate hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. Data on file, Forest Laboratories, New York, NYData on file, Forest Laboratories, New York, NY

Effect of Nebivolol and Metroprolol on Sexual Effect of Nebivolol and Metroprolol on Sexual Function: IIEFFunction: IIEF

Nebivolol 5 mgNebivolol 5 mgMetoprolol succinate 95 mgMetoprolol succinate 95 mg

Hazard Ratio Plots for Total Mortality for Hazard Ratio Plots for Total Mortality for Comparable Patient SubgroupsComparable Patient Subgroups

Nebivolol. Marit D. Moen and Antona J. Wagstaff. Nebivolol. Marit D. Moen and Antona J. Wagstaff. DrugsDrugs 2006;66(10):1389–1409 2006;66(10):1389–1409

NebivololNebivolol




NebivololNebivolol




ß-Blocker Trialsß-Blocker Trialsß-Blocker Trialsß-Blocker Trials

00 0.50.5 11 1.51.5 22

Hazard RatioHazard Ratio

00 0.50.5 11 1.51.5 22

Hazard RatioHazard Ratio

ConclusionsConclusions

► Beta blockers are not all created equallyBeta blockers are not all created equally

► Third generation, cardioselective beta blockers Third generation, cardioselective beta blockers may produce clinical outcomes that differ from may produce clinical outcomes that differ from traditional beta-blockerstraditional beta-blockers

► Ongoing trials will help differentiate indications, Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta-clinical roles, and optimal strategies for beta-blocker useblocker use

► Beta blockers are not all created equallyBeta blockers are not all created equally

► Third generation, cardioselective beta blockers Third generation, cardioselective beta blockers may produce clinical outcomes that differ from may produce clinical outcomes that differ from traditional beta-blockerstraditional beta-blockers

► Ongoing trials will help differentiate indications, Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta-clinical roles, and optimal strategies for beta-blocker useblocker use

Case Studies—Applying Landmark Trials to Real World

Management


Program Moderator And Program Moderator And Faculty Panel MembersFaculty Panel Members

Case 1Case 1

Patient ProfilePatient Profile

PresentationPresentation► 58-year-old African American social worker with 20-58-year-old African American social worker with 20-

year history of hypertension and 2-year history of type year history of hypertension and 2-year history of type 2 diabetes2 diabetes

► Presents with headaches and swelling of lower legsPresents with headaches and swelling of lower legs► Denies chest pain, although has shortness of breath Denies chest pain, although has shortness of breath

with exertionwith exertion► Problem with obesity since early teens: weight Problem with obesity since early teens: weight

currently fluctuates between 240-260 lbs.currently fluctuates between 240-260 lbs.

- Weight increased 20 lbs. in last six months- Weight increased 20 lbs. in last six months

- Admits no effort to exercise or restrict dietary salt- Admits no effort to exercise or restrict dietary salt


Medical/Treatment HistoryMedical/Treatment History► Previously treated with several antihypertensive Previously treated with several antihypertensive

medicationsmedications► Discontinued use due to side effects and/or costDiscontinued use due to side effects and/or cost► Current medications; rosigiltazone and metforminCurrent medications; rosigiltazone and metformin► Only prior surgery was cholecystectomyOnly prior surgery was cholecystectomy

Family HistoryFamily History► Diabetes, hypertension and obesityDiabetes, hypertension and obesity► Both parents died of stroke in their 60sBoth parents died of stroke in their 60s

Social HistorySocial History► Nonsmoker; does not drink alcoholNonsmoker; does not drink alcohol

