New Dimensions and Landmark Practice Advances in Hypertension and Heart Disease Focus on Optimizing the Use of Novel, Cardioselectve Beta-BlockersFrom Evidence to Practice Investigation Innovation Application Ken Jamerson, MD, FACC Program Chairman Professor of Medicine Division of Cardiovascular Medicine University of Michigan Health System Ann Arbor, Michigan President, Board of Trustees International Society on Hypertension in Blacks (ISHIB) Ken Jamerson, MD, FACC Program Chairman Professor of Medicine Division of Cardiovascular Medicine University of Michigan Health System Ann Arbor, Michigan President, Board of Trustees International Society on Hypertension in Blacks (ISHIB)

CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Forest Laboratories Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview Welcome and Program Overview

Program Educational Objectives 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: 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 Faculty Program Chairman Kenneth A. Jamerson – Program Chairman Professor of Internal Medicine Cardiovascular Medicine University of Michigan Medical School Medical Director, Program of Multi-Cultural Health University of Michigan Ann Arbor, MI Henry R. Black, MD Clinical Professor of Medicine New York University Medical Center New York, NY L. Michael Prisant, MD, FACP, FACC, FAHA Professor of Medicine Medical College of Georgia Director of Hypertension & Lipid Clinic Augusta, GA

Faculty COI Disclosures Faculty COI Disclosures Kenneth A. Jamerson – Program Chairman Grant/Research: NIH, NHLBI, NIDDK, Novartis, King Consultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventis Speakers Bureau: BMS, Merck, Novartis Other: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) as president, to obtain industry support Henry R. Black, MD Grant/Research: Pfizer Consultant: Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, Myogen Speakers Bureau: Sankyo, BI, Novartis, Pfizer L. Michael Prisant, MD, FACP, FACC, FAHA Grant/Research: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, Novartis Consultant: Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Reliant, Schwarz, SunTech Medical Speakers Bureau: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Merck, Merck-Schering-Plough, Reliant Kenneth A. Jamerson – Program Chairman Grant/Research: NIH, NHLBI, NIDDK, Novartis, King Consultant: Abbott, BMS, GSK, King, Merck, Novartis, Sankyo, sanofi-aventis Speakers Bureau: BMS, Merck, Novartis Other: Act on behalf of the International Society of Hypertension in Blacks (ISHIB,) as president, to obtain industry support Henry R. Black, MD Grant/Research: Pfizer Consultant: Pfizer, Sankyo, MSD, BI, BMS/Sanofi, Novartis, Myogen Speakers Bureau: Sankyo, BI, Novartis, Pfizer L. Michael Prisant, MD, FACP, FACC, FAHA Grant/Research: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, Eli-Lilly, Novartis Consultant: Astra-Zeneca, Abbott, CV Therapeutics, Merck, Merck/Schering-Plough, Reliant, Schwarz, SunTech Medical Speakers Bureau: Astra-Zeneca, Abbott, Boerhinger-Ingelheim, CV Therapeutics, Merck, Merck-Schering-Plough, Reliant

Global Disease Mortality 2002 Mortality (millions) World Health Organization. The World Health Report 2003: Shaping the Future Cardiovascular disease Malignant neoplasms Injuries Respiratory infections COPD and asthma HIV/AIDS Perinatal conditions Digestive diseases Diarrhoeal diseases Tuberculosis Childhood diseases Malaria Diabetes

Prevalence of Conventional Risk Factors in Patients with Coronary Heart Disease 19.4 % 43.0 % 27.8 % 8.9 % 4 Risk Factors (< 1 %) (< 1 %) No Risk Factors 1 Risk Factor 2 Risk Factors 3 Risk Factors 62.4 % Khot U et al, JAMA 2003;290: RISK FACTORS SmokingHTNCholesterolDM (N = 87,869)

Update on Hypertension Management Recent Advances – Focus on Combination Therapy, Guideline Modifications, and Comprehensive Cardiovascular Protection Primary Care Summit In Cardiovascular Medicine Henry R. Black, MD Clinical Professor of Medicine NYU Center for the Prevention of Cardiovascular Disease Medical Center New York, NY Henry R. Black, MD Clinical Professor of Medicine NYU Center for the Prevention of Cardiovascular Disease Medical Center New York, NY

Achievements in Public Health, 20 th Century Age-adjusted to the 2000 US population.; Sources: NHLBI, Morbidity and Mortality Chart Book 2000 CDC, Health, United States 2001 Total cardiovascular diseases Diseases of the heart Coronary heart disease Stroke

Leading Causes of Death for All Ages United States CLRD=chronic lower respiratory diseases. Centers for Disease Control and Prevention. Available at: hus05.pdf. Accessed July 4, ,000 Year Deaths per 100,000 Population (log scale) Unintentional injuries Stroke Cancer CLRD Heart disease All causes SGR VA STUDY DIURETICS STATINS

Impact 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 seconds 2500 CVD deaths each day: ~ 1 death every 35 seconds CVD claims more lives each year than the next 3 leading causes of death combined CVD claims more lives each year than the next 3 leading causes of death 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 seconds 2500 CVD deaths each day: ~ 1 death every 35 seconds CVD claims more lives each year than the next 3 leading causes of death combined CVD claims more lives each year than the next 3 leading causes of death combined AHA Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006; Deaths per 100,000 CVD Cancer Respiratory Disease Trauma

Global Mortality 2000: Impact of Hypertension Lower mortality, developing region Attributable Mortality (in thousands; total 55,861,000) High blood pressure Tobacco High cholesterol Unsafe sex High BMI Physical inactivity Alcohol Underweight High mortality, developing region Developed region BMI = body mass index. Adapted with permission from Ezzati M, et al. Lancet. 2002;360:

Residual Lifetime Risk of Hypertension in Women and Men Aged 65 Years Vasan RS et al. JAMA. 2002;287: Risk of hypertension (%) Follow-up (y) Men Women

Consequences of Hypertension: Organ Damage CHF=congestive heart failure; CHD=coronary heart disease; LVH=left ventricular hypertrophy. Chobanian AV et al. JAMA. 2003;289: Hypertension LVH, CHD, CHF Chronic kidney disease Retinopathy Transient ischemic attack, stroke Peripheralarterialdisease

Risk Factors: Diabetes Hypertension Vascular Dysfunction Vascular Disease Tissue Injury (MI, Stroke) Pathological Remodeling Target Organ Dysfunction (HF, Renal) End-stage Organ Failure Death Oxidative Stress / Endothelial Dysfunction Target Organ Damage Damage Adapted from Dzau et al. Circulation. 2006;114: The Cardiovascular Continuum MI: Myocardial infarction HF: Heart failure

Jackson R et al. Lancet. 2005;365: Synergistic Interaction of Multiple CV Risk Factors 0 Reference 5-Year CVD Risk (per 100 people) TC = 270 mg/dL Smoker HDL-C = 39 mg/dL Male Diabetes Aged 60 Years % 33% 24% 18% 12% 6% 3% 110 SBP (mm Hg) Additive Risk Factors

Trends in CV Risk Factors, US Adults Aged Years (NHES: ; NHANES: to ) Gregg EW, et al. JAMA. 2005;293: High total cholesterol was defined as 240 mg/dL; hypertension was defined as 140/90 mm Hg. NHES=National Health Examination Survey.

HTN Commonly Clusters with Other Risk Factors HTN + 1 other risk factor HTN + 3 other risk factors risk factors HTN + 2 other risk factors risk factors HTN only *Body mass index >30 kg/m 2 Kaiser Permanente Northwest database; N=57,573 aged > 35 years with HTN and no CVD Weycker D et al. Am J Hypertens. 2007;20: 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 1 st MI 69% of patients with 1 st MI 77% of patients with 1 st stroke 77% of patients with 1 st stroke 74% of patients with HF 74% of patients with HF Hypertension precedes HF in 91% of cases Hypertension precedes HF in 91% of cases Hypertension is associated with a 2- to 3-times higher risk for HF Hypertension is associated with a 2- to 3-times higher risk for HF Hypertension Co-Morbidities BP, blood pressure; HF, heart failure; MI, myocardial infarction. Thom T et al. Circulation. 2006;113:e85-e151.

MEN WOMEN Non-smoker mmol/l45678 mg/dl mmol/l45678 mg/dl Cholesterol mmol/l45678 mg/dl mmol/l45678 mg/dl Cholesterol Smoker age 70 age 60 age 50 age 40 age Non-smoker mmol/l45678 mg/dl mmol/l45678 mg/dl Cholesterol mmol/l45678 mg/dl mmol/l45678 mg/dl Cholesterol Smoker age 70 age 60 age 50 age 40 age 30 Very high High Moderate Mild Low >40% 20–40% 10 – 20% 5–10% <5% 10 Year Risk Level SBP (mmHg) Coronary Heart Disease Risk Chart

ATP III: The Metabolic Syndrome ( 3 risk factors are required for diagnosis) Modifications as of 10/2005 <40 mg/dL or Rx <50 mg/dL or Rx Men Women >40 in (37-39 gen. predisp; 35 for As. Am) >35 in (31-35 gen. predisp; 31 for As. Am) Men Women 100 mg/dL 100 mg/dL Fasting glucose 130 or 85 mm Hg or Rx for BP 130 or 85 mm Hg or Rx for BP Blood pressure HDL-C 150 mg/dL or Rx 150 mg/dL or RxTG Abdominal obesity (Waist circumference * ) Defining Level Risk Factor Grundy SM et al. Circulation. 2005;28:

Visceral obesity Insulin resistance Insulin resistance Raised blood pressure Atherogenic dyslipidemia Proinflammatory state Prothrombotic state The Metabolic Syndrome and its Consequences Type 2 Diabetes CardiovascularDisease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:

Lakka et al. JAMA 2002;288: Cardiovascular Disease Mortality RR (95% Cl), 3.55 ( ) Metabolic Syndrome YesNo Cumulative Hazard, % Follow-up, y Adverse Cardiovascular Prognosis in Metabolic Syndrome Population-Based Observational Study in 1209 Men

JNC I JNC II JNC III JNC IV JNC V JNC VI Consider therapy Hyper- tensive MildMildMild Stage 1 ModerateModerateModerate Stage 2 Severe Severe Severe Stage 3 Stage 2 Stage 4 High- normal NormalNormalNormalNormal Optimal DBP (mm Hg) Optimal JNC 7 Stage 1 Stage 2 Prehyper-tension Normal JNC IV. Arch Intern Med. 1988;148: JNC V. Arch Intern Med. 1993;153: JNC VI. Arch Intern Med. 1997;157: Chobanian AV et al. JAMA. 2003;289: JNC I. JAMA. 1977;237: JNC II. Arch Intern Med. 1980;140: JNC III. Arch Intern Med. 1984;144: Hypertension JNC BP Classifications: DBP

JNC V Optimal JNC IV. Arch Intern Med. 1988;148: JNC V. Arch Intern Med. 1993;153: JNC VI. Arch Intern Med. 1997;157: Chobanian AV et al. JAMA. 2003;289: JNC I JNC II JNC III JNC IV JNC VI Border- line ISH Stage 1 Stage 2 Stage 3 High- normal NormalNormal Optimal SBP (mm Hg) Normal Border- line ISH Stage 4 No recommendations for SBP in JNC I or JNC II JNC 7 Stage 1 Prehyper-tension Normal Stage 3 Stage 2 JNC I. JAMA. 1977;237: JNC II. Arch Intern Med. 1980;140: JNC III. Arch Intern Med. 1984;144: Hypertension JNC BP Classifications: SBP Stage 2

Mortality According to Blood Pressure in Men Age 50 to 69 Society of Actuaries. Blood Pressure Study, Ratio (%) of actual to expected mortality Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

Hypertension JNC 7 Blood Pressure (mm Hg) Category SystolicDiastolic <120 and <80 Normal or Prehypertension or Stage 1 hypertension 160 or 100 Stage 2 hypertension Chobanian AV, et al. Hypertension. 2003;42: JNC 7: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Life Time Risk of Stroke Framingham Adapted from Lloyd-Jones, Hypertension Primer, Fourth Edition, 2007

Stroke and Ischemic Heart Disease Mortality vs Usual Systolic BP by Age Mortality (Floating absolute risk and 95% CI) Usual Systolic BP (mm Hg) years years years years Stroke Age at risk: Ischemic Heart Disease Usual Systolic BP (mm Hg) years years years years Age at risk: years Lancet. 2002;360:

BP Reductions as Small as 2 mmHg Reduce the Risk of CV Events by Up to 10% Meta-analysis of 61 prospective, observational studies Meta-analysis of 61 prospective, observational studies 1 million adults 1 million adults 12.7 million person-years 12.7 million person-years Prospective Studies Collaboration. Lancet. 2002;360: mmHg decrease in mean SBP 10% reduction in risk of stroke mortality 7% reduction in risk of ischemic heart disease mortality

CV Mortality Risk Systolic/Diastolic Blood Pressure (mmHg) /75135/85155/95175/105 Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg BP Increment* Lewington S, et al. Lancet. 2002;360: * Individuals aged years, starting at BP 115/75 mm Hg

Prospective Studies Collaboration Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mmHg. Lancet. 2002;360:1903 –1913.

