How Should One Decide Whom to Treat for Hypertension

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How Should One Decide Whom to Treat for Hypertension? Jay N. Cohn, M.D. Professor of Medicine Director, Rasmussen Center for Cardiovascular Disease Prevention University of Minnesota Medical School Minneapolis, MN

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CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment* *Individuals aged 40-69 years, starting at BP 115/75 mm Hg. CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure Lewington S, et al. Lancet. 2002; 60:1903-1913. JNC VII. JAMA. 2003. CV mortality risk SBP/DBP (mm Hg) 0 1 2 3 4 5 6 7 8 115/75 135/85 155/95 175/105

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Impact of “High-Normal” BP on CV Risk Data from the Framingham Heart Study 16 12 8 4 0 Optimal BP Normal BP 12 8 4 0 0 2 4 6 8 10 12 Years Optimal BP Normal BP High-normal BP Women Men Cumulative incidence of CV events (%) High-normal BP Vasan et al. N Engl J Med. 2001;345:1291-7. Optimal BP: <120/80 Normal BP: 120-129/80-84 High-normal BP: 130-139/85-89

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Hypothesis The apparent linear relationship between blood pressure and ischemic disease events as well as age and ischemic disease events does not necessarily mean that age or blood pressure cause events but that both markers capture a progressively higher proportion of people with early disease.

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Blood Pressure and Likelihood of Disease 100 Frequency in Population (%) 50 0 75 100 125 150 175 200 Systolic Blood Pressure (mmHg) No Disease Possible Disease Likely Disease

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Systolic BP Reduction and CVD Mortality ? Systolic BP (control - experimental, mm Hg) Cardiovascular Mortality Odds Ratio Staessen JA et al. Lancet. 2001;358:1305 -1315.

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SBP Reductions as Little as 2 mm Hg Reduce the Risk of CV Events by Up to 10% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years Lewington S et al. Lancet. 2002;360:1903-1913. 2 mm Hg decrease in mean SBP 10% reduction in risk of stroke mortality 7% reduction in risk of ischemic heart disease mortality

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Hypothesis The apparent linear relationship between the magnitude of drug-induced BP fall and the reduction of morbid events does not necessarily indicate that blood pressure reduction prevents events but that the drugs protect the arteries and heart (while also lowering blood pressure). A corollary: the greater the BP reduction from a drug the less the vascular disease - i.e., BP fall identifies a low-risk population.

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Antihypertensive Drugs that Slow Disease Progression in Known Doses Vascular Cardiac Ramipril Enalapril Perindopril Captopril ?other ACEIs Carvedilol Amlodipine Metoprolol Valsartan Bucindolol Losartan Valsartan Hydrochlorothiazide Candesartan Spironolactone Eplerenone ISDN/hydralazine

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Old Paradigm BP Cholesterol Disease Disease Treatment Treatment Normal Normal GOAL: Target Response

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Current Paradigm DISEASE BP Cholesterol GOAL: ?Target Response TREATMENT

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Pathophysiology of CV Continuum Genes Environment Ethnicity Diet Family Hx Exercise Polymorphisms Stress Proteomics Smoking Blood Vessel/ Heart Angiotensin Nitric Oxide Progression Aldosterone Norepinephrine Cytokines Structural Remodeling CAD Cerebrovascular Disease Heart Failure Renal Failure PVD Dementia

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Genes, Ethnicity, Diet, Exercise, Smoking, Obesity, Lipids Small Artery Arterial Structural Cardiac Elasticity Abnormalities Abnormalities (Endothelial Microalbumin LVM Dysfunction) IMT BNP BP Retinal Vasculopathy ECG PNE Large Artery Elasticity AngII Exercise BP Resting BP Disease Drug Therapy RAAS Blockade Statins NO Enhancers Antihypertensives Antioxidants ?Antiinflammatories

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ASH Writing Group: Proposed New Definition of Hypertension Hypertension is a progressive cardiovascular syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before blood pressure elevation is sustained; therefore, hypertension cannot be classified solely by discrete blood pressure thresholds. Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature and other organs and lead to premature morbidity and death. ASH Writing Group 2005.

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†CVD designation is determined by the constellation of risk factors, early disease markers, and target-organ disease. CVD, cardiovascular disease. ASH Writing Group Definition and Classification of Hypertension ASH Writing Group 2005.