Physical ExaminationPhysical Examination

► Height: 5’4”Height: 5’4”► Weight: 262 lbsWeight: 262 lbs► BMI: 45.0BMI: 45.0► BP: 166/106 mmHgBP: 166/106 mmHg► Pulse: 88 bpmPulse: 88 bpm► Normocephalic and without injuryNormocephalic and without injury► Extrocular movements full; pupils equal and reactive to Extrocular movements full; pupils equal and reactive to

lightlight► Pharynx benign, neck supple, lungs clearPharynx benign, neck supple, lungs clear► Funduscopy reveals arteriolar narrowing and Funduscopy reveals arteriolar narrowing and

atrioventricular nickingatrioventricular nicking


Cardiac ExaminationCardiac Examination► Resting tachycardia with S4 gallop and systolic Resting tachycardia with S4 gallop and systolic

murmur best heard at left sternal bordermurmur best heard at left sternal border► Normoactive bowel soundsNormoactive bowel sounds► Extremities reveal 2+ pedal edemaExtremities reveal 2+ pedal edema► Diminished lower extremity pulsesDiminished lower extremity pulses► 2-second capillary refill in fingers and toes2-second capillary refill in fingers and toes► Electrocardiogram: normal sinus rhythm, left axis Electrocardiogram: normal sinus rhythm, left axis

deviation, voltage criteria for LVH, nonspecific ST-T deviation, voltage criteria for LVH, nonspecific ST-T wave changeswave changes

► Chest film shows enlarged cardiac silhouetteChest film shows enlarged cardiac silhouette


Laboratory FindingsLaboratory Findings► BUN: 28 mg/dLBUN: 28 mg/dL► Creatinine: 1.3 mg/dLCreatinine: 1.3 mg/dL► Total cholesterol: 283 mg/dLTotal cholesterol: 283 mg/dL► HDL: 24 mg/dLHDL: 24 mg/dL► LDL: 204 mg/dLLDL: 204 mg/dL► Hemoglobin A1C = 7.0Hemoglobin A1C = 7.0► Fasting glucose: 115 mg/dLFasting glucose: 115 mg/dL► UrinalysisUrinalysis

- Specific gravity: 1.015- Specific gravity: 1.015

- Protein: >1 mg/dL- Protein: >1 mg/dL

- Rare red blood cells- Rare red blood cells

- Rare bacteria- Rare bacteria

DiscussionDiscussion

What should be the target BP for this patient?What should be the target BP for this patient?

A:A: <140/<90 mmHg <140/<90 mmHg

B:B: <135/<85 mmHg <135/<85 mmHg

C:C: <130/<80 mmHg <130/<80 mmHg

D:D: <120/<70 mmHg <120/<70 mmHg


What factors would you consider when selecting an What factors would you consider when selecting an appropriate therapy?appropriate therapy?

A:A: Underlying pathophysiology of hypertension Underlying pathophysiology of hypertension

B:B: Concomitant medical conditions, including diabetes Concomitant medical conditions, including diabetes and edemaand edema

C:C: Adherence issues Adherence issues

D:D: Baseline risk for CVD Baseline risk for CVD


Would a Would a ßß-blocker be appropriate for this patient?-blocker be appropriate for this patient?

A:A: Yes Yes

B:B: No No


What is an optimal strategy for controlling blood What is an optimal strategy for controlling blood pressure?pressure?

A:A: Diuretic + ACE inhibitor Diuretic + ACE inhibitor

B:B: Diuretic + ARB Diuretic + ARB

C:C: Diuretic + Diuretic + ßß-blocker-blocker

D:D: Diuretic + calcium-channel blocker Diuretic + calcium-channel blocker

Case 2Case 2


► 76-year-old retired Caucasian male with 20-year history of 76-year-old retired Caucasian male with 20-year history of hypertensionhypertension

► Previously treated with diuretics and calcium channel blockersPreviously treated with diuretics and calcium channel blockers► Admitted noncompliance with medicationAdmitted noncompliance with medication

- Believes BP normal increases with age; drugs cause intolerable - Believes BP normal increases with age; drugs cause intolerable side effectsside effects

► Attempted to control BP with proper nutrition and regular Attempted to control BP with proper nutrition and regular exerciseexercise

- Plays golf 3-4 times per week- Plays golf 3-4 times per week► Notes that his BP at home is “normal”Notes that his BP at home is “normal”

- Systolic pressure: 170-190 mmHg- Systolic pressure: 170-190 mmHg

- Distolic pressure: 70-85 mmHg- Distolic pressure: 70-85 mmHg► Denies headache, chest pain, shortness of breath, claudification, Denies headache, chest pain, shortness of breath, claudification,

or leg swellingor leg swelling

► 76-year-old retired Caucasian male with 20-year history of 76-year-old retired Caucasian male with 20-year history of hypertensionhypertension