The Spectrum of Hypertension in America PRE- HTN AT GOAL HTH NOT AT GOAL NOT RESISTANT HTN NOT AT GOAL RESISTANT MILLION MILLION MILLION (37% at GOAL) 3-11MILLION

*BP 140/90 mm Hg Prevalence of Hypertension* in US Adults: NHANES 2005–2006 NHANES 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 SBP=systolic blood pressure DBP=diastolic blood pressure Percent years and over Men Women Mexican American Non-Hispanic White Non-Hispanic Black

Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Data Brief no. 3; National Health and Nutrition Examination Survey SBP=systolic blood pressure DBP=diastolic blood pressure Prevalence of Hypertension* in US Adults: NHANES 2005–2006 NHANES 2005–2006 *SBP = mm Hg DBP = mm Hg Percent years and over Men Women Mexican American Non-Hispanic White Non-Hispanic Black

Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Lifestyle Modifications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. Stage 2 Hypertension (SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications

Goal Of Antihypertensive Therapy < 140 mm Hg and < 90 mm Hg for most patients < 140 mm Hg and < 90 mm Hg for most patients < 130 mm Hg and < 80 mm Hg for diabetics, patients with HF and those with CRF and any day now for those with CAD < 130 mm Hg and < 80 mm Hg for diabetics, patients with HF and those with CRF and any day now for those with CAD Goal is not dependent on age, gender or co-morbidity THE GOAL IS THE CEILING, NOT THE FLOOR. < 140 mm Hg and < 90 mm Hg for most patients < 140 mm Hg and < 90 mm Hg for most patients < 130 mm Hg and < 80 mm Hg for diabetics, patients with HF and those with CRF and any day now for those with CAD < 130 mm Hg and < 80 mm Hg for diabetics, patients with HF and those with CRF and any day now for those with CAD Goal is not dependent on age, gender or co-morbidity THE GOAL IS THE CEILING, NOT THE FLOOR.

HF of Ischemic Etiology ACS - STEMI ACS – UA and NSTEMI CAD and Stable Angina Primary Prevention Diagnosis Rosendorff et al. Circulation. 2007;115: 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 <130/80 Diabetes, Chronic Kidney Disease, CAD, CAD Equivalents, or Framingham Risk Score 10% Diabetes, Chronic Kidney Disease, CAD, CAD Equivalents, or Framingham Risk Score 10% Target BP (mm Hg) <140/90 AHA Scientific StatementTreatment of Hypertension in the Prevention and Management of Ischemic Heart Disease

AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; βB, ß-blocker; CCB, calcium channel blocker; MI, myocardial infarction; CAD, coronary artery disease. Chobanian AV, et al. JAMA. 2003;289(19): The Seventh Report of the Joint National Committee Compelling Indications Diuretic ßBßBßBßBACEIARBCCBAA Heart failure Post-MI High CAD risk Diabetes Chronic kidney disease Recurrent stroke prevention

JNC 7: Combination Therapy When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations.When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations. Hypertension, 2003;42:1221b

years and over Mexican American Non-Hispanic White Non-Hispanic Black Percent Awareness of Hypertension in US Adults: NHANES 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 Total Men Women Total Men Women

Pharmacological Treatment of Hypertensive Adults in the US: NHAMES Mexican American Non-Hispanic White Non-Hispanic Black Percent Total Men Women Total Men Women 60 years and over

Centers for Disease Control and Prevention/National Center for Health Statistics. (CDC/NCHS). Data Brief no. 3; National Health and Nutrition Examination Survey Treated Hypertensive Adults at Goal BP; NHANES Mexican American Non-Hispanic White Non-Hispanic Black Percent Total Men Women Total Men Women 60 years and over

Percentage of Patients Requiring 2 Antihypertensive Drugs to Reach BP Targets Percent 1. HOT: Hansson et al. Lancet. 1998;351:1755– LIFE: Dahlöf et al. Lancet. 2002;359: ALLHAT: Cushman et al. J Clin Hypertens. 2002;4:393– CONVINCE: Black et al. JAMA. 2003;289: ASCOT: Dahlöf et al. Lancet. 2005;366: HOTLIFEALLHATCONVINCEASCOT

Position Statement: Monotherapy Versus Combination Therapy ESC/ESH Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients. Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients. Use of more than one agent is necessary to achieve target BP in the majority of patients. A vast array of effective and well tolerated combinations is available. Use of more than one agent is necessary to achieve target BP in the majority of patients. A vast array of effective and well tolerated combinations is available. Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed. Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed. Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high. Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high. Fixed combinations of two drugs can simplify treatment schedule and favor compliance. Fixed combinations of two drugs can simplify treatment schedule and favor compliance. Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients. Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients. Use of more than one agent is necessary to achieve target BP in the majority of patients. A vast array of effective and well tolerated combinations is available. Use of more than one agent is necessary to achieve target BP in the majority of patients. A vast array of effective and well tolerated combinations is available. Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed. Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed. Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high. Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total cardiovascular risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high. Fixed combinations of two drugs can simplify treatment schedule and favor compliance. Fixed combinations of two drugs can simplify treatment schedule and favor compliance.

Advantages of Multidrug Therapy in Hypertension Increased efficacy of each drug compared to either as monotherapy Increased efficacy of each drug compared to either as monotherapy More prompt achievement of goal More prompt achievement of goal Reduced side effects, clinical and metabolic Reduced side effects, clinical and metabolic Alterations in pharmacodynamics allowing longer duration of action Alterations in pharmacodynamics allowing longer duration of action Broader spectrum of response Broader spectrum of response Increased efficacy of each drug compared to either as monotherapy Increased efficacy of each drug compared to either as monotherapy More prompt achievement of goal More prompt achievement of goal Reduced side effects, clinical and metabolic Reduced side effects, clinical and metabolic Alterations in pharmacodynamics allowing longer duration of action Alterations in pharmacodynamics allowing longer duration of action Broader spectrum of response Broader spectrum of response Complementary mechanisms of action Complementary mechanisms of action Fewer pills should mean better adherence Fewer pills should mean better adherence Fewer co-pays if given as a fixed dose combination and often cheaper than buying each individually Fewer co-pays if given as a fixed dose combination and often cheaper than buying each individually Adapted and updated from Black HR. Patient Care, 1997.

ESH 2003: Possible Combinations of Different Classes of Antihypertensive Agents -blockers -blockers Calcium antagonists AT 1 -receptor blockers Diuretics ACE inhibitors The most effective and well tolerated combinations are shown as solid lines ESH Guidelines. J Hypertens. 2007;25: ESH= European Society of Hypertension

2006 Revision -Blockers Removed <55 Years 55 years or Black Patients at any Age A* C or D Step 1 A* + C or A* + D Step 2 A* + C + DStep 3 Step 4 Add: further diuretic therapy or alpha-blocker or beta-blocker Consider seeking specialist advice

HR, heart rate; BP, blood pressure. 1. Tse WY et al. Diabet Med. 1994;11(2): Fonarow GC. Am J Med. 2004;116(Suppl 5A):76S-88S. 3. Bell DS. The Endocrinologist. 2003;13: Potential Cardiac Benefits of β-Blockade in Patients With Hypertension Antiatherogenicreduces inflammation, shear stress, endothelial dysfunction, and risk for plaque rupture 1,2,3 Antiatherogenicreduces inflammation, shear stress, endothelial dysfunction, and risk for plaque rupture 1,2,3 Antiarrhythmic 1 Antiarrhythmic 1 decreases HR 2 decreases HR 2 decreases sympathetic activity 1 decreases sympathetic activity 1 increases cardiac vagal tone 1 increases cardiac vagal tone 1 Anti-ischemic 1 Anti-ischemic 1 decreases HR and BP 2 decreases HR and BP 2 prolongs diastole (filling coronary arteries) 2 prolongs diastole (filling coronary arteries) 2 Reverses cardiac remodeling 2 Reverses cardiac remodeling 2 Antiatherogenicreduces inflammation, shear stress, endothelial dysfunction, and risk for plaque rupture 1,2,3 Antiatherogenicreduces inflammation, shear stress, endothelial dysfunction, and risk for plaque rupture 1,2,3 Antiarrhythmic 1 Antiarrhythmic 1 decreases HR 2 decreases HR 2 decreases sympathetic activity 1 decreases sympathetic activity 1 increases cardiac vagal tone 1 increases cardiac vagal tone 1 Anti-ischemic 1 Anti-ischemic 1 decreases HR and BP 2 decreases HR and BP 2 prolongs diastole (filling coronary arteries) 2 prolongs diastole (filling coronary arteries) 2 Reverses cardiac remodeling 2 Reverses cardiac remodeling 2

Phase of Treatment Acutetreatment Secondaryprevention Overall Total # Patients 28,970 24,298 53, RR of death b-blocker better RR (95% CI) Placebo better 0.87 ( ) 0.77 ( ) 0.81 ( ) -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 textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, Summary of Secondary Prevention Trials of b-blocker Therapy CI=Confidence interval, RR=Relative risk

–22% –20% Hanes DS et al. J Clin Hypertens (Greenwich). 2001;3(4): Risk Reduction With β-Blockers in Post-MI Patients –30% –40% –20% –10% 0% –33% Overallmortality Suddencardiacdeath Non-suddendeath Nonfatal MI 15 Trials (n =18,995)

-Blocker Trials in Heart Failure: Overview -Blocker Trials in Heart Failure: Overview Relative Risk and 95% Confidence Intervals Annual Mortality BEST 24 months placebo 17% bucindolol 15% CIBIS-II 15 months placebo 13.2% bisoprolol 8.8% MERIT-HF 12 months placebo 11.0% metoprolol succinate 7.2% COPERNICUS 10.4 months placebo 18.5% carvedilol 11.4% % Patients P=.0001 P=.0062 P=.0014 RR 34% 35% 34% P=.10 10% P Value Lancet. 1999:353: ; CIBIS II Investigator and Committees. Lancet. 1999;353:9-13; Packer M et al. N Engl J Med. 2001;344: ; Beta-blockers Evaluation Survival Trial Investigators. N Engl J Med. 2001;344: Mean Follow-up

-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 DM, unless contraindicated -blocker in those with other forms of CV disease or DM, unless contraindicated *Relative contraindications include asthma, chronic obstructive pulmonary disease, insulin dependent diabetes mellitus, severe peripheral arterial disease, and a PR interval >0.24 seconds ACS=Acute coronary syndrome, CV=Cardiovascular, DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction -blocker Recommendations* -blocker Recommendations* Secondary Prevention

Timeline of β-Blocker Introduction in the US Propanolol Metoprololtartrate Nadolol Atenolol Timolol Pindolol Acebutolol LabetalolPenbutololCarteolol Betaxolol MetoprololSuccinate Bisoprolol CarvedilolNebivolol Nonselective Vasodilating Selective

Hemodynamic Effects of Nebivolol and Atenolol in Patients with Hypertension* Left ventricular end-diastolic volume (mL) Left ventricular end­systolic volume (mL) Stroke volume (mL) Heart rate (beats/min) Cardiac output (L/min) Peripheral resistance (dyne/cm-5) Ejection fraction (%) Atenolol (100 mg/qd) Nebivolol (5 mg/qd) Kamp et al. Am J Cardiol. 2003;92:344 *At 2 weeks

Incident Diabetes in Clinical Trials of Antihypertensive Drugs – A Network Meta-analysis Odds ratio of incident diabetes Incoherence= ARBs ACE Inhibitors CCBs Placebo Β blockers Diuretics Referent 0.90 ( ) p= ( ) p= ( ) p= ( ) p< ( ) p< Elliott WJ, Meyer PM. Lancet. 2007;369:201–207.

