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 with

Each 20/10 mm Hg BP Increment*
8
7
6
CV
mortality
risk

5
4
3
2
1
0
115/75

135/85

155/95

SBP/DBP (mm Hg)

*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.

175/105

Impact of High-Normal BP
on CV Risk
Data from the Framingham Heart Study
16

Men

12

High-normal BP
Normal BP

8
Cumulative
incidence of
CV events
(%)

Optimal BP

4
0
12

Women

High-normal BP

Normal BP

4
0

Optimal BP
0

Optimal BP: <120/80

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

6
Years

10

12

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

Lower Is Better

IHD Rates by SBP, DBP, and Age

B: Diastolic Blood Pressure

256

Age at risk:
80-89 years

128

70-79 years

64

60-69 years

32

50-59 years

16

40-49 years

8
4
2
1

120

140

160

180

Usual SBP (mm Hg)

Age at risk:
IHD Mortality
(Floating Absolute Risk and 95% CI)

IHD Mortality
(Floating Absolute Risk and 95% CI)

A: Systolic Blood Pressure

256

80-89 years

128

70-79 years

64

60-69 years

32

50-59 years

16

40-49 years

8
4
2
1

70

80

90

100

110

Usual DBP (mm Hg)

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

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 (%)
Likely
Disease

50
Possible
Disease
No
Disease

0
75
100
125
150
175
Systolic Blood Pressure (mmHg)

200

Systolic BP Reduction
and CVD Mortality
Cardiovascular Mortality Odds Ratio

1.50

1.25

MIDAS/NICS/VHAS
UKPDS C vs A

NORDIL
STOP2/ACEIs

1. 00
STOP2/CCBs

HOT M vs H
MRC1
MRC2
STONE

0.75

P =.003

INSIGHT
HOT L vs H

SHEP

CAPPP HOPE
Syst-Eur
UKPDS L vs H
Syst-China

HEP
EWPHE
RCT70-80

0.50
PART2/SCAT
ATMH

STOP1

0.25
-5

10

15

20

25

Systolic BP (control - experimental, mm Hg)

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

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
7% reduction in
risk of ischemic
heart disease
mortality

2 mm Hg
decrease in
mean SBP

10% reduction in
risk of stroke
mortality

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

CCOZ_18815_Giles_DT2

Benefits of Intensive BP Reduction

HOT Study
Target
DBP
(mm Hg)

Achieved
SBP
(mm Hg)

Achieved
DBP*
(mm Hg)

90

143.7

85.2

85

141.4

83.2

80

138.7

Number of MIs

100

P=0.05 for trend

80
60
40
20

81.1
0
85.2

83.2

81.1

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

Pg 9

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.

Antihypertensive Drugs that

Slow Disease Progression in Known Doses
Vascular

Cardiac

Ramipril
Perindopril
?other ACEIs
Amlodipine
Valsartan
Losartan
Hydrochlorothiazide

Enalapril
Captopril
Carvedilol
Metoprolol
Bucindolol
Valsartan
Candesartan
Spironolactone
Eplerenone
ISDN/hydralazine

Old Paradigm
BP

Cholesterol

Disease

Disease
Treatment

Normal

Treatment
Normal

GOAL: Target Response

Current Paradigm

TREATMENT

DISEASE

BP

Cholesterol

GOAL: ?Target Response

Pathophysiology of CV Continuum
Genes
Ethnicity
Family Hx
Polymorphisms
Proteomics

Environment
Diet
Exercise
Stress
Smoking
Blood Vessel/ Heart

Progression

Angiotensin
Nitric Oxide
Aldosterone
Norepinephrine
Cytokines

Structural Remodeling
CAD
Heart Failure
PVD

Cerebrovascular Disease
Renal Failure
Dementia

Genes, Ethnicity, Diet, Exercise, Smoking, Obesity, Lipids

Small Artery
Elasticity
(Endothelial
Dysfunction)
BP
PNE
AngII

Arterial Structural
Cardiac
Abnormalities
Abnormalities
Microalbumin
LVM
IMT
BNP
Retinal Vasculopathy
ECG
Large Artery Elasticity
Exercise BP
Resting BP

Disease
Drug Therapy
RAAS Blockade
Statins
NO Enhancers
Antihypertensives
Antioxidants
?Antiinflammatories

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.

ASH Writing Group Definition and

Classification of Hypertension
Classification

Normal

Stage 1
hypertension

Stage 2
hypertension

Stage 3
hypertension

Normal BP or rare
blood pressure
elevations
AND
No identifiable
CVD

Occasional or
intermittent BP
elevations
OR
Early
CVD

Sustained BP
elevations
OR
Progressive
CVD

Marked and
sustained BP
elevations
OR
Advanced
CVD

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

Descriptive
Category

Cardiovascular
Risk Factors

CVD designation is determined by the constellation of risk factors, early disease markers, and target-organ disease.
CVD, cardiovascular disease.

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 mass
-B-type natriuretic peptide

-Increased LV volume
-Abnormal ECG

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

RASMUSSEN CENTER
Screening Tests for Early
Detection

Vascular Evaluation

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

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

Low Risk Modest Risk
36%

31%

Frequency

33%

High Risk

Rasmussen Score

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 54
HR 64 b/min

Weight 126 lb.

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

Patient: 62-year-old female florist

Past History: Asymptomatic, plays tennis and golf
Elevated cholesterol: Atorvastatin, 10 mg
Family History: Negative
Physical Exam:

Height 55
HR 74 b/min

Weight 128 lb.

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

Patient: 49-year-old male executive

Past History: Overweight, elevated BP, asymptomatic, no therapy
Family History: Hypertension, coronary disease
Physical Exam:

Height 58
HR 76 b/min

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

Weight 240 lb.

BP 144/84 mmHg

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
Primary Prevention
Cardiac and Vascular
Structural Abnormalities
Secondary Prevention
Death

Non-Fatal
Morbid
Events
Tertiary Prevention

Recurrence
Progression

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