► Previously treated with diuretics and calcium channel blockersPreviously treated with diuretics and calcium channel blockers► Admitted noncompliance with medicationAdmitted noncompliance with medication

- Believes BP normal increases with age; drugs cause intolerable - Believes BP normal increases with age; drugs cause intolerable side effectsside effects

► Attempted to control BP with proper nutrition and regular Attempted to control BP with proper nutrition and regular exerciseexercise

- Plays golf 3-4 times per week- Plays golf 3-4 times per week► Notes that his BP at home is “normal”Notes that his BP at home is “normal”

- Systolic pressure: 170-190 mmHg- Systolic pressure: 170-190 mmHg

- Distolic pressure: 70-85 mmHg- Distolic pressure: 70-85 mmHg► Denies headache, chest pain, shortness of breath, claudification, Denies headache, chest pain, shortness of breath, claudification,

or leg swellingor leg swelling


Medical/Treatment HistoryMedical/Treatment History► Macular degeneration in both eyesMacular degeneration in both eyes► No current medications or known drug allergiesNo current medications or known drug allergies► No prior surgeryNo prior surgery

Family HistoryFamily History► UnremarkableUnremarkable

Social HistorySocial History► Smoked cigarettes for 40 years; stopped 15 years agoSmoked cigarettes for 40 years; stopped 15 years ago► Does not drink alcoholDoes not drink alcohol

Medical/Treatment HistoryMedical/Treatment History► Macular degeneration in both eyesMacular degeneration in both eyes► No current medications or known drug allergiesNo current medications or known drug allergies► No prior surgeryNo prior surgery

Family HistoryFamily History► UnremarkableUnremarkable

Social HistorySocial History► Smoked cigarettes for 40 years; stopped 15 years agoSmoked cigarettes for 40 years; stopped 15 years ago► Does not drink alcoholDoes not drink alcohol


► Height: 5’10”Height: 5’10”► Weight: 166 lbsWeight: 166 lbs► BMI: 23.6BMI: 23.6► BP: 182/80 mmHgBP: 182/80 mmHg► Pulse 74 bpmPulse 74 bpm► Funduscopy reveals bilateral macular degeneration, Funduscopy reveals bilateral macular degeneration,

copper wiring, and arteriorventricular nickingcopper wiring, and arteriorventricular nicking

- No hemorrhages or exudates- No hemorrhages or exudates► Neck shows 2+ carotid pulses with systolic heart Neck shows 2+ carotid pulses with systolic heart

sounds, which could be transmitted aortic plow sounds, which could be transmitted aortic plow murmurmurmur

► Height: 5’10”Height: 5’10”► Weight: 166 lbsWeight: 166 lbs► BMI: 23.6BMI: 23.6► BP: 182/80 mmHgBP: 182/80 mmHg► Pulse 74 bpmPulse 74 bpm► Funduscopy reveals bilateral macular degeneration, Funduscopy reveals bilateral macular degeneration,

copper wiring, and arteriorventricular nickingcopper wiring, and arteriorventricular nicking

- No hemorrhages or exudates- No hemorrhages or exudates► Neck shows 2+ carotid pulses with systolic heart Neck shows 2+ carotid pulses with systolic heart

sounds, which could be transmitted aortic plow sounds, which could be transmitted aortic plow murmurmurmur


Cardiac ExaminationCardiac Examination

► Regular rate and rhythm, with harsh systolic murmur grade 2/6Regular rate and rhythm, with harsh systolic murmur grade 2/6► Point of maximal intensity nondisplacedPoint of maximal intensity nondisplaced► Lungs clearLungs clear► Abdomen without scars, masses, tenderness, or organomegalyAbdomen without scars, masses, tenderness, or organomegaly► No abnormal bruits and 2+ femoral pulsesNo abnormal bruits and 2+ femoral pulses► Neurologic exam is grossly intact, without focal deficits or pathologic Neurologic exam is grossly intact, without focal deficits or pathologic