Effect of -Blockers on Insulin Sensitivity in Hypertensive Patients Propranolol Metoprolol Atenolol Pindolol Dilevalol Carvedilol Celiprolol % Change Above Baseline Jacob S et al. Am J Hypertens. 1998;11: 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. Other Antihypertensive Treatments Analysis of 5 studies: Atenolol versus other antihypertensive therapy Analysis of 5 studies: Atenolol versus other antihypertensive therapy 17,671 patients included, with a mean follow-up of 4.6 years 17,671 patients included, with a mean follow-up of 4.6 years No differences in BP lowering No differences in BP lowering Analysis of 5 studies: Atenolol versus other antihypertensive therapy Analysis of 5 studies: Atenolol versus other antihypertensive therapy 17,671 patients included, with a mean follow-up of 4.6 years 17,671 patients included, with a mean follow-up of 4.6 years No differences in BP lowering No differences in BP lowering Trials included in meta-analysis: MRC Old (Medical Research Council Trial of Treatment of Hypertension in Older Adults); UKPDS (United Kingdom Prospective Diabetes Study); ELSA (European Lacidipine Study of Atherosclerosis); HAPPHY (The Heart Attack Primary Prevention in Hypertension Trial); LIFE (The Losartan Intervention for Endpoint Reduction Study). Risk Reduction (95% CI) All-Cause Mortality 1.13(1.02–1.25) CV Mortality 1.16(1.00–1.34) Myocardial Infarction 1.04(.89–1.20) Stroke1.30(1.12–1.50) Carlberg B. Lancet. 2004;364:1684–1689

All β-Blockers vs Placebo or No Treatment: Outcomes Lindholm LH et al. Lancet. 2005;366: End Point β-Blocker n/N Placebo n/N RR (95% CI) Stroke325/ / ( ) Myocardial infarction 413/ / ( ) Mortality for all causes 606/ / ( )

Atenolol vs. Other Antihypertensive Treatments: Outcomes Endpoint -blocker n/N -blocker n/N Other Drug n/N RR (95% CI) Stroke1019/ / ( ) Myocardial Infarction 1216/ / ( ) Mortality for All Causes 2387/ / ( ) Lindholm LH, et al. Lancet. 2005;366:

Follow-up 2006 Meta-Analysis: Atenolol vs Other Treatments 2006 Meta-analysis End Point Summary OR (95% CI) Death 1.10 ( ) P=0.003 CV Death 1.13 ( ) (P=0.005) MI 1.05 ( ) P=0.19 Stroke 1.26 ( ) P= Elliott WJ. JACC. 2006;47 (Suppl):361A.

Study Population blocker n/N blocker n/N Other Drugs n/N RR (95% CI) Participants <60 yrs 745/ / ( ) Participants 60 yrs 3588/ / ( ) Beta-Blockers vs. Other Antihypertensive Drugs: Composite Outcome* *Death, stroke or MI Khan N, et al. CMAJ. 2006;174:

Why they SHOULD be dropped: There are more effective alternatives. TRUE There are more effective alternatives. TRUE They are not effective antihypertensives in older and African American patients. NEITHER ARE ACE-I or ARBs. They are not effective antihypertensives in older and African American patients. NEITHER ARE ACE-I or ARBs. They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. TRUE They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. TRUE They do not reduce systolic BP as well as other agents. TRUE They do not reduce systolic BP as well as other agents. TRUE There are safer alternatives. BLOCKERS MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS. There are safer alternatives. BLOCKERS MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS. Why they SHOULD be dropped: There are more effective alternatives. TRUE There are more effective alternatives. TRUE They are not effective antihypertensives in older and African American patients. NEITHER ARE ACE-I or ARBs. They are not effective antihypertensives in older and African American patients. NEITHER ARE ACE-I or ARBs. They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. TRUE They reduce BP (by reducing cardiac output) in a way that is unphysiologic for most patients. TRUE They do not reduce systolic BP as well as other agents. TRUE They do not reduce systolic BP as well as other agents. TRUE There are safer alternatives. BLOCKERS MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS. There are safer alternatives. BLOCKERS MAY BE SAFE, BUT THERE ARE NO HYPERTENSION TRIALS TO RELY ON WITH THESE AGENTS. Should ß-Blockers be Dropped as Initial Therapy for Hypertension?

Why they should NOT be dropped: They have been used successfully as initial therapy in trials since the 1970s. BUT SO HAVE OTHER CLASSES They have been used successfully as initial therapy in trials since the 1970s. BUT SO HAVE OTHER CLASSES Doctors are very familiar with how to use them. BUT THEY KNOW HOW TO USE OTHER CLASSES AS WELL Doctors are very familiar with how to use them. BUT THEY KNOW HOW TO USE OTHER CLASSES AS WELL They have important additional properties and indications. BUT SO DO OTHER CLASSES They have important additional properties and indications. BUT SO DO OTHER CLASSES They are widely available and generic. BUT SO ARE OTHER CLASSES They are widely available and generic. BUT SO ARE OTHER CLASSES Why they should NOT be dropped: They have been used successfully as initial therapy in trials since the 1970s. BUT SO HAVE OTHER CLASSES They have been used successfully as initial therapy in trials since the 1970s. BUT SO HAVE OTHER CLASSES Doctors are very familiar with how to use them. BUT THEY KNOW HOW TO USE OTHER CLASSES AS WELL Doctors are very familiar with how to use them. BUT THEY KNOW HOW TO USE OTHER CLASSES AS WELL They have important additional properties and indications. BUT SO DO OTHER CLASSES They have important additional properties and indications. BUT SO DO OTHER CLASSES They are widely available and generic. BUT SO ARE OTHER CLASSES They are widely available and generic. BUT SO ARE OTHER CLASSES So Should ß-Blockers be Dropped as Initial Therapy for Hypertension?

So Should -Blockers be Dropped as Initial Therapy for Hypertension? In my opinion: -BLOCKERS should be not be used for initial treatment unless the patient has a compelling or specific indication. -BLOCKERS should be not be used for initial treatment unless the patient has a compelling or specific indication. Diuretics, ACE-I/ARBs and CCBs should be considered as TIER 1 drugs and used before - BLOCKERS in other patients. Diuretics, ACE-I/ARBs and CCBs should be considered as TIER 1 drugs and used before - BLOCKERS in other patients. -BLOCKERS should be considered as a common additional agent to those patients resistant to properly selected TIER 1 agents. -BLOCKERS should be considered as a common additional agent to those patients resistant to properly selected TIER 1 agents. In my opinion: -BLOCKERS should be not be used for initial treatment unless the patient has a compelling or specific indication. -BLOCKERS should be not be used for initial treatment unless the patient has a compelling or specific indication. Diuretics, ACE-I/ARBs and CCBs should be considered as TIER 1 drugs and used before - BLOCKERS in other patients. Diuretics, ACE-I/ARBs and CCBs should be considered as TIER 1 drugs and used before - BLOCKERS in other patients. -BLOCKERS should be considered as a common additional agent to those patients resistant to properly selected TIER 1 agents. -BLOCKERS should be considered as a common additional agent to those patients resistant to properly selected TIER 1 agents.

Current Role of Vasodilatory 1 -Blockers for Hypertension Management L. Michael Prisant, MD, FACC Cardiologist Professor of Medicine Medical College of Georgia Augusta, Georgia L. Michael Prisant, MD, FACC Cardiologist Professor of Medicine Medical College of Georgia Augusta, Georgia Novel Mechanisms of Action, Hemodynamic Effects, Cardiometabolic Profiles, and Clinical Efficacy Across the Cardiovascular Risk Spectrum

The Heart in Hypertension Coronary Ischemia Heart Failure Atrial Fibrillation Diastolic Heart Failure Diastolic SystolicHeartFailureSystolicHeartFailure Ventricular Ectopy, Ventricular Fibrillation, Sudden Cardiac Death

-blockers: Compelling Indications -blockers: Compelling Indications Modified from Chobanian AV, et al. JAMA 2003;289: Diuretic -blocker -blocker ACE Inhibitor Angiotensin II Blocker Calcium Antagonists Aldosterone Antagonist Heart Failure Post Heart Attack High CAD Risk Diabetes Mellitus Chronic Renal Disease Recurrent Stroke New studies

-blocker History -blocker History First Generation Nonselective Propranolol Timolol Second Generation Selective Atenolol Metoprolol Bisoprolol Third Generation Vasodilatory Labetalol Carvedilol Nebivolol First Generation Nonselective Propranolol Timolol Second Generation Selective Atenolol Metoprolol Bisoprolol Third Generation Vasodilatory Labetalol Carvedilol Nebivolol

-blockers Approved in the United States -blockers Approved in the United States Source: Nadolol1979 Timolol1981 Labetalol1984Labetalol1984 Propranolol1967 Acebutolol1984Acebutolol1984 MetoprololTartrate1978 Sotalol1992 Bisoprolol1992 Carvedilol 1995 Carvedilol CR Betaxolol 1989 Penbutolol1987Penbutolol1987 Nebivolol2007Nebivolol2007 Propranolol XL 2003 Vasodilating -blockers are yellow Date of New Drug Application Approval LM Prisant 2008 Pindolol1982Pindolol1982 Propranolol LA Esmolol1986Esmolol1986 Carteolol1988Carteolol1988 Metoprolol Succinate 1992 Metoprolol Atenolol1981Atenolol1981

Effects Mediated by 1 - and 2 -adrenoceptors TissueReceptorEffect Heart SA node 1, 2 heart rate AV node 1, 2 conduction velocity Atria 1, 2 contractility Ventricles 1, 2 contractility, conduction velocity & automaticity of idioventricular pacemakers Arteries 2 Vasodilation Veins 2 Vasodilation Skeletal muscle 2 Vasodilation, contractility Glycogenolysis, K+ uptake Liver 2 Glycogenolysis and gluconeogenesis Pancreas ( cells) 2 Insulin and glucagon secretion Parathyroid glands 1, 2 Parathormone secretion Thyroid gland 2 T4T3 conversion Fat cells 1 Lipolysis Bronchi 2 Bronchodilation Kidney 1 Renin release Urinary bladder detrusor 2 Relaxation Gallbladder and ducts 2 Relaxation Gastrointestinal 2 Relaxation Uterus 2 Relaxation Nerve terminals 2 Promotes noradrenaline release López-Sendón J, et al. Eur Heart J 2004;25:

-blockers: Targets and Receptor Selectivity -blockers: Targets and Receptor Selectivity M2 M2 M2 M2 a1 a1 a1 a1 b2 b2 b2 b2 b2 b2 b2 b2 a2 a2 a2 a2 a2 a2 a2 a2 a2 a2 a2 a2 NE ACh Sympathetic Nerve Terminal _ NE NE + __ Heart Blood Vessel InotropyChronotropyDromotropy VasoconstrictionVasoconstrictionVasodilationVasodilation 1 -selective blocker 1 -selective blocker -nonselective blocker -nonselective blocker -nonselective blocker with 1 - blocking activity -nonselective blocker with 1 - blocking activity a =alpha receptor, Ach=acetylcholine, b =beta receptor, M=muscarinic receptor, NE=Norepinephrine M2M2M2M2 Klabunde RE (ed). Cardiovascular Physiology Concepts LWW 2001 Parasympathetic Nerve Terminal Sympathetic Cholinergic Nerve Terminal a1 a1 a1 a1 M2 M2 M2 M2 b2 b2 b2 b2 b1 b1 b1 b1 –

ß-blockers: Heterogenous Drug Class ß 1 / ß 2 Selectivity ß-blockers MetabolicProfileSideEffects VasodilatoryProperties OutcomesTrials -blockers -blockers Which One?