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Early Markers for Hypertensive Vascular Disease Blood Pressure -Exaggerated response to exercise -Widened pulse pressure Vascular -Reduced small artery elasticity -Reduced large artery elasticity -Endothelial dysfunction -Increased pulsewave velocity -Increased carotid intima-medial thickness -Retinal vascular changes -Microalbuminuria Cardiac -Increased LV wall thickness -Increased LV volume -Increased LV mass -Abnormal ECG -B-type natriuretic peptide

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R A S M U S S E N C E N T E R for CARDIOVASCULAR DISEASE PREVENTION

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RASMUSSEN CENTER Screening Tests for Early Detection Arterial Elasticity (Pulse Contour Analysis) - Small Artery (C2) - Large Artery (C1) Rest and exercise BP (3-minute treadmill) Retinal digital photograph Urine for microalbumin/creatinine ratio Carotid intimal-medial thickness Vascular Evaluation

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RASMUSSEN CENTER Screening Tests for Early Detection Cardiac Evaluation Electrocardiogram Cardiac ultrasound (LVID & LVWT) Plasma BNP (Biosite)

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RASMUSSEN CENTER Screening Tests for Early Detection Modifiable Disease Contributors Fasting lipids (LDL, HDL, Trig) Fasting blood sugar hsCRP Homocysteine

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Results of Rasmussen Center Screening Frequency Rasmussen Score Low Risk 33% Modest Risk 36% High Risk 31%

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Patient: 60-year-old female registered nurse Past History: negative except high cholesterol Family History: both parents smoked, no significant CV disease Physical Exam: Height 5’4” Weight 126 lb. HR 64 b/min BP 132/66 mmHg Screening Results: C1 = 8.5 ml/mmHg x10 (abnormal) C2 = 2.4 ml/mmHg x100 (abnormal) Exercise BP = 173/64 mmHg (abnormal) Retinal photo = A:V nicking (abnormal) Microalbumin = 0.86 mg/mmol (abnormal) LV ultrasound = increased mass (abnormal) Rasmussen score = 12 points Blood Chemistry: LDL 187 mg/dl; HDL 70 mg/dl Interpretation: Advanced CV Disease Treatment: Antihypertensive, statin

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Patient: 62-year-old female florist Past History: Asymptomatic, plays tennis and golf Elevated cholesterol: Atorvastatin, 10 mg Family History: Negative Physical Exam: Height 5’5” Weight 128 lb. HR 74 b/min BP 140/80 mmHg Screening Results: C1 = 8.7 ml/mmHg x10 (abnormal) C2 = 1.6 ml/mmHg x100 (abnormal) Exercise BP = 182/80 mmHg (abnormal) Retinal photo = decreased A:V ratio (borderline) Microalbumin = 1.98 mg/mmol (abnormal) Rasmussen score = 9 points Blood Chemistry: LDL 137 mg/dl; HDL 129 mg/dl; CRP 0.13 mg/dl Interpretation: Advancing CV Disease Treatment: ACE/ARB; BP Control; Increase atorvastatin

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Patient: 49-year-old male executive Past History: Overweight, elevated BP, asymptomatic, no therapy Family History: Hypertension, coronary disease Physical Exam: Height 5’8” Weight 240 lb. HR 76 b/min BP 144/84 mmHg Screening Results: C1 = 16.1 ml/mmHg x10 (normal) C2 = 6.4 ml/mmHg x100 (normal) Exercise BP = 154/74 mmHg (normal) All other tests normal Rasmussen score = 2 points (BP only) Blood Chemistry: LDL 172 mg/dl; HDL 38 mg/dl; FBS 108 mg/dl; CRP 1.0 mg/dl Interpretation: No CV Disease Treatment: Diet, ?statin

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Strategies for Aggressive Treatment PRIMARY PREVENTION Primary Prevention (global) Polypill Everyone >55 years old Impractical Inefficient Benefit: risk ratio untested Primary Prevention (targeted) Risk factor identification Treatment targets risk factor Misses many at-risk Risk factor levels? Benefit: risk?

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Strategies for Aggressive Treatment SECONDARY PREVENTION Secondary Prevention (early) Detect markers for early disease Treat disease not risk factor Sensitivity/specificity of detection? Benefit: risk better? Prolonged event-free survival Reduced health care costs Secondary Prevention (late) Patients with symptomatic disease Treatment can prevent events/prolong life Increased burden of health care costs

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Risk Factors Biomarkers Cardiac and Vascular Structural Abnormalities Death Non-Fatal Morbid Events Recurrence Progression Primary Prevention Secondary Prevention Tertiary Prevention

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Who to Treat with Antihypertensives (Pressure Orientation) SBP>160 mmHg most of the time SBP>140 mmHg most of the time & evidence for vascular or cardiac functional/structural abnormalities SBP>130 mmHg with symptomatic vascular or cardiac disease or diabetes ?SBP>130 mmHg with evidence for vascular or cardiac functional/structural abnormalities GOAL: Lower Blood Pressure

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Who to Treat with Antihypertensives (Pathophysiologic Orientation) Anyone with symptomatic atherosclerotic vascular or cardiac disease ?Anyone with vascular or cardiac functional/structural abnormalities and BP >120/80 mmHg GOAL: Slow Disease Progression

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Future Paradigm Early Disease Statin RAAS Blockade Antihypertensives NO donor/enhancer Innovative Therapy Slow Progression GOAL: ?Target Dose

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Strategies to Identify At-Risk Population Blood pressure level Which measurement? What level? Cholesterol level Which fraction? Reproducibility? Blood pressure + cholesterol (BP + Ch) Sensitivity, specificity BP + Ch + other “risk factors” Sensitivity, specificity Early disease detection Endothelial dysfunction Vascular functional/structural abnormalities Cardiac functional/structural abnormalities

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