reflexesreflexes► Extremities show no peripheral edema or joint deformitiesExtremities show no peripheral edema or joint deformities► 1+ peripheral pulses with 2-second capillary refill in fingers and toes1+ peripheral pulses with 2-second capillary refill in fingers and toes► Echocardiogram shows normal sinus rhythm with mild left Echocardiogram shows normal sinus rhythm with mild left

centricular hypertrophy by voltagecentricular hypertrophy by voltage

Cardiac ExaminationCardiac Examination

► Regular rate and rhythm, with harsh systolic murmur grade 2/6Regular rate and rhythm, with harsh systolic murmur grade 2/6► Point of maximal intensity nondisplacedPoint of maximal intensity nondisplaced► Lungs clearLungs clear► Abdomen without scars, masses, tenderness, or organomegalyAbdomen without scars, masses, tenderness, or organomegaly► No abnormal bruits and 2+ femoral pulsesNo abnormal bruits and 2+ femoral pulses► Neurologic exam is grossly intact, without focal deficits or pathologic Neurologic exam is grossly intact, without focal deficits or pathologic

reflexesreflexes► Extremities show no peripheral edema or joint deformitiesExtremities show no peripheral edema or joint deformities► 1+ peripheral pulses with 2-second capillary refill in fingers and toes1+ peripheral pulses with 2-second capillary refill in fingers and toes► Echocardiogram shows normal sinus rhythm with mild left Echocardiogram shows normal sinus rhythm with mild left

centricular hypertrophy by voltagecentricular hypertrophy by voltage


Laboratory FindingsLaboratory Findings► BUN: 18 mg/dLBUN: 18 mg/dL► Creatinine: 1.4 mg/dLCreatinine: 1.4 mg/dL► Total cholesterol: 192 mg/dLTotal cholesterol: 192 mg/dL► HDL: 44 mg/dLHDL: 44 mg/dL► LDL: 120 mg/dLLDL: 120 mg/dL► Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no

bacteriabacteria

Laboratory FindingsLaboratory Findings► BUN: 18 mg/dLBUN: 18 mg/dL► Creatinine: 1.4 mg/dLCreatinine: 1.4 mg/dL► Total cholesterol: 192 mg/dLTotal cholesterol: 192 mg/dL► HDL: 44 mg/dLHDL: 44 mg/dL► LDL: 120 mg/dLLDL: 120 mg/dL► Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no

bacteriabacteria


What should be the target BP for this patient?What should be the target BP for this patient?

A:A: <140/<90 mmHg <140/<90 mmHg

B:B: <135/<85 mmHg <135/<85 mmHg

C:C: <130/<80 mmHg <130/<80 mmHg

D:D: <120/<70 mmHg <120/<70 mmHg


What factors would you consider when selecting an What factors would you consider when selecting an appropriate therapy?appropriate therapy?

A:A: Age of patient Age of patient

B:B: Impact of therapy on cognitive function Impact of therapy on cognitive function

C:C: Impact of therapy on heart rate Impact of therapy on heart rate

D:D: Impact of therapy of orthostatic hypotension Impact of therapy of orthostatic hypotension

E:E: Vasodilatory properties of the agent Vasodilatory properties of the agent


Would a Would a ßß-blocker be appropriate for this patient?-blocker be appropriate for this patient?

A:A: Yes Yes

B:B: No No


What is an optimal strategy for controlling blood What is an optimal strategy for controlling blood pressure?pressure?

A:A: Diuretic alone Diuretic alone

B:B: Diuretic + ACE inhibitor Diuretic + ACE inhibitor

C:C: Diuretic + ARB Diuretic + ARB

D:D: Diuretic + Diuretic + ßß-blocker-blocker

E:E: Diuretic + calcium-channel blocker Diuretic + calcium-channel blocker

Case 3Case 3

► PL is a 62-year-old white female returning to your PL is a 62-year-old white female returning to your office for a routine follow-up visit (lost to follow-up for office for a routine follow-up visit (lost to follow-up for the past 3 years)the past 3 years)

► Medical history significant for exertional angina, Medical history significant for exertional angina, diagnosed 4 years previouslydiagnosed 4 years previously