Why There is No Class Effect: Characteristics of -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 -receptors: Selectivity for the -receptors: Non-selective: Produce a competitive blockade of both 1 - and 2 - adrenergic receptors: Non-selective: Produce a competitive blockade of both 1 - and 2 - adrenergic receptors: 1.Carteolol 2.Nadolol 3.Penbutolol 4.Pindolol 5.Propranolol 6.Sotalol (not indicated for hypertension) 7.Timolol 1 -selective: higher affinity for the 1 - than for the 2 -receptors 1 -selective: higher affinity for the 1 - than for the 2 -receptors Selectivity for the -receptors: Selectivity for the -receptors: Non-selective: Produce a competitive blockade of both 1 - and 2 - adrenergic receptors: Non-selective: Produce a competitive blockade of both 1 - and 2 - adrenergic receptors: 1.Carteolol 2.Nadolol 3.Penbutolol 4.Pindolol 5.Propranolol 6.Sotalol (not indicated for hypertension) 7.Timolol 1 -selective: higher affinity for the 1 - than for the 2 -receptors 1 -selective: higher affinity for the 1 - than for the 2 -receptors -blocker Characteristics -blocker Characteristics Raynauds

1 -Selectivity 1 -Selectivity Brixius K, et al. Br J Pharmacol 2002;133:

-blocker Characteristics -blocker Characteristics 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.Elderly 2.Heart failure 3.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.Elderly 2.Heart failure 3.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 Elimination 100%50%0% 0%20%40%60%80%100% Liver Elimination PropranololMetoprololLabetalolBetaxololPenbutololCarvedilolNebivololTimololAcebutololPindololBisoprolol Diacetolol Diacetolol AtenololNadolol Sotalol * Carteolol Carteolol Adapted from Meier J. Cardiology 1979;64 (Suppl 1):1-13. Renal Elimination *Antiarrhythmic agent No longer available in US for hypertensionNo longer available in US for hypertension Metabolite of acebutololMetabolite of acebutolol

-blocker Characteristics -blocker Characteristics Partial Agonist Activity: Partial Agonist Activity: Also called intrinsic sympathomimetic activity (ISA)Also called intrinsic sympathomimetic activity (ISA) Stimulate and block the -receptorStimulate and block the -receptor Act as partial -agonists, but:Act as partial -agonists, but: 1.Still blocks the more significant agonist effects of endogenous catecholamines 2.Tends 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 intrinsic sympathomimetic activity (ISA)Also called intrinsic sympathomimetic activity (ISA) Stimulate and block the -receptorStimulate and block the -receptor Act as partial -agonists, but:Act as partial -agonists, but: 1.Still blocks the more significant agonist effects of endogenous catecholamines 2.Tends to slow the heart rate less Associated with more adverse cardiac eventsAssociated with more adverse cardiac events

Characteristics *Membrane Stabilizing Activity AntioxidantAntioxidant Nitric oxide-mediated vasodilationNitric oxide-mediated vasodilation ¶Class III antiarrhythmic No -blocker is cardioselective in large doses 2 -blockade is needed for tremor and migraines 2 -blockade is needed for tremor and migraines 1 -blockers are better for bronchospasm & insulin-requiring diabetes 1 -blockers are better for bronchospasm & insulin-requiring diabetes ISA- Nadolol Propranolol* Timolol Sotalol¶ ISA- Nadolol Propranolol* Timolol Sotalol¶ ISA+ Pindolol Carteolol Penbutolol ISA+ Pindolol Carteolol Penbutolol ISA- Atenolol Esmolol Metoprolol Nebivolol Bisoprolol Betaxolol* ISA- Atenolol Esmolol Metoprolol Nebivolol Bisoprolol Betaxolol* ISA+ Acebutolol* ISA+ Acebutolol* Nonselective Selective 1 -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 -blockers Percentage of Control Peripheral Resistance Arterial Pressure Cardiac Output Central Activity Renin Activity WeekYearMonthDay Man int Veld AJ, Schalekamp MADH. Br J Clin Pharmacol 1982;13(suppl 2):245S-257S.

-blockers: Long-Term Hemodynamic Effects -blockers: Long-Term Hemodynamic Effects Vascular Resistance (%) Cardiac Output (%) Timolol Man int Veld AJ, Schalekamp MADH. Br J Clin Pharmacol. 1982;13(suppl 2):245S-257S. Propranolol Metoprolol Atenolol Penbutolol Acebutolol Alprenolol Oxprenolol Practolol Pindolol Pretreatment Values

-blockers: Peripheral Vasodilating Activity -blockers: Peripheral Vasodilating Activity Several Mechanisms Bucindolol (not marketed because of BEST) Bucindolol (not marketed because of BEST) Produces vasodilatation by ? cGMP-dependent mechanism Produces vasodilatation by ? cGMP-dependent mechanism Carvedilol, labetalol: due to 1 -blockade Carvedilol, labetalol: due to 1 -blockade Celiprolol: due to 2 -adrenergic receptor agonism (not marketed in US, due to hepatic dysfunction) Celiprolol: due to 2 -adrenergic receptor agonism (not marketed in US, due to hepatic dysfunction) Nebivolol Nebivolol Lipophilic Lipophilic Racemic mixture Racemic mixture Nitric oxide (NO)-mediated vasodilator properties Nitric oxide (NO)-mediated vasodilator properties Bucindolol (not marketed because of BEST) Bucindolol (not marketed because of BEST) Produces vasodilatation by ? cGMP-dependent mechanism Produces vasodilatation by ? cGMP-dependent mechanism Carvedilol, labetalol: due to 1 -blockade Carvedilol, labetalol: due to 1 -blockade Celiprolol: due to 2 -adrenergic receptor agonism (not marketed in US, due to hepatic dysfunction) Celiprolol: due to 2 -adrenergic receptor agonism (not marketed in US, due to hepatic dysfunction) Nebivolol Nebivolol Lipophilic Lipophilic Racemic mixture Racemic mixture Nitric oxide (NO)-mediated vasodilator properties Nitric oxide (NO)-mediated vasodilator properties

Nebivolol: Ultraselective, Vasodilating 1 -blocker OH F HNHN O OF l-nebivolol d-nebivolol Vasorelaxant 1-blocker Racemic Mixture Prisant LM. J Clin Pharmacol 2008; 48:

Vascular Relaxation via the L-arginine–Nitric-Oxide Pathway Veverka A, et al. Am Pharmacother 2006;40: L-arginine Nitric oxide (diffuses into smooth muscle) EndothelialNOS Guanylyl Cyclase Activated Guanylyl Cyclase cGMP GTP Vascular Smooth Muscle Relaxation –

Nebivolol: Nitric Oxide Mediates Stimulation of Endothelium-Dependent Venodilation Bowman AJ, et al. Br J Clin Pharmacol 1994;38: Nebivolol Dose (mol min -1 ) Venodilation (%) Without NO Inhibitor With NO Inhibitor

Time (s) Calcium ionophore White African American + Nebivolol 300 mM 30 mM Release of Nitric Oxide from Human Endothelium: White vs Blacks Mason RP, et al. Circulation 2005;112: Nitric Oxide: NO Superoxide Anion: O 2 - Peroxynitrite: ONOO -

Hemodynamic Effects of Nebivolol and Atenolol in Hypertensive Patients* Left ventricular end-diastolic volume (mL) Left ventricular end­systolic volume (mL) Stroke volume (mL) Heart rate (beats/min) Cardiac output (L/min) Peripheral resistance (dyne/cm-5) Ejection fraction (%) Atenolol (100 mg/qd) Nebivolol (5 mg/qd) Kamp, et al. Am J Cardiol 2003;92:344 *At 2 weeks

Insulin Resistance Berne C, Pollare T, Lithell H. Diabetes Care 1991 (Suppl 4);39-47 Prisant LM, Carr AA. Am J Hypertens 1992; White WB, Prisant LM, Wright JT Am J Med 2000;108: Propranolol Metoprolol Atenolol Spironolactone Pindolol HCTZ Isradipine Verapamil Furosemide Diltiazem Captopril Prazosin Doxazosin Effects of 3–6 Months of Antihypertensive Monotherapy on Insulin Sensitivity Index % Change

Objective:Compare effects of -blockers with different pharmacologic properties on glycemic and metabolic control in patients with diabetes and hypertension receiving RAAS blockade Participants:1235 patients Treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or Metoprolol tartrate 50 mg to 200 mg bid (n = 737) Follow-up:35 weeks Objective:Compare effects of -blockers with different pharmacologic properties on glycemic and metabolic control in patients with diabetes and hypertension receiving RAAS blockade Participants:1235 patients Treatment: Carvedilol 6.25 mg to 25 mg bid (n = 498) or Metoprolol tartrate 50 mg to 200 mg bid (n = 737) Follow-up:35 weeks Glycemic Effects in diabetes Mellitus: carvedilol-metoprolol comparison IN hypertensives study Bakris GL, et al. JAMA 2004;292: GEMINI

GEMINI: Blood Pressure and Heart Rate Mean Systolic BPMean Diastolic BPMean Heart Rate (mm Hg)(mm Hg)(beats/minute) Carvedilol (n = 454) Metoprolol (n = 636) Bakris GL, et al. JAMA 2004;292: Treatment Difference (Carvedilol vs Metoprolol) (95% CI) (95% CI) P Value SBP, mm Hg 2 –1.0 (–2.60, –0.58) 0.21 DBP, mm Hg (–0.61, 1.20) 0.53 HR, beats/min (0.70, 2.58) < Baseline Month 5 Baseline Baseline

Metoprolol tartrate Metoprolol tartrateCarvedilol % (SD) P P HbA 1c 0.15 (0.04) < (0.04) 0.02 (0.04)0.65 Insulin sensitivity – – GEMINI: Change in HbA 1c and Insulin Sensitivity Endpoint (mean ) Bakris GL, et al. JAMA 2004;292:

Insulin Resistance p<0.01 Poirer L, et al. J Hypertens 2001;19: Insulin Sensitivity Index 36-week Randomized, Double-blind Crossover Design (n = 25)

Post Myocardial Infarction Diuretic -blocker -blocker ACE Inhibitor ARB Calcium Antagonist Aldosterone Antagonist Post-Myocardial Infarction

Myocardial Infarction: Is there a Class Effect for -blockers? Freemantle N, et al. BMJ 1999;318: Total Mortality Reduction after Myocardial Infarction AcebutololAcebutolol AlprenololAlprenolol AtenololAtenolol Carvedilol * MetoprololMetoprolol OxprenololOxprenolol PindololPindolol PractololPractolol PropranololPropranolol SotalolSotalol TimololTimolol XamoterolXamoterol |0|0|1|1|2|2|3|3|4|4|5|5|6|6 Odd Ratio of Death n = 54,234 *Meta-analysis did NOT include CAPRICORN Trial (Lancet 2001;357: ), which showed 23% in all- cause mortality (Hazard ratio = 0.77 [95% Confidence interval = ], p=0.03)

CAPRICORN Study Design Dargie HJ, et al. Eur J Heart Fail 2000;2: Placebo 6.25 mg BID Baseline 12.5 mg BID 3–10Days3–10Days633Events Visits Every 3–4 Months Carvedilol 25 mg BID Encouraged adjunctive therapy Encouraged adjunctive therapy Receiving ACE inhibitor 48 hrs Receiving ACE inhibitor 48 hrs Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarction Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarction Encouraged adjunctive therapy Encouraged adjunctive therapy Receiving ACE inhibitor 48 hrs Receiving ACE inhibitor 48 hrs Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarction Clinically stable, but may have had pulmonary edema or cardiogenic shock during index infarction

CAPRICORN: All-Cause Mortality The CAPRICORN Investigators. Lancet 2001;357: ,644 patients with LVEF<40% after a MI with or without HF randomized to carvedilol or placebo for 24 months 6,644 patients with LVEF<40% after a MI with or without HF randomized to carvedilol or placebo for 24 months Carvedilol Placebo Years Proportion Event-free n=975 n=984 Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) HR = 0.77 ( ) p = 0.031

Expansion of Infarct Hours to Days Initial Infarct Ventricular Remodeling After Myocardial Infarction Jessup M, Brozena S. N Engl J Med 2003;348:2007: Global Remodeling Days to Months

Heart Failure Diuretic -blocker -blocker ACE Inhibitor ARB Calcium Antagonist Aldosterone Antagonist Heart Failure

