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

CV Mortality Risk Doubles withCV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment*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 pressureLewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.

CVmortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

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

Impact of “High-Normal” BP on Impact of “High-Normal” BP on CV RiskCV Risk

Data from the Framingham Heart StudyData from the Framingham Heart Study

16

12

8

4

0

Optimal BP

Normal BP

12

8

4

00 2 4 6 8 10 12

Years

Optimal BP

Normal BP

High-normal BPWomen

Men

Cumulative

incidence of CV events

(%)

High-normal BP

Vasan et al. N Engl J Med. 2001;345:1291-7.

Optimal BP: <120/80Normal BP: 120-129/80-84High-normal BP: 130-139/85-89

Lower Is BetterLower Is BetterIHD Rates by SBP, DBP, and AgeIHD Rates by SBP, DBP, and Age

A: Systolic Blood Pressure

40-49 years

50-59 years

60-69 years

70-79 years

80-89 yearsAge at risk:

IHD

Mo

rtal

ity

(Flo

atin

g A

bso

lute

Ris

k a

nd

95

% C

I) 256

128

64

32

16

8

4

2

1

120 140 160 180

Usual SBP (mm Hg)

B: Diastolic Blood Pressure

IHD

Mo

rtal

ity

(Flo

atin

g A

bso

lute

Ris

k a

nd

95

% C

I) 256

128

64

32

16

8

4

2

1

70 80 90 100 110

Usual DBP (mm Hg)

Lewington et al. Lancet. 2002;360:1903-1913.

Age at risk:

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

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.

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

Systolic BP Reduction Systolic BP Reduction and CVD Mortality and CVD Mortality

Systolic BP (control - experimental, mm Hg)

Car

dio

vas

cula

r M

ort

alit

y O

dd

s R

atio

Staessen JA et al. Lancet. 2001;358:1305 -1315.

1.50

1.25

1. 00

0.75

0.50

0.25

-5 0 5 10 15 20 25

P =.003

MIDAS/NICS/VHASUKPDS C vs A

INSIGHTHOT L vs H

HOT M vs HMRC1

MRC2

SHEPHEP

EWPHE

RCT70-80

Syst-Eur

STONE

Syst-ChinaUKPDS L vs H

HOPE

PART2/SCATATMH

STOP1

CAPPP

STOP2/CCBs

STOP2/ACEIs

NORDIL

SBP Reductions as Little as SBP Reductions as Little as 2 mm Hg Reduce the Risk of CV Events by 2 mm Hg Reduce the Risk of CV Events by

Up to 10%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

Pg 9

CCOZ_18815_Giles_DT2

Benefits of Intensive BP ReductionHOT Study

**Mean BP from 6 months of follow-up to end of study. Hansson L et al. Lancet. 1998;351:1755-1762.

**Mean BP from 6 months of follow-up to end of study. Hansson L et al. Lancet. 1998;351:1755-1762.

Achieved DBP* (mm Hg)

85.2 83.2 81.1

100

80

40

0

20

60

P=0.05 for trend

Nu

mb

er o

f M

Is

90 143.7 85.2

85 141.4 83.2

80 138.7 81.1

TargetDBP

(mm Hg)

AchievedSBP

(mm Hg)

AchievedDBP*

(mm Hg)

HypothesisThe 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.

Antihypertensive Drugs that Slow Disease Progression in Known Doses

Vascular CardiacRamipril EnalaprilPerindopril Captopril?other ACEIs Carvedilol

Amlodipine MetoprololValsartan BucindololLosartan ValsartanHydrochlorothiazide Candesartan

SpironolactoneEplerenoneISDN/hydralazine

Old Paradigm

BP Cholesterol

Disease Disease

Treatment Treatment

Normal Normal

GOAL: Target Response

Current Paradigm

DISEASE

BP Cholesterol

GOAL: ?Target Response

TR

EA

TM

EN

T

Pathophysiology of CV ContinuumGenes EnvironmentEthnicity DietFamily Hx ExercisePolymorphisms StressProteomics Smoking

Blood Vessel/ Heart

AngiotensinNitric Oxide

Progression AldosteroneNorepinephrineCytokines

Structural Remodeling

CAD Cerebrovascular DiseaseHeart Failure Renal FailurePVD Dementia

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 TherapyRAAS Blockade StatinsNO Enhancers Antihypertensives Antioxidants ?Antiinflammatories

ASH Writing Group: ASH Writing Group: Proposed New Definition of HypertensionProposed 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.

†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 ASH Writing Group Definition and Classification of HypertensionClassification of Hypertension

Classification Normal Stage 1 hypertension

Stage 2 hypertension

Stage 3 hypertension

Descriptive Category

Normal BP or rare blood pressure

elevationsAND

No identifiable CVD†

Occasional or intermittent BP

elevationsOR

Early CVD†

Sustained BPelevations

ORProgressive

CVD†

Marked and sustained BP

elevationsOR

Advanced CVD†

Cardiovascular Risk Factors

None or few Several Many Many

Early Disease Markers

None Usually present Overtly present Overtly present with progression

Target-organ Disease

None None Early signs present

Overtly present with or without

CVD events

ASH Writing Group 2005.

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

R A S M U S S E NC E N T E R

forCARDIOVASCULAR

DISEASE PREVENTION

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

RASMUSSEN CENTER

Screening Tests for Early Detection

Cardiac Evaluation

• Electrocardiogram

• Cardiac ultrasound (LVID & LVWT)

• Plasma BNP (Biosite)

RASMUSSEN CENTER

Screening Tests for Early Detection

Modifiable Disease Contributors

• Fasting lipids (LDL, HDL, Trig)

• Fasting blood sugar

• hsCRP

• Homocysteine

Results of Rasmussen Center Screening

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14 16

3-D Column 1

Fre

qu

ency

Rasmussen Score

Low Risk

33%

Modest Risk

36%

High Risk

31%

Patient: 60-year-old female registered nursePast History: negative except high cholesterolFamily 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 DiseaseTreatment: Antihypertensive, statin

Patient: 62-year-old female floristPast History: Asymptomatic, plays tennis and golf

Elevated cholesterol: Atorvastatin, 10 mgFamily 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 DiseaseTreatment: ACE/ARB; BP Control; Increase atorvastatin

Patient: 49-year-old male executivePast 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 normalRasmussen 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 DiseaseTreatment: Diet, ?statin

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?

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

Risk Factors

Biomarkers

Cardiac and VascularStructural Abnormalities

DeathNon-Fatal

MorbidEvents

RecurrenceProgression

Primary Prevention

Secondary Prevention

Tertiary Prevention

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

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

Future Paradigm

Early Disease

Statin

RAAS Blockade

Antihypertensives

NO donor/enhancer

Innovative Therapy

Slow Progression

GOAL: ?Target Dose

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