– a recent cardiac catheterization showed luminal a recent cardiac catheterization showed luminal irregularities with no critical stenosisirregularities with no critical stenosis

– currently experiences angina with moderate exercise, currently experiences angina with moderate exercise, such as climbing >2 flights of stairs, mowing lawnsuch as climbing >2 flights of stairs, mowing lawn

► Family history:Family history:– mother died of heart failure at 58 years of agemother died of heart failure at 58 years of age– father alive and wellfather alive and well

► Non-smoker; denies alcohol consumptionNon-smoker; denies alcohol consumption

Case - PLCase - PLPatient ProfilePatient Profile

► Blood pressure: 149/97 mm HgBlood pressure: 149/97 mm Hg

► Pulse: 85 and regularPulse: 85 and regular

► BMI: 28 Waist circumference: 36BMI: 28 Waist circumference: 36

► Physical examination is otherwise unremarkablePhysical examination is otherwise unremarkable

Case - PLCase - PLPhysical ExaminationPhysical Examination

BMI, body mass index.

► Laboratory dataLaboratory data

Serum creatinineSerum creatinine 1.0 mg/dL 1.0 mg/dL

Serum potassiumSerum potassium 4.0 mmol/L4.0 mmol/L

Fasting glucoseFasting glucose 97 mg/dL97 mg/dL

Total cholesterolTotal cholesterol 199 mg/dL199 mg/dL

LDL-C 121 mg/dLLDL-C 121 mg/dL HDL-C 48 mg/dL TG 150 mg/dLHDL-C 48 mg/dL TG 150 mg/dL

UrinalysisUrinalysis No proteinuria or cellular elementsNo proteinuria or cellular elements

ElectrocardiogramElectrocardiogram Non-specific ST segment changes Non-specific ST segment changes without evidence of left ventricular hypertrophywithout evidence of left ventricular hypertrophy

► Current medicationsCurrent medications

Sublingual nitroglycerin, as neededSublingual nitroglycerin, as needed

Aspirin 81 mg once dailyAspirin 81 mg once daily

► Laboratory dataLaboratory data

Serum creatinineSerum creatinine 1.0 mg/dL 1.0 mg/dL

Serum potassiumSerum potassium 4.0 mmol/L4.0 mmol/L

Fasting glucoseFasting glucose 97 mg/dL97 mg/dL

Total cholesterolTotal cholesterol 199 mg/dL199 mg/dL

LDL-C 121 mg/dLLDL-C 121 mg/dL HDL-C 48 mg/dL TG 150 mg/dLHDL-C 48 mg/dL TG 150 mg/dL

UrinalysisUrinalysis No proteinuria or cellular elementsNo proteinuria or cellular elements

ElectrocardiogramElectrocardiogram Non-specific ST segment changes Non-specific ST segment changes without evidence of left ventricular hypertrophywithout evidence of left ventricular hypertrophy

► Current medicationsCurrent medications

Sublingual nitroglycerin, as neededSublingual nitroglycerin, as needed

Aspirin 81 mg once dailyAspirin 81 mg once daily

Case - PLCase - PLLaboratory Values and Current MedicationsLaboratory Values and Current Medications

LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Case - PLCase - PLClinical Question #1Clinical Question #1

What are this patient’s cardiovascular risk What are this patient’s cardiovascular risk factors?factors?


What is PL’s blood pressure goal?What is PL’s blood pressure goal?

A.A. 130/85 mm Hg 130/85 mm Hg

B.B. 140/90 mm Hg 140/90 mm Hg

C.C. 130/80 mm Hg 130/80 mm Hg

D.D. 120/80 mm Hg 120/80 mm Hg

What would be your first stepsWhat would be your first stepsregarding PL’s blood pressure?regarding PL’s blood pressure?

A.A. Repeat measurement on at least one Repeat measurement on at least one other occasionother occasion

B.B. Encourage her to lose weight Encourage her to lose weight

C.C. Initiate antihypertensive medication Initiate antihypertensive medication


What type of antihypertensive agentWhat type of antihypertensive agentwould you prescribe 1would you prescribe 1stst-line?-line?