Heart Failure: Is There Class Effect for -blockers? MERIT-HF. Lancet 1999;353: ; CIBIS-II. Lancet 1999;353:9-13; Packer M, et al. N Engl J Med 2001;344: ; BEST. N Engl J Med 2001;344: Relative risk and 95% confidence intervals AnnualMortalityAnnualMortality BEST (n=2708) Placebo17.0% Bucindolol15.0% CIBIS-II (n=2647) Placebo13.2% Bisoprolol8.8% MERIT-HF (n=3991) Placebo11.0% Metoprolol succinate7.2% COPERNICUS (n=2289) Placebo18.5% Carvedilol11.4% BEST (n=2708) Placebo17.0% Bucindolol15.0% CIBIS-II (n=2647) Placebo13.2% Bisoprolol8.8% MERIT-HF (n=3991) Placebo11.0% Metoprolol succinate7.2% COPERNICUS (n=2289) Placebo18.5% Carvedilol11.4% MeanRiskP Follow-up ReductionValue MeanRiskP Follow-up ReductionValue 10.4 mo35%p = mo34%p = mo34%p = mo10%p =. 10

SENIORS Study HR 0.86 (0.74–0.99) P = Time (months) All-cause Mortality or CV Hospital Admission (Primary Outcome) Nebivolol Time (months) All-cause Mortality (Main Secondary Outcome) HR 0.88 (0.71–1.08) P = Placebo Event- free survival (%) Nebivolol Placebo Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure Flather MD, et al. Eur Heart J 2005; 26: patients 70 years heart failure history (admission < 1 year or known EF 35%) to nebivolol, titrated to 10 mg QD, or placebo Median 21 months

2005 ACC/AHA Heart Failure Guidelines Within drug classes, agents may differ pharmacologically Within drug classes, agents may differ pharmacologically These pharmacological differences may translate into differences in clinical outcomes These pharmacological differences may translate into differences in clinical outcomes When multiple agents within a class produce discordant results on clinical outcomes, class effect cannot be presumed (eg, -blockers) When multiple agents within a class produce discordant results on clinical outcomes, class effect cannot be presumed (eg, -blockers) Use of 1 of the 3 β-blockers proven to reduce mortality (ie, bisoprolol, carvedilol, and metoprolol succinate) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated IIIaIIbIII Hunt SA, et al. Circulation 2005;112:1825–1852.

Other FDA Indications of Available Oral -blockers for Hypertension LV MIDysfunctionHeartAtrialVentricular DrugHTNAnginaProphylaxisPost-MIFailureFibrillationArrhythmias Acebutolol Acebutolol Atenolol * Betaxolol Betaxolol Bisoprolol Bisoprolol Carvedilol Carvedilol Carvedilol CR Carvedilol CR Labetalol Labetalol Metoprolol tartrate Metoprolol tartrate Metoprolol succinate Metoprolol succinate Nadolol Nadolol Nebivolol Nebivolol Penbutolol Penbutolol Pindolol Pindolol Propranolol §, ¶ Propranolol §, ¶ Propranolol LA §, ¶ Propranolol LA §, ¶ Propranolol XL Propranolol XL Timolol ¶ Timolol ¶ LV MIDysfunctionHeartAtrialVentricular DrugHTNAnginaProphylaxisPost-MIFailureFibrillationArrhythmias Acebutolol Acebutolol Atenolol * Betaxolol Betaxolol Bisoprolol Bisoprolol Carvedilol Carvedilol Carvedilol CR Carvedilol CR Labetalol Labetalol Metoprolol tartrate Metoprolol tartrate Metoprolol succinate Metoprolol succinate Nadolol Nadolol Nebivolol Nebivolol Penbutolol Penbutolol Pindolol Pindolol Propranolol §, ¶ Propranolol §, ¶ Propranolol LA §, ¶ Propranolol LA §, ¶ Propranolol XL Propranolol XL Timolol ¶ Timolol ¶ * Acute MI only (0-7 days) Acute MI and for up to 3 months Acute MI and for up to 3 months Stable survivors of acute MI to reduce CV mortality Stable survivors of acute MI to reduce CV mortality § Hypertrophic subaortic stenosis, essential tremor ¶ Migraine prophylaxis FDA indication FDA indication Trial data support an indication Trial data support an indication Intravenous formulation available

Summary -blockers are a diverse class of drugs -blockers are a diverse class of drugs They differ in their indications and their effectiveness for various disorders They differ in their indications and their effectiveness for various disorders Selective, vasodilatory -blockers are: Selective, vasodilatory -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 various disorders They differ in their indications and their effectiveness for various disorders Selective, vasodilatory -blockers are: Selective, vasodilatory -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 Beta Blockade in Special Populations Kenneth A. Jamerson, MD Professor of Internal Medicine, Medical School University of Michigan Medical Director, Program of Multi-Cultural Health University of Michigan Ann Arbor, MI Kenneth A. Jamerson, MD Professor of Internal Medicine, Medical School University of Michigan Medical Director, Program of Multi-Cultural Health University of Michigan Ann Arbor, MI Primary Care Summit In Cardiovascular Medicine

Key Points of this Presentation Most hypertensive patients who are receiving treatment may not be optimally controlled Most hypertensive patients who are receiving treatment may not be optimally controlled To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. High Risk Sub-groups deserve special consideration High Risk Sub-groups deserve special consideration Most hypertensive patients who are receiving treatment may not be optimally controlled Most hypertensive patients who are receiving treatment may not be optimally controlled To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. High Risk Sub-groups deserve special consideration High Risk Sub-groups deserve special consideration

Obesity Trends* Among US Adults (*BMI 30 kg/m 2, or about 30 lb overweight for 5 4 person) % to 19% 10%-14%<10%20%-24% No data 25% 25% Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System. Available at: ppt#1. Accessed May 31, 2006 BRFSS: 1996 and 2004

The Problem

Adding Fat Inflames the Fat: Adipose Tissue Angiotensin Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112: Angiotensinogen ACE

Ventricular Remodeling Vascular Remodeling Energetic Failure Neurohormonal Activation Across the CV Spectrum RAAS=renin angiotensin-aldosterone system; SNS=sympathetic nervous system Diabetes and Hypertension Post-MI LV Dysfunction End-Stage Cardiomyopathy RAAS + SNS

The Tecumseh Blood Pressure Study A prospective epidemiological study of the antecedents of hypertension and cardiovascular disease in 1,100 young men and women Ann Arbor Tecumseh

Hematocrit Cholesterol Overweight Heart Rate Insulin Triglycerides DBP N=124 (aged years) Adapted from Julius et al. JAMA 1990;264: P<0.001P<0.01P<0.05 Tecumseh BP Study: Association of DBP and Other CHD Risk Factors

S. Julius, et al: JAMA 264: , 1990 Blood Pressure Trends in Tecumseh, MI HypertensiveNormotensive * * * * ** * P<.01 ** P<.001 * Hypertensive and Normotensive at 31 Years of Age Blood Pressure mmHg

Insulin Resistance Syndrome Insulinresistance Inherited genetic defect Obesity Excessive caloric intake NDDM Hyperinsulinemia Hypertension Atherosclerosis HypertriglyceridemiaHypercholesterolemia Decreased HDL-C Diabetes Care 1991;14:

Thigh Cuff Inflation to Elicit a Physiologic Increase in Sympathetic Tone Inflate Thigh Cuffs Decrease Venous Return Cardio- Pulmonary Receptors Decrease Right Atrial Pressure Forearm Vasoconstriction Decrease Forearm Blood Flow Vasomotor Center Increased Sympathetic Outflow - - +

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

The Effects of Pressers on Glucose Metabolism in Skeletal Muscle NOR EPI PROP+NOR EPI

Sympathetic Nerve Activity in Patients With HTN, Diabetes, or Both Sympathetic nerve activity is significantly higher in: Sympathetic nerve activity is significantly higher in: Patients with essential HTN compared with normotensive patients (P<.01) Patients with essential HTN compared with normotensive patients (P<.01) Patients with diabetes compared with normotensive patients (P<.001) Patients with diabetes compared with normotensive patients (P<.001) Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes (P<.001) Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes (P<.001) Sympathetic nerve activity is significantly higher in: Sympathetic nerve activity is significantly higher in: Patients with essential HTN compared with normotensive patients (P<.01) Patients with essential HTN compared with normotensive patients (P<.01) Patients with diabetes compared with normotensive patients (P<.001) Patients with diabetes compared with normotensive patients (P<.001) Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes (P<.001) Sympathetic nerve activity is higher in patients with both type 2 diabetes and essential HTN compared with patients with either essential HTN or type 2 diabetes (P<.001) Huggett RJ. Circulation. 2003;108: Data derived from 68 closely matched subjects with n=17 for all groups compared

Effect of -Blockers on Insulin Sensitivity in Hypertensive Patients Propranolol Metoprolol Atenolol Pindolol Dilevalol Carvedilol Celiprolol % Change Above Baseline Jacob S et al. Am J Hypertens. 1998;11:

The Pathobiology of Obesity: A Syndrome of Risk Factors for CVD Myocardial Infarction Infarction Stroke HeartFailure Atherosclerosis Obesity Hypertension Dyslipidemia ClinicalDiabetes

Gibbons 2004 Obesity-Related Cardiovascular Disease: Pro-Inflammatory Adipokines as Mediators Adiponectin O2-O2-IL-6TNF-αCRP Ang II Oxidative Stress InflammationHypertension Obesity Atherosclerosis Diabetes Endothelial DysfunctionInsulin Resistance

The Problem

Does Being African American Modify the Problem?

International Society of Hypertension in Blacks IMPACT Campaign Science Guidelines Behavioral Change

Race is a crude proxy. DISEASE Individual -biology -genotype Environment - diet, lifestyle - SES, exposures Race is a crude proxy. DISEASE Individual -biology -genotype Environment - diet, lifestyle - SES, exposures DISEASE Individual -biology -genotype Environment - diet, lifestyle - SES, exposures

Models to Explain Health Disparities Racial Genetic Model Racial Genetic Model Cause of HD: population differences in the distribution of genetic variants Cause of HD: population differences in the distribution of genetic variants Health-behavior Model Health-behavior Model Cause of HD: differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco useCause of HD: differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco use SES Model SES Model Cause of HD: over-representation of some R/E groups within lower SES Cause of HD: over-representation of some R/E groups within lower SES Psychosocial Stress Model Psychosocial Stress Model Cause of HD: stresses associated with minority group status, especially the experience of racism and discrimination Cause of HD: stresses associated with minority group status, especially the experience of racism and discrimination Racial Genetic Model Racial Genetic Model Cause of HD: population differences in the distribution of genetic variants Cause of HD: population differences in the distribution of genetic variants Health-behavior Model Health-behavior Model Cause of HD: differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco useCause of HD: differences between R/E groups in the distribution of individual behaviors related to health such as diet, exercise, and tobacco use SES Model SES Model Cause of HD: over-representation of some R/E groups within lower SES Cause of HD: over-representation of some R/E groups within lower SES Psychosocial Stress Model Psychosocial Stress Model Cause of HD: stresses associated with minority group status, especially the experience of racism and discrimination Cause of HD: stresses associated with minority group status, especially the experience of racism and discrimination

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

Plot of Individual Ancestry Estimates Using STRUCTURE on 112 AIMs Bamileke (Cameroon) European Americans (MD) African Americans (DC) (23.2% European ancestry) (23.2% European ancestry) Falush et al. 2003

Ancestry can be Estimated Across Chromosomal Regions. Seldin et al. Genome Res. 14: , 2004 Smith et al. AJHG 74: , 2004

European Genetic Contribution in African-American Populations 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 Driven this Modular Evolution. Optimal phenotype for traditional diet/ lifestyle Thrifty-genotype hypothesis.. Fat storage?IGF and LPL related genes Fat storage?IGF and LPL related genes Salt sensitivity?CYP3A, ICAM gene clusters Salt sensitivity?CYP3A, ICAM gene clusters Higher testosterone?CYP3A, AR, SRD5AR, CYP17 Higher testosterone?CYP3A, AR, SRD5AR, CYP17 Darker skin color?Vitamin D related genes Darker skin color?Vitamin D related genes Optimal phenotype for traditional diet/ lifestyle Thrifty-genotype hypothesis.. Fat storage?IGF and LPL related genes Fat storage?IGF and LPL related genes Salt sensitivity?CYP3A, ICAM gene clusters Salt sensitivity?CYP3A, ICAM gene clusters Higher testosterone?CYP3A, AR, SRD5AR, CYP17 Higher testosterone?CYP3A, AR, SRD5AR, CYP17 Darker skin color?Vitamin D related genes Darker skin color?Vitamin D related genes

