How Should One Decide Whom to Treat for Hypertension?

1
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 withEach 20/10 mm Hg
BP Increment
8
7
6
5
CVmortalityrisk
4
3
2
1
0
115/75
135/85
155/95
175/105
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
601903-1913. JNC VII. JAMA. 2003.
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Impact of High-Normal BP on CV RiskData from
the Framingham Heart Study
16
Men
High-normal BP
12
Normal BP
8
Optimal BP
4
Cumulative
incidence of
0
CV events
12
()
Women
High-normal BP
8
Normal BP
4
Optimal BP
0
0
2
4
6
8
10
12
Years
Optimal BP lt120/80 Normal BP 120-129/80-84 High-
normal BP 130-139/85-89
Vasan et al. N Engl J Med. 20013451291-7.
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Lower Is BetterIHD Rates by SBP, DBP, and Age
B Diastolic Blood Pressure
A Systolic Blood Pressure
Age at risk
Age at risk
80-89 years
256
256
70-79 years
128
128
60-69 years
64
64
50-59 years
32
32
16
16
IHD Mortality
(Floating Absolute Risk and 95 CI)
IHD Mortality
(Floating Absolute Risk and 95 CI)
40-49 years
8
8
4
4
2
2
1
1
70
80
90
100
110
120
140
160
180
Usual SBP (mm Hg)
Usual DBP (mm Hg)
Lewington et al. Lancet. 20023601903-1913.
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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)

Likely Disease
Possible Disease
No Disease
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Systolic BP Reduction and CVD Mortality
Cardiovascular Mortality Odds Ratio
? Systolic BP (control - experimental, mm Hg)
Staessen JA et al. Lancet. 20013581305 -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

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. 20023601903-1913.
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Benefits of Intensive BP ReductionHOT Study
P0.05 for trend
TargetDBP(mm Hg)
AchievedSBP(mm Hg)
AchievedDBP(mm Hg)
Number of MIs
?90 143.7 85.2 ?85 141.4 83.2 ?80 138.7 81.1
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.
19983511755-1762.
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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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ASH Writing Group Definition and Classification
of Hypertension
Classification Normal Stage 1 hypertension Stage 2 hypertension Stage 3 hypertension
Descriptive Category 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
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
CVD designation is determined by the
constellation of risk factors, early disease
markers, and target-organ disease. CVD,
cardiovascular disease.
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 NC E N T E
RforCARDIOVASCULARDISEASE PREVENTION
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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
• Carotid intimal-medial thickness

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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
Low Risk
Modest Risk
High Risk
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36
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Frequency
Rasmussen Score
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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 54 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 AV 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 55 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 AV 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 58 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 gt55 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
Primary Prevention
Cardiac and Vascular Structural Abnormalities
Secondary Prevention
Death
Non-Fatal Morbid Events
Tertiary Prevention
Recurrence Progression
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Who to Treat with Antihypertensives (Pressure
Orientation)

• SBPgt160 mmHg most of the time
• SBPgt140 mmHg most of the time evidence for
  vascular or cardiac functional/structural
  abnormalities
• SBPgt130 mmHg with symptomatic vascular or cardiac
  disease or diabetes
• ?SBPgt130 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
  gt120/80 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