A.A. ACE inhibitor ACE inhibitor

B.B. Diuretic Diuretic

C.C. Beta-blocker Beta-blocker

D.D. Angiotensin-receptor blocker Angiotensin-receptor blocker

E.E. Calcium-channel blocker Calcium-channel blocker


On 2 separate occasions, PL’s BP is 142/91 mm Hg and On 2 separate occasions, PL’s BP is 142/91 mm Hg and 143/92 mm Hg. She also no longer seems to be having 143/92 mm Hg. She also no longer seems to be having anginal symptoms.anginal symptoms.

What would you now do?What would you now do?

A.A. Nothing; BP is only a couple of Nothing; BP is only a couple of mm above goal mm above goal

B.B. Encourage weight loss Encourage weight loss

C.C. Proceed with developing a more Proceed with developing a more aggressive antihypertensive aggressive antihypertensive treatment regimentreatment regimen


What would you prescribe now presuming that a What would you prescribe now presuming that a -blocker-blocker was was the agent selected as first-step therapy?the agent selected as first-step therapy?

A.A. Uptitration of the Uptitration of the -blocker-blocker

B.B. Add an ACE inhibitor Add an ACE inhibitor

C.C. Add an angiotensin-receptor Add an angiotensin-receptor blockerblocker

D.D. Add a calcium-channel blocker Add a calcium-channel blocker

E.E. Add a thiazide-type diuretic Add a thiazide-type diuretic


Case 4Case 4

Patient PresentationPatient Presentation

► A 76-year-old white man has diminished vision and a A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. treated with diuretics and calcium channel blockers.

► He does not always take his medication, however, He does not always take his medication, however, because he believes that BP normally increases with because he believes that BP normally increases with age and that antihypertensive medications and drugs, age and that antihypertensive medications and drugs, in general, cause troubling side effects.in general, cause troubling side effects.

► A 76-year-old white man has diminished vision and a A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. treated with diuretics and calcium channel blockers.

► He does not always take his medication, however, He does not always take his medication, however, because he believes that BP normally increases with because he believes that BP normally increases with age and that antihypertensive medications and drugs, age and that antihypertensive medications and drugs, in general, cause troubling side effects.in general, cause troubling side effects.

Patient PresentationPatient Presentation

► He tries to control his BP by eating properly and He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his He notes that at home he has normal BP, since his diastolic pressure ranges from 70-85 mmHg and his diastolic pressure ranges from 70-85 mmHg and his systolic pressure, from 170-190 mmHg. He denies any systolic pressure, from 170-190 mmHg. He denies any headache, chest pain, and shortness of breath, headache, chest pain, and shortness of breath, claudication, or leg swelling.claudication, or leg swelling.

► His medical history is remarkable for macular His medical history is remarkable for macular degeneration in both eyes. He has had no prior degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not about 40 years but stopped 15 yrs. ago. He does not drink alcohol. drink alcohol.

► He tries to control his BP by eating properly and He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his He notes that at home he has normal BP, since his diastolic pressure ranges from 70-85 mmHg and his diastolic pressure ranges from 70-85 mmHg and his systolic pressure, from 170-190 mmHg. He denies any systolic pressure, from 170-190 mmHg. He denies any headache, chest pain, and shortness of breath, headache, chest pain, and shortness of breath, claudication, or leg swelling.claudication, or leg swelling.

► His medical history is remarkable for macular His medical history is remarkable for macular degeneration in both eyes. He has had no prior degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not about 40 years but stopped 15 yrs. ago. He does not drink alcohol. drink alcohol.


► On physical examination, he appears to be a healthy On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 5’10”, elderly man, who looks his age. His height is 5’10”, and his weight, 166 lb. His BP is 182/80 mmHg in both and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart arms and does not change with position. His heart rate is 74 beats per minute. rate is 74 beats per minute.

► Fundoscopic exam shows bilateral macular Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good hemorrhages or exudates. His neck shows good carotid pulses without bruits.carotid pulses without bruits.