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

Obesity in Normotensive African-American Women Inflammation and Oxidative Stress CRP Biomarker Profile of Obesity Pemu, Ofili Gibbons Isoprostanes Isoprostanes Lean Obese Adiponectin

The Role of 1 Cardioselective Beta Blockers for Management of Hypertension and Related Cardiovascular Conditions

2006 AACE Hypertension Guidelines ß-blocker use recommended as 2 nd or 3 rd line in hypertension ß-blocker use recommended as 2 nd or 3 rd line in hypertension Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation ß- blockers (such as nebivolol) or drugs that block both α and ß receptors (such as carvedilol) may prove to be particularly beneficial. These agents cause vasodilatation and an increase in insulin sensitivity. ß-blocker use recommended as 2 nd or 3 rd line in hypertension ß-blocker use recommended as 2 nd or 3 rd line in hypertension Because the major adverse effects of BBs may be mediated by peripheral vasoconstriction and increasing insulin resistance, the use of the new third-generation ß- blockers (such as nebivolol) or drugs that block both α and ß receptors (such as carvedilol) may prove to be particularly beneficial. These agents cause vasodilatation and an increase in insulin sensitivity. AACE Hypertension Task Force. Endocr Pract. 2006;12:

The Evolution of ß-Blockers 1960s1970s1980s-1990s2007 Non-SelectiveNon-Selective Vasodilating Vasodilating Non-Selective Non-Selective Selective Propranolol Atenolol Metroprolol Carvedilol Labetalol Nebivolol

Nebivolol: Mechanism of Action Nebivolol Selective ß 1 -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 < 10 mg., nebivolol is preferentially ß 1 selective. Decreased peripheral vascular resistance.Decreased peripheral vascular resistance. Nebivolol package insert. New York, NY. Forest Laboratoies, Inc.; 2007.

Nebivolol Reduces Peripheral Vascular Resistance in Patients with Hypertension Percent change vs baseline Peripheral resistance (dyne/cm5) Stroke volume (mL) Cardiac output (L/min) * * *N=25; parameters at 2 weeks At 2 weeks; *P<0.05 vs pretreatment. Change in SBP/DBP was -19/12 mm Hg for nebivolol Adapted from Kamp O et al. Am J Cardiol. 2003;92: Heart rate (bpm) Beats per minute

Nebivolol Enhances Vasodilation in Hypertensive Patients Nebivolol

Time (s) Calcium ionophore White African American + Nebivolol 300 mM30 mM NO O2-O2- ONOO - Release of Nitric Oxide from Human Endothelium: White and African Americans Mason RP et al. Circulation 2005;112:

ß 1 selectivity Human Myocardium Bucindolol Carvedilol Metoprolol Bisoprolol Nebivolol ß 1 Selectivity = K 1 (ß 2 )/K 1 (ß 1 ). In extensive metabolizers and at doses less than or equal to 10 mg, nebivolol is preferentially ß 1 selective. Brixius K et al. Br J Pharmacol. 2001;133: Nebivolol: ß 1 Receptor Selectivity

Nebivolol and Metoprolol: Effect on BP at 3 Months Mean Δ vs baseline (mm Hg) * * * * N Baseline BP (mmHg) DBP SBP *P<0.05 vs. baseline BP = sitting blood pressure; DBP=sitting diastolic blood pressure; SBP=sitting systolic blood pressure Uhlir O et al. Drug Invest 1991;3(auppl 1):

Mean Δ in BP vs baseline (mm Hg) N Baseline DBP (mm Hg) Baseline SBP (mm Hg) Saunders E et al. J Clin Hypertens. 2007;9: Placebo DBP Placebo SBP DosePlacebo5 mg10 mg20 mg Efficacy of Nebivolol in Black Patients: Diastolic and Systolic BP

Mean Δ in BP vs baseline (mm Hg) N Baseline DBP (mm Hg) Baseline SBP (mm Hg) Obesity defined as body mass index >30 kg/m 2. Data on file, Forest Laboratories, Inc. New York, NY Placebo DBP Placebo SBP DosePlacebo5 mg10 mg20 mg Efficacy of Nebivolol in Obese* Patients: Diastolic and Systolic BP

Incidence Rate (%) Discontinuation Rate (%) Adverse Event (%) Placebo (n=205) Nebivolol 5mg-40mg (n=1597) Placebo (n=205) Nebivolol 5mg-40mg (n=1597) Fatigue Dyspnea Bradycardia Erectile Dysfunction Erectile Dysfunction Depression Nebivolol Profile with Respect to Side Effects Commonly Associated with ß-Blockers* *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 mg Registration trials. Data on file, Forest Laboratories, Inc. New York, NY

Insulin Resistance: Effect of Nebivolol vs. Atenolol p<0.01 Insulin Sensitivity Index 36-week Randomized, Double-blind Crossover Design n = 25 Poirer L, et al. J Hypertens 2001;19:

Baseline Month 6 Nebivolol 5 mg (n=37) Baseline Month 6 Metoprolol 100 mg (n=35) P=0.008 P=0.003 P=NS Effect of Nebivolol and Metoprolol on Insulin Resistance Mean insulin resistance by HOMA (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 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. Celik T et al. J Hypertens 2006;24:

Mean Δ from baseline (mg/dL) Placebo(n=196) Nebivolol 5 mg (n=432) 10 mg (n=435) 20 mg (n=438) Nebivolol: Effect on Glucose Levels Pooled 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 hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. Data on file, Forest Laboratories, New York, NY

mg/dL LDL (mean) HDL (mean) Triglycerides(median) Nebivolol: Effect on Lipid Levels Pooled Analysis of the Three Monotherapy US Registration Trials 1.Registration trials. Data on file, Forest Laboratories, Inc. New York, NY 2.Nebivolol package insert. New York, NY. Forest Laboratories, Inc; 2007

Laboratory Parameters In controlled monotherapy trials, nebivolol was associated with: In controlled monotherapy trials, nebivolol was associated with: - An increase in BUN, uric acid, and triglycerides - 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 hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy. Data on file, Forest Laboratories, New York, NY

Effect of Nebivolol and Metroprolol on Sexual Function: IIEF Nebivolol 5 mg Metoprolol succinate 95 mg

Hazard Ratio Plots for Total Mortality for Comparable Patient Subgroups Nebivolol. Marit D. Moen and Antona J. Wagstaff. Drugs 2006;66(10):1389–1409 NebivololCarvedilolMetoprololBisoprololNebivololCarvedilolMetoprololBisoprolol ß-Blocker Trials Hazard Ratio Hazard Ratio

Conclusions Beta blockers are not all created equally Beta blockers are not all created equally Third generation, cardioselective beta blockers may produce clinical outcomes that differ from traditional beta-blockers Third generation, cardioselective beta blockers may produce clinical outcomes that differ from traditional beta-blockers Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta- blocker use Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta- blocker use Beta blockers are not all created equally Beta blockers are not all created equally Third generation, cardioselective beta blockers may produce clinical outcomes that differ from traditional beta-blockers Third generation, cardioselective beta blockers may produce clinical outcomes that differ from traditional beta-blockers Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta- blocker use Ongoing trials will help differentiate indications, clinical roles, and optimal strategies for beta- blocker use

Case StudiesApplying Landmark Trials to Real World Management Primary Care Summit In Cardiovascular Medicine Program Moderator And Faculty Panel Members Program Moderator And Faculty Panel Members

Case 1

Patient Profile Presentation 58-year-old African American social worker with 20- year history of hypertension and 2-year history of type 2 diabetes 58-year-old African American social worker with 20- year history of hypertension and 2-year history of type 2 diabetes Presents with headaches and swelling of lower legs Presents with headaches and swelling of lower legs Denies chest pain, although has shortness of breath with exertion Denies chest pain, although has shortness of breath with exertion Problem with obesity since early teens: weight currently fluctuates between lbs. Problem with obesity since early teens: weight currently fluctuates between lbs. - Weight increased 20 lbs. in last six months - Admits no effort to exercise or restrict dietary salt Presentation 58-year-old African American social worker with 20- year history of hypertension and 2-year history of type 2 diabetes 58-year-old African American social worker with 20- year history of hypertension and 2-year history of type 2 diabetes Presents with headaches and swelling of lower legs Presents with headaches and swelling of lower legs Denies chest pain, although has shortness of breath with exertion Denies chest pain, although has shortness of breath with exertion Problem with obesity since early teens: weight currently fluctuates between lbs. Problem with obesity since early teens: weight currently fluctuates between lbs. - Weight increased 20 lbs. in last six months - Admits no effort to exercise or restrict dietary salt

Patient Profile Medical/Treatment History Previously treated with several antihypertensive medications Previously treated with several antihypertensive medications Discontinued use due to side effects and/or cost Discontinued use due to side effects and/or cost Current medications; rosigiltazone and metformin Current medications; rosigiltazone and metformin Only prior surgery was cholecystectomy Only prior surgery was cholecystectomy Family History Diabetes, hypertension and obesity Diabetes, hypertension and obesity Both parents died of stroke in their 60s Both parents died of stroke in their 60s Social History Nonsmoker; does not drink alcohol Nonsmoker; does not drink alcohol Medical/Treatment History Previously treated with several antihypertensive medications Previously treated with several antihypertensive medications Discontinued use due to side effects and/or cost Discontinued use due to side effects and/or cost Current medications; rosigiltazone and metformin Current medications; rosigiltazone and metformin Only prior surgery was cholecystectomy Only prior surgery was cholecystectomy Family History Diabetes, hypertension and obesity Diabetes, hypertension and obesity Both parents died of stroke in their 60s Both parents died of stroke in their 60s Social History Nonsmoker; does not drink alcohol Nonsmoker; does not drink alcohol

Physical Examination Height: 54 Height: 54 Weight: 262 lbs Weight: 262 lbs BMI: 45.0 BMI: 45.0 BP: 166/106 mmHg BP: 166/106 mmHg Pulse: 88 bpm Pulse: 88 bpm Normocephalic and without injury Normocephalic and without injury Extrocular movements full; pupils equal and reactive to light Extrocular movements full; pupils equal and reactive to light Pharynx benign, neck supple, lungs clear Pharynx benign, neck supple, lungs clear Funduscopy reveals arteriolar narrowing and atrioventricular nicking Funduscopy reveals arteriolar narrowing and atrioventricular nicking Height: 54 Height: 54 Weight: 262 lbs Weight: 262 lbs BMI: 45.0 BMI: 45.0 BP: 166/106 mmHg BP: 166/106 mmHg Pulse: 88 bpm Pulse: 88 bpm Normocephalic and without injury Normocephalic and without injury Extrocular movements full; pupils equal and reactive to light Extrocular movements full; pupils equal and reactive to light Pharynx benign, neck supple, lungs clear Pharynx benign, neck supple, lungs clear Funduscopy reveals arteriolar narrowing and atrioventricular nicking Funduscopy reveals arteriolar narrowing and atrioventricular nicking

Physical Examination Cardiac Examination Resting tachycardia with S4 gallop and systolic murmur best heard at left sternal border Resting tachycardia with S4 gallop and systolic murmur best heard at left sternal border Normoactive bowel sounds Normoactive bowel sounds Extremities reveal 2+ pedal edema Extremities reveal 2+ pedal edema Diminished lower extremity pulses Diminished lower extremity pulses 2-second capillary refill in fingers and toes 2-second capillary refill in fingers and toes Electrocardiogram: normal sinus rhythm, left axis deviation, voltage criteria for LVH, nonspecific ST-T wave changes Electrocardiogram: normal sinus rhythm, left axis deviation, voltage criteria for LVH, nonspecific ST-T wave changes Chest film shows enlarged cardiac silhouette Chest film shows enlarged cardiac silhouette Cardiac Examination Resting tachycardia with S4 gallop and systolic murmur best heard at left sternal border Resting tachycardia with S4 gallop and systolic murmur best heard at left sternal border Normoactive bowel sounds Normoactive bowel sounds Extremities reveal 2+ pedal edema Extremities reveal 2+ pedal edema Diminished lower extremity pulses Diminished lower extremity pulses 2-second capillary refill in fingers and toes 2-second capillary refill in fingers and toes Electrocardiogram: normal sinus rhythm, left axis deviation, voltage criteria for LVH, nonspecific ST-T wave changes Electrocardiogram: normal sinus rhythm, left axis deviation, voltage criteria for LVH, nonspecific ST-T wave changes Chest film shows enlarged cardiac silhouette Chest film shows enlarged cardiac silhouette