► On physical examination, he appears to be a healthy On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 5’10”, elderly man, who looks his age. His height is 5’10”, and his weight, 166 lb. His BP is 182/80 mmHg in both and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart arms and does not change with position. His heart rate is 74 beats per minute. rate is 74 beats per minute.

► Fundoscopic exam shows bilateral macular Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good hemorrhages or exudates. His neck shows good carotid pulses without bruits.carotid pulses without bruits.


► Cardiac exam shows a regular rate and rhythm, with a Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or abdomen is without scars, masses, tenderness, or organomegaly. organomegaly.

► There are no abnormal bruits, and he has 2+ femoral There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. focal deficits or pathologic reflexes.

► His extremities show no peripheral edema or joint His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2-deformities. He has 1+ peripheral pulses with 2-second capillary refill in his fingers and toessecond capillary refill in his fingers and toes..

► Cardiac exam shows a regular rate and rhythm, with a Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or abdomen is without scars, masses, tenderness, or organomegaly. organomegaly.

► There are no abnormal bruits, and he has 2+ femoral There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. focal deficits or pathologic reflexes.

► His extremities show no peripheral edema or joint His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2-deformities. He has 1+ peripheral pulses with 2-second capillary refill in his fingers and toessecond capillary refill in his fingers and toes..

Laboratory EvaluationLaboratory Evaluation

► Laboratory findings show the following values: BUN, Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. no bacteria.

► Echocardiogram shows normal sinus rhythm with mild Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy.left ventricular hypertrophy.

► Laboratory findings show the following values: BUN, Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. no bacteria.

► Echocardiogram shows normal sinus rhythm with mild Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy.left ventricular hypertrophy.

What is the optimal strategy for What is the optimal strategy for controlling blood pressure in this controlling blood pressure in this

patient?patient?

Are there any associated risks Are there any associated risks with this therapywith this therapy? ?

What is the optimal strategy for What is the optimal strategy for controlling blood pressure in this controlling blood pressure in this

patient?patient?

Are there any associated risks Are there any associated risks with this therapywith this therapy? ?

Discussion ManagementDiscussion Management

► This patient has been essentially healthy all of his life. This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal which was previously thought to be a normal measurement. measurement.

► More recent findings indicate that a systolic pressure More recent findings indicate that a systolic pressure this high is in fact not normal. this high is in fact not normal.

► Rather, it is associated with increasing risk for Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal (MI) congestive heart failure, and progressive renal insufficiency. insufficiency.

► Treatment will reduce these risksTreatment will reduce these risks..

► This patient has been essentially healthy all of his life. This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal which was previously thought to be a normal measurement. measurement.

► More recent findings indicate that a systolic pressure More recent findings indicate that a systolic pressure this high is in fact not normal. this high is in fact not normal.

► Rather, it is associated with increasing risk for Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal (MI) congestive heart failure, and progressive renal insufficiency. insufficiency.

► Treatment will reduce these risksTreatment will reduce these risks..


► Findings from the Systolic Hypertension in the Elderly Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. a more aggressive approach in lowering systolic BP.

► In SHEP, reducing a pretreatment systolic BP of 160-In SHEP, reducing a pretreatment systolic BP of 160-180 mmHg to lower than 160 mmHg or by more than 180 mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. 20 mmHg significantly improved survival rates.

► Clinical therapies used in SHEP were mainly low-dose Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. chlorthalidone and/or the beta-blocker atenolol.

► Because this trial proved the success of these drugs in Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients classes are viewed as treatments of choice in patients with isolated systolic hypertension.with isolated systolic hypertension.

► Findings from the Systolic Hypertension in the Elderly Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. a more aggressive approach in lowering systolic BP.

► In SHEP, reducing a pretreatment systolic BP of 160-In SHEP, reducing a pretreatment systolic BP of 160-180 mmHg to lower than 160 mmHg or by more than 180 mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. 20 mmHg significantly improved survival rates.

► Clinical therapies used in SHEP were mainly low-dose Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. chlorthalidone and/or the beta-blocker atenolol.

► Because this trial proved the success of these drugs in Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients classes are viewed as treatments of choice in patients with isolated systolic hypertension.with isolated systolic hypertension.


► Recent clinical trials demonstrated that using calcium channel Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well.therapy reduce stroke rate as well.

► With increasing age come substantial changes in circulation: With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing.observed widening of the pulse pressure with ageing.

► Recent clinical trials demonstrated that using calcium channel Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well.therapy reduce stroke rate as well.

► With increasing age come substantial changes in circulation: With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing.observed widening of the pulse pressure with ageing.


► Low-dose diuretics are advantageous in the elderly Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest to vasodilation. These agents may also offer a modest natriuretic effect in older patients. natriuretic effect in older patients.

► Any vasodilator therapy is appropriate, because it Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated targets the major pathophysiologic problem: elevated vascular resistance. vascular resistance.

► Which vasodilator to use depends heavily on Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the coexisting coronary disease by having increased the rate-pressure product. rate-pressure product.

► Low-dose diuretics are advantageous in the elderly Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest to vasodilation. These agents may also offer a modest natriuretic effect in older patients. natriuretic effect in older patients.

► Any vasodilator therapy is appropriate, because it Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated targets the major pathophysiologic problem: elevated vascular resistance. vascular resistance.

► Which vasodilator to use depends heavily on Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the coexisting coronary disease by having increased the rate-pressure product. rate-pressure product.


► Older patients have specific pharmacotherapeutic Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. orthostatic hypertension.

► Because these patients have reduced metabolic Because these patients have reduced metabolic capabilities, they should be given medication in a dose capabilities, they should be given medication in a dose that is about 50% of that given initially to younger that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age-patients; however, not all elderly patients exhibit age-related declines in renal function.related declines in renal function.

► Cognitive function is also a concern; older patients Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. must be able to sustain their activities of daily living.

► The patient in this case, for example, should not The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability receive pharmacotherapy that interferes with his ability to play golf.to play golf.

► Older patients have specific pharmacotherapeutic Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. orthostatic hypertension.

► Because these patients have reduced metabolic Because these patients have reduced metabolic capabilities, they should be given medication in a dose capabilities, they should be given medication in a dose that is about 50% of that given initially to younger that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age-patients; however, not all elderly patients exhibit age-related declines in renal function.related declines in renal function.

► Cognitive function is also a concern; older patients Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. must be able to sustain their activities of daily living.

► The patient in this case, for example, should not The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability receive pharmacotherapy that interferes with his ability to play golf.to play golf.


► The only additional test relevant to this The only additional test relevant to this patient would be an assessment of left patient would be an assessment of left ventricular function with echocardiography, if ventricular function with echocardiography, if there is any suspicion of pump dysfunction. there is any suspicion of pump dysfunction.

► Confirmation of pump dysfunction should Confirmation of pump dysfunction should steer the physician toward more disease-steer the physician toward more disease-state specific therapies.state specific therapies.

► The only additional test relevant to this The only additional test relevant to this patient would be an assessment of left patient would be an assessment of left ventricular function with echocardiography, if ventricular function with echocardiography, if there is any suspicion of pump dysfunction. there is any suspicion of pump dysfunction.

► Confirmation of pump dysfunction should Confirmation of pump dysfunction should steer the physician toward more disease-steer the physician toward more disease-state specific therapies.state specific therapies.

Clinical Pearls and PitfallsClinical Pearls and Pitfalls

► Because high systolic BP may cause target organ Because high systolic BP may cause target organ injury, it must be treated aggressively.injury, it must be treated aggressively.

► Low-dose thiazides are optimal as an initial Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase helpful, preferably with agents that do not increase heart rate.heart rate.

► Agents that interfere with cognitive function or Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used precipitate orthostatic hypotension should be used sparingly. sparingly.

► Because high systolic BP may cause target organ Because high systolic BP may cause target organ injury, it must be treated aggressively.injury, it must be treated aggressively.

► Low-dose thiazides are optimal as an initial Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase helpful, preferably with agents that do not increase heart rate.heart rate.

► Agents that interfere with cognitive function or Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used precipitate orthostatic hypotension should be used sparingly. sparingly.

New Dimensions and Landmark Practice Advances in Hypertension and Heart Disease Focus on Optimizing...

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