Physical Examination Laboratory Findings BUN: 28 mg/dL BUN: 28 mg/dL Creatinine: 1.3 mg/dL Creatinine: 1.3 mg/dL Total cholesterol: 283 mg/dL Total cholesterol: 283 mg/dL HDL: 24 mg/dL HDL: 24 mg/dL LDL: 204 mg/dL LDL: 204 mg/dL Hemoglobin A1C = 7.0 Hemoglobin A1C = 7.0 Fasting glucose: 115 mg/dL Fasting glucose: 115 mg/dL Urinalysis Urinalysis - Specific gravity: Protein: >1 mg/dL - Rare red blood cells - Rare bacteria Laboratory Findings BUN: 28 mg/dL BUN: 28 mg/dL Creatinine: 1.3 mg/dL Creatinine: 1.3 mg/dL Total cholesterol: 283 mg/dL Total cholesterol: 283 mg/dL HDL: 24 mg/dL HDL: 24 mg/dL LDL: 204 mg/dL LDL: 204 mg/dL Hemoglobin A1C = 7.0 Hemoglobin A1C = 7.0 Fasting glucose: 115 mg/dL Fasting glucose: 115 mg/dL Urinalysis Urinalysis - Specific gravity: Protein: >1 mg/dL - Rare red blood cells - Rare bacteria

Discussion What should be the target BP for this patient? A: <140/<90 mmHg B: <135/<85 mmHg C: <130/<80 mmHg D: <120/<70 mmHg What should be the target BP for this patient? A: <140/<90 mmHg B: <135/<85 mmHg C: <130/<80 mmHg D: <120/<70 mmHg

Discussion What factors would you consider when selecting an appropriate therapy? A: Underlying pathophysiology of hypertension B: Concomitant medical conditions, including diabetes and edema C: Adherence issues D: Baseline risk for CVD What factors would you consider when selecting an appropriate therapy? A: Underlying pathophysiology of hypertension B: Concomitant medical conditions, including diabetes and edema C: Adherence issues D: Baseline risk for CVD

Discussion Would a ß-blocker be appropriate for this patient? A: Yes B: No Would a ß-blocker be appropriate for this patient? A: Yes B: No

Discussion What is an optimal strategy for controlling blood pressure? A: Diuretic + ACE inhibitor B: Diuretic + ARB C: Diuretic + ß-blocker D: Diuretic + calcium-channel blocker What is an optimal strategy for controlling blood pressure? A: Diuretic + ACE inhibitor B: Diuretic + ARB C: Diuretic + ß-blocker D: Diuretic + calcium-channel blocker

Case 2

Patient Profile 76-year-old retired Caucasian male with 20-year history of hypertension 76-year-old retired Caucasian male with 20-year history of hypertension Previously treated with diuretics and calcium channel blockers Previously treated with diuretics and calcium channel blockers Admitted noncompliance with medication Admitted noncompliance with medication - Believes BP normal increases with age; drugs cause intolerable side effects Attempted to control BP with proper nutrition and regular exercise Attempted to control BP with proper nutrition and regular exercise - 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: mmHg - Distolic pressure: mmHg Denies headache, chest pain, shortness of breath, claudification, or leg swelling Denies headache, chest pain, shortness of breath, claudification, or leg swelling 76-year-old retired Caucasian male with 20-year history of hypertension 76-year-old retired Caucasian male with 20-year history of hypertension Previously treated with diuretics and calcium channel blockers Previously treated with diuretics and calcium channel blockers Admitted noncompliance with medication Admitted noncompliance with medication - Believes BP normal increases with age; drugs cause intolerable side effects Attempted to control BP with proper nutrition and regular exercise Attempted to control BP with proper nutrition and regular exercise - 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: mmHg - Distolic pressure: mmHg Denies headache, chest pain, shortness of breath, claudification, or leg swelling Denies headache, chest pain, shortness of breath, claudification, or leg swelling

Patient Profile Medical/Treatment History Macular degeneration in both eyes Macular degeneration in both eyes No current medications or known drug allergies No current medications or known drug allergies No prior surgery No prior surgery Family History Unremarkable Unremarkable Social History Smoked cigarettes for 40 years; stopped 15 years ago Smoked cigarettes for 40 years; stopped 15 years ago Does not drink alcohol Does not drink alcohol Medical/Treatment History Macular degeneration in both eyes Macular degeneration in both eyes No current medications or known drug allergies No current medications or known drug allergies No prior surgery No prior surgery Family History Unremarkable Unremarkable Social History Smoked cigarettes for 40 years; stopped 15 years ago Smoked cigarettes for 40 years; stopped 15 years ago Does not drink alcohol Does not drink alcohol

Physical Examination Height: 510 Height: 510 Weight: 166 lbs Weight: 166 lbs BMI: 23.6 BMI: 23.6 BP: 182/80 mmHg BP: 182/80 mmHg Pulse 74 bpm Pulse 74 bpm Funduscopy reveals bilateral macular degeneration, copper wiring, and arteriorventricular nicking Funduscopy reveals bilateral macular degeneration, copper wiring, and arteriorventricular nicking - No hemorrhages or exudates Neck shows 2+ carotid pulses with systolic heart sounds, which could be transmitted aortic plow murmur Neck shows 2+ carotid pulses with systolic heart sounds, which could be transmitted aortic plow murmur Height: 510 Height: 510 Weight: 166 lbs Weight: 166 lbs BMI: 23.6 BMI: 23.6 BP: 182/80 mmHg BP: 182/80 mmHg Pulse 74 bpm Pulse 74 bpm Funduscopy reveals bilateral macular degeneration, copper wiring, and arteriorventricular nicking Funduscopy reveals bilateral macular degeneration, copper wiring, and arteriorventricular nicking - No hemorrhages or exudates Neck shows 2+ carotid pulses with systolic heart sounds, which could be transmitted aortic plow murmur Neck shows 2+ carotid pulses with systolic heart sounds, which could be transmitted aortic plow murmur

Patient Profile Cardiac Examination Regular rate and rhythm, with harsh systolic murmur grade 2/6 Regular rate and rhythm, with harsh systolic murmur grade 2/6 Point of maximal intensity nondisplaced Point of maximal intensity nondisplaced Lungs clear Lungs clear Abdomen without scars, masses, tenderness, or organomegaly Abdomen without scars, masses, tenderness, or organomegaly No abnormal bruits and 2+ femoral pulses No abnormal bruits and 2+ femoral pulses Neurologic exam is grossly intact, without focal deficits or pathologic reflexes Neurologic exam is grossly intact, without focal deficits or pathologic reflexes Extremities show no peripheral edema or joint deformities Extremities show no peripheral edema or joint deformities 1+ peripheral pulses with 2-second capillary refill in fingers and toes 1+ peripheral pulses with 2-second capillary refill in fingers and toes Echocardiogram shows normal sinus rhythm with mild left centricular hypertrophy by voltage Echocardiogram shows normal sinus rhythm with mild left centricular hypertrophy by voltage Cardiac Examination Regular rate and rhythm, with harsh systolic murmur grade 2/6 Regular rate and rhythm, with harsh systolic murmur grade 2/6 Point of maximal intensity nondisplaced Point of maximal intensity nondisplaced Lungs clear Lungs clear Abdomen without scars, masses, tenderness, or organomegaly Abdomen without scars, masses, tenderness, or organomegaly No abnormal bruits and 2+ femoral pulses No abnormal bruits and 2+ femoral pulses Neurologic exam is grossly intact, without focal deficits or pathologic reflexes Neurologic exam is grossly intact, without focal deficits or pathologic reflexes Extremities show no peripheral edema or joint deformities Extremities show no peripheral edema or joint deformities 1+ peripheral pulses with 2-second capillary refill in fingers and toes 1+ peripheral pulses with 2-second capillary refill in fingers and toes Echocardiogram shows normal sinus rhythm with mild left centricular hypertrophy by voltage Echocardiogram shows normal sinus rhythm with mild left centricular hypertrophy by voltage

Physical Examination Laboratory Findings BUN: 18 mg/dL BUN: 18 mg/dL Creatinine: 1.4 mg/dL Creatinine: 1.4 mg/dL Total cholesterol: 192 mg/dL Total cholesterol: 192 mg/dL HDL: 44 mg/dL HDL: 44 mg/dL LDL: 120 mg/dL LDL: 120 mg/dL Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no bacteria Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no bacteria Laboratory Findings BUN: 18 mg/dL BUN: 18 mg/dL Creatinine: 1.4 mg/dL Creatinine: 1.4 mg/dL Total cholesterol: 192 mg/dL Total cholesterol: 192 mg/dL HDL: 44 mg/dL HDL: 44 mg/dL LDL: 120 mg/dL LDL: 120 mg/dL Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no bacteria Urinalysis: no protein, 1-2 WBC, 1-2 RBC, and no bacteria

Discussion What should be the target BP for this patient? A: <140/<90 mmHg B: <135/<85 mmHg C: <130/<80 mmHg D: <120/<70 mmHg What should be the target BP for this patient? A: <140/<90 mmHg B: <135/<85 mmHg C: <130/<80 mmHg D: <120/<70 mmHg

Discussion What factors would you consider when selecting an appropriate therapy? A: Age of patient B: Impact of therapy on cognitive function C: Impact of therapy on heart rate D: Impact of therapy of orthostatic hypotension E: Vasodilatory properties of the agent What factors would you consider when selecting an appropriate therapy? A: Age of patient B: Impact of therapy on cognitive function C: Impact of therapy on heart rate D: Impact of therapy of orthostatic hypotension E: Vasodilatory properties of the agent

Discussion Would a ß-blocker be appropriate for this patient? A: Yes B: No Would a ß-blocker be appropriate for this patient? A: Yes B: No

Discussion What is an optimal strategy for controlling blood pressure? A: Diuretic alone B: Diuretic + ACE inhibitor C: Diuretic + ARB D: Diuretic + ß-blocker E: Diuretic + calcium-channel blocker What is an optimal strategy for controlling blood pressure? A: Diuretic alone B: Diuretic + ACE inhibitor C: Diuretic + ARB D: Diuretic + ß-blocker E: Diuretic + calcium-channel blocker

Case 3

PL is a 62-year-old white female returning to your office for a routine follow-up visit (lost to follow-up for the past 3 years) PL is a 62-year-old white female returning to your office for a routine follow-up visit (lost to follow-up for the past 3 years) Medical history significant for exertional angina, diagnosed 4 years previously Medical history significant for exertional angina, diagnosed 4 years previously – a recent cardiac catheterization showed luminal irregularities with no critical stenosis – currently experiences angina with moderate exercise, such as climbing >2 flights of stairs, mowing lawn Family history: Family history: – mother died of heart failure at 58 years of age – father alive and well Non-smoker; denies alcohol consumption Non-smoker; denies alcohol consumption PL is a 62-year-old white female returning to your office for a routine follow-up visit (lost to follow-up for the past 3 years) PL is a 62-year-old white female returning to your office for a routine follow-up visit (lost to follow-up for the past 3 years) Medical history significant for exertional angina, diagnosed 4 years previously Medical history significant for exertional angina, diagnosed 4 years previously – a recent cardiac catheterization showed luminal irregularities with no critical stenosis – currently experiences angina with moderate exercise, such as climbing >2 flights of stairs, mowing lawn Family history: Family history: – mother died of heart failure at 58 years of age – father alive and well Non-smoker; denies alcohol consumption Non-smoker; denies alcohol consumption Case - PL Patient Profile

Blood pressure: 149/97 mm Hg Blood pressure: 149/97 mm Hg Pulse: 85 and regular Pulse: 85 and regular BMI: 28 Waist circumference: 36 BMI: 28 Waist circumference: 36 Physical examination is otherwise unremarkable Physical examination is otherwise unremarkable Blood pressure: 149/97 mm Hg Blood pressure: 149/97 mm Hg Pulse: 85 and regular Pulse: 85 and regular BMI: 28 Waist circumference: 36 BMI: 28 Waist circumference: 36 Physical examination is otherwise unremarkable Physical examination is otherwise unremarkable Case - PL Physical Examination BMI, body mass index.

Laboratory data Laboratory data Serum creatinine1.0 mg/dL Serum potassium4.0 mmol/L Fasting glucose97 mg/dL Total cholesterol199 mg/dL LDL-C 121 mg/dLHDL-C 48 mg/dL TG 150 mg/dL UrinalysisNo proteinuria or cellular elements ElectrocardiogramNon-specific ST segment changes without evidence of left ventricular hypertrophy Current medications Current medications Sublingual nitroglycerin, as needed Aspirin 81 mg once daily Laboratory data Laboratory data Serum creatinine1.0 mg/dL Serum potassium4.0 mmol/L Fasting glucose97 mg/dL Total cholesterol199 mg/dL LDL-C 121 mg/dLHDL-C 48 mg/dL TG 150 mg/dL UrinalysisNo proteinuria or cellular elements ElectrocardiogramNon-specific ST segment changes without evidence of left ventricular hypertrophy Current medications Current medications Sublingual nitroglycerin, as needed Aspirin 81 mg once daily Case - PL Laboratory Values and Current Medications LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Case - PL Clinical Question #1 What are this patients cardiovascular risk factors?

Case - PL Clinical Question #2 What is PLs blood pressure goal? A. 130/85 mm Hg B. 140/90 mm Hg C. 130/80 mm Hg D. 120/80 mm Hg

What would be your first steps regarding PLs blood pressure? A. Repeat measurement on at least one other occasion B. Encourage her to lose weight C. Initiate antihypertensive medication A. Repeat measurement on at least one other occasion B. Encourage her to lose weight C. Initiate antihypertensive medication Case - PL Clinical Question #3

What type of antihypertensive agent would you prescribe 1 st -line? A. ACE inhibitor B. Diuretic C. Beta-blocker D. Angiotensin-receptor blocker E. Calcium-channel blocker A. ACE inhibitor B. Diuretic C. Beta-blocker D. Angiotensin-receptor blocker E. Calcium-channel blocker Case - PL Clinical Question #4

On 2 separate occasions, PLs BP is 142/91 mm Hg and 143/92 mm Hg. She also no longer seems to be having anginal symptoms. What would you now do? A. Nothing; BP is only a couple of mm above goal B. Encourage weight loss C. Proceed with developing a more aggressive antihypertensive treatment regimen A. Nothing; BP is only a couple of mm above goal B. Encourage weight loss C. Proceed with developing a more aggressive antihypertensive treatment regimen Case - PL Clinical Question #5

What would you prescribe now presuming that a -blocker was the agent selected as first-step therapy? A. Uptitration of the -blocker B. Add an ACE inhibitor C. Add an angiotensin-receptor blocker D. Add a calcium-channel blocker E. Add a thiazide-type diuretic A. Uptitration of the -blocker B. Add an ACE inhibitor C. Add an angiotensin-receptor blocker D. Add a calcium-channel blocker E. Add a thiazide-type diuretic Case - PL Clinical Question #6

Case 4

Patient Presentation A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. He does not always take his medication, however, because he believes that BP normally increases with age and that antihypertensive medications and drugs, in general, cause troubling side effects. He does not always take his medication, however, because he believes that BP normally increases with age and that antihypertensive medications and drugs, in general, cause troubling side effects. A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. A 76-year-old white man has diminished vision and a 20-yr history of hypertension, which has been variably treated with diuretics and calcium channel blockers. He does not always take his medication, however, because he believes that BP normally increases with age and that antihypertensive medications and drugs, in general, cause troubling side effects. He does not always take his medication, however, because he believes that BP normally increases with age and that antihypertensive medications and drugs, in general, cause troubling side effects.

Patient Presentation He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his diastolic pressure ranges from mmHg and his systolic pressure, from mmHg. He denies any headache, chest pain, and shortness of breath, claudication, or leg swelling. He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his diastolic pressure ranges from mmHg and his systolic pressure, from mmHg. He denies any headache, chest pain, and shortness of breath, claudication, or leg swelling. His medical history is remarkable for macular degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not drink alcohol. His medical history is remarkable for macular degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not drink alcohol. He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his diastolic pressure ranges from mmHg and his systolic pressure, from mmHg. He denies any headache, chest pain, and shortness of breath, claudication, or leg swelling. He tries to control his BP by eating properly and exercising regularly. He plays golf 3-4 times per week. He notes that at home he has normal BP, since his diastolic pressure ranges from mmHg and his systolic pressure, from mmHg. He denies any headache, chest pain, and shortness of breath, claudication, or leg swelling. His medical history is remarkable for macular degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not drink alcohol. His medical history is remarkable for macular degeneration in both eyes. He has had no prior surgery. He has no known drug allergies, and he is not taking any medications. He smoked cigarettes for about 40 years but stopped 15 yrs. ago. He does not drink alcohol.

Physical Examination On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 510, and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart rate is 74 beats per minute. On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 510, and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart rate is 74 beats per minute. Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good carotid pulses without bruits. Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good carotid pulses without bruits. On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 510, and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart rate is 74 beats per minute. On physical examination, he appears to be a healthy elderly man, who looks his age. His height is 510, and his weight, 166 lb. His BP is 182/80 mmHg in both arms and does not change with position. His heart rate is 74 beats per minute. Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good carotid pulses without bruits. Fundoscopic exam shows bilateral macular degeneration, copper wiring, and AV- nicking but no hemorrhages or exudates. His neck shows good carotid pulses without bruits.

Physical Examination Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or organomegaly. Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or organomegaly. There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2- second capillary refill in his fingers and toes. His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2- second capillary refill in his fingers and toes. Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or organomegaly. Cardiac exam shows a regular rate and rhythm, with a harsh systolic murmur grade 2/6. Point of maximal intensity is nondisplaced. His lungs are clear. His abdomen is without scars, masses, tenderness, or organomegaly. There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. There are no abnormal bruits, and he has 2+ femoral pulses. Neurologic exam is grossly intact, without focal deficits or pathologic reflexes. His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2- second capillary refill in his fingers and toes. His extremities show no peripheral edema or joint deformities. He has 1+ peripheral pulses with 2- second capillary refill in his fingers and toes.

Laboratory Evaluation Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy. Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy. Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. Laboratory findings show the following values: BUN, 18 mg/dL; creatinine, 1.4 mg/dL; total cholesterol, 192 mg/dL; HDL, 44 mg/dL; and LDL, 120 mg/dL. Urinalysis shows no protein, 1-2 WBC, 1-2 RBC, and no bacteria. Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy. Echocardiogram shows normal sinus rhythm with mild left ventricular hypertrophy.

What is the optimal strategy for controlling blood pressure in this patient? Are there any associated risks with this therapy?

Discussion Management This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal measurement. This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal measurement. More recent findings indicate that a systolic pressure this high is in fact not normal. More recent findings indicate that a systolic pressure this high is in fact not normal. Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal insufficiency. Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal insufficiency. Treatment will reduce these risks. Treatment will reduce these risks. This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal measurement. This patient has been essentially healthy all of his life. He has a systolic BP of about 100 mmHg plus his age, which was previously thought to be a normal measurement. More recent findings indicate that a systolic pressure this high is in fact not normal. More recent findings indicate that a systolic pressure this high is in fact not normal. Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal insufficiency. Rather, it is associated with increasing risk for cardiovascular accident (CVA), myocardial infarction (MI) congestive heart failure, and progressive renal insufficiency. Treatment will reduce these risks. Treatment will reduce these risks.

Discussion Management Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. In SHEP, reducing a pretreatment systolic BP of mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. In SHEP, reducing a pretreatment systolic BP of mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients with isolated systolic hypertension. Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients with isolated systolic hypertension. Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. Findings from the Systolic Hypertension in the Elderly Program (SHEP) have encouraged practitioners to use a more aggressive approach in lowering systolic BP. In SHEP, reducing a pretreatment systolic BP of mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. In SHEP, reducing a pretreatment systolic BP of mmHg to lower than 160 mmHg or by more than 20 mmHg significantly improved survival rates. Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. Clinical therapies used in SHEP were mainly low-dose chlorthalidone and/or the beta-blocker atenolol. Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients with isolated systolic hypertension. Because this trial proved the success of these drugs in reducing morbidity and mortality, these two drug classes are viewed as treatments of choice in patients with isolated systolic hypertension.

Discussion Management Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well. Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well. With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing. With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing. Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well. Recent clinical trials demonstrated that using calcium channel blocker-based therapy to lower systolic BP can also effectively reduce morbidity and mortality related CVA. The use of calcium channel blockers for this purpose is generally taken under consideration relative to how drugs in this class potentially increase resting heart rate in some patients. Recent studies have also demonstrated that ARBs and ACE inhibitor therapy reduce stroke rate as well. With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing. With increasing age come substantial changes in circulation: As vascular compliance diminishes, vascular volume tends to decline. With loss of compliance of the aorta, each stroke volume results in a much higher systolic BP and loss of the pulse wave reflection during diastole. For this reason, systolic BP rises with age, and diastolic BP drops, thus the commonly observed widening of the pulse pressure with ageing.

Discussion Management Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest natriuretic effect in older patients. Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest natriuretic effect in older patients. Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated vascular resistance. Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated vascular resistance. Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the rate-pressure product. Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the rate-pressure product. Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest natriuretic effect in older patients. Low-dose diuretics are advantageous in the elderly patient with systolic hypertension, largely because the long-term antihypertensive effects of these drugs relate to vasodilation. These agents may also offer a modest natriuretic effect in older patients. Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated vascular resistance. Any vasodilator therapy is appropriate, because it targets the major pathophysiologic problem: elevated vascular resistance. Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the rate-pressure product. Which vasodilator to use depends heavily on coexistent medical problems. It is important to avoid a significant increase in heart rate, which would lower the threshold for an ischemic event in a patient with coexisting coronary disease by having increased the rate-pressure product.

Discussion Management Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. Because these patients have reduced metabolic capabilities, they should be given medication in a dose that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age- related declines in renal function. Because these patients have reduced metabolic capabilities, they should be given medication in a dose that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age- related declines in renal function. Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability to play golf. The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability to play golf. Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. Older patients have specific pharmacotherapeutic problems. Often the elderly have diminished baroreceptor reflexes, and as a result, are prone to orthostatic hypertension. Because these patients have reduced metabolic capabilities, they should be given medication in a dose that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age- related declines in renal function. Because these patients have reduced metabolic capabilities, they should be given medication in a dose that is about 50% of that given initially to younger patients; however, not all elderly patients exhibit age- related declines in renal function. Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. Cognitive function is also a concern; older patients must be able to sustain their activities of daily living. The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability to play golf. The patient in this case, for example, should not receive pharmacotherapy that interferes with his ability to play golf.

Discussion Management The only additional test relevant to this patient would be an assessment of left ventricular function with echocardiography, if there is any suspicion of pump dysfunction. The only additional test relevant to this patient would be an assessment of left ventricular function with echocardiography, if there is any suspicion of pump dysfunction. Confirmation of pump dysfunction should steer the physician toward more disease- state specific therapies. Confirmation of pump dysfunction should steer the physician toward more disease- state specific therapies. The only additional test relevant to this patient would be an assessment of left ventricular function with echocardiography, if there is any suspicion of pump dysfunction. The only additional test relevant to this patient would be an assessment of left ventricular function with echocardiography, if there is any suspicion of pump dysfunction. Confirmation of pump dysfunction should steer the physician toward more disease- state specific therapies. Confirmation of pump dysfunction should steer the physician toward more disease- state specific therapies.

Clinical Pearls and Pitfalls Because high systolic BP may cause target organ injury, it must be treated aggressively. Because high systolic BP may cause target organ injury, it must be treated aggressively. Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase heart rate. Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase heart rate. Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used sparingly. Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used sparingly. Because high systolic BP may cause target organ injury, it must be treated aggressively. Because high systolic BP may cause target organ injury, it must be treated aggressively. Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase heart rate. Low-dose thiazides are optimal as an initial treatment strategy. Additional vasodilator therapy is helpful, preferably with agents that do not increase heart rate. Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used sparingly. Agents that interfere with cognitive function or precipitate orthostatic hypotension should be used sparingly.