New Epidemiologic Data on Cardiovascular Risk: Are They of Clinical Importance

1
New Epidemiologic Data on Cardiovascular Risk
Are They of Clinical Importance?
Stanley S. Franklin, MD, FACP, FACC, FASN
University of California, Irvine
2
Why is hypertension considered a major Public
health problem in the United States?
Firstly, hypertension is very common In the
adult population
3
Increased Prevalence of Hypertension in the
United States from 1988-1994 (NHANES III) to
1999-2000 NHANES
30 increase, plt.001
Population With Hypertension (millions)
Nearly 1 in 3 Adults (31) in the US Has
Hypertension
Fields, et al. Hypertension. 200444398f
4
Age Distribution of Hypertensives in US
Population NHANES III and the 1991 Census
26
74
23.7
47.4 million hypertensives 26.0 of US population
21.3
19.2
Hypertensives Within Age Group ()
13
9.5
9.6
3.7
Age Groups (y)
Franklin SS. J Hypertension. 199917(suppl
5)S29-S36.
5
Distribution of Hypertension Subtype in the
Untreated Hypertensive Population by Age (NHANES
III)

Diastolic Hypertension
17
16
16
20
20
11
Frequency of hypertension subtypes in all
untreated hypertensives ()
lt40
40-49
50-59
60-69
70-79
80
Age (y)
Numbers at top of bars represent the overall
percentage distribution of untreated hypertension
by age. Franklin et al. Hypertension.
200137 869-874.
6
1976-98 Cumulative Incidence of HTN in Women and
Men Aged 65 Years
Risk of Hypertension
Years of Follow-up
Vasan, et al. JAMA.20022871003
7
Secondly, hypertension is associated with
considerable cardiovascular risk.
8
Global Mortality 2000 Impact of Hypertension and
Other Health Risk Factors
High blood pressure
Tobacco
High cholesterol
Underweight
Unsafe sex
High BMI
Physical inactivity
Alcohol
Indoor smoke from solid fuels
Iron deficiency
0
8000
7000
6000
5000
4000
3000
2000
1000
Attributable Mortality (In thousands total
55,861,000)
Ezzati et al. Lancet. 20023601347-1360.
9
BP and Ischemic Heart Disease Mortality
Age at Risk (y)
Age at Risk (y)
80-89
256
256
80-89
70-79
70-79
60-69
60-69
50-59
32
32
50-59
IHD Mortality (Floating Absolute Risk and 95 CI)
40-49
40-49
4
4
0
0
160
180
140
90
100
110
120
70
80
Usual SBP (mm Hg)
Usual DBP (mm Hg)
Adapted from Prospective Studies Collaboration.
Lancet. 20023601903-1913.
10
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 40-70 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 7. JAMA. 20032892560-2572.
11
JNC Reclassification of BP Based on Risk
JNC VI
JNC 7
DBP (mm Hg)
SBP (mm Hg)
DBP (mm Hg)
SBP (mm Hg)
Category
Category
Source for JNC VI Arch Intern Med.
19971572413-2446. Adapted with permission from
Chobanian AV et al. Hypertension.
2003421206-1252.
12
Prevalence of Blood Pressure Categories in US
Adults 20 Years of Age (NHANES 1999-2000)
Greenlund, Croft, Mensah (CDC). Arch Intern Med.
20041642113f
13
Prehypertension

• Is not a disease,
• Is not hypertension,
• Is not an indication for drug treatment of HTN,
• Does not have a BP goal,
• Does predict a higher risk for developing CV
  events,
• Does predict a higher risk for developing HTN,
• Should be an incentive to improve lifestyle
  practices for prevention of HTN and CVD.

14
Thirdly, there is considerable reduction in
cardiovascular risk with effective lowering of
blood pressure with therapy.
15
Long-Term Antihypertensive Therapy Significantly
Reduces CV Events
Stroke
Heart failure
Myocardial
infarction
0
10
20
Average reduction in events ()
20-25
30
40
35-40
50
gt50
60
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20003551955-1964.
16
BP-Lowering Treatment TrialistsComparisons of
Different Active Treatments
BP Difference(mm Hg)
Relative Risk
RR (95 CI)
Major CV events
CV mortality
Total mortality
FavorsFirst Listed
FavorsSecond Listed
0.5
1.0
2.0
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
17
Rationale for Specific Goals

• Specific BP targets
• General population BP lt140/90 mmHg based on
  worldwide standards
• High-risk groups (diabetes or chronic kidney
  disease) BP lt130/80 mmHg based on increased
  absolute risk of CVD in these groups

JNC 7. Hypertension 2003421206-1252.
18
Fourthly, there is insufficient awareness,
treatment and control of hypertension.
19
Hypertension Awareness, Treatment, and Control
US 1976 to 2000
73
70
68
Awareness
59
55
54
51
34
31
Adults
29
27
Treated
10
Control
NHANES III (Phase 2) 1991-1994
NHANES II 1976-1980
NHANES III (Phase 1) 1988-1991
NHANES 1999-2000
Chobanian et al. JAMA. 20032892560-2572.
20
Percentage of Treated Patients with Hypertension
at Goal

• Caucasians 56
• African-Americans 45
• Hispanics 44
• Patients ?60 years old 44
• Patients with diabetes 25

Hajjar I, Kotchen TA. (2003), JAMA 290(2)199-206
21
Percentage of Treated Patients with CVD Events
and Hypertension at Goal

• Chronic kidney disease 25
• Stroke
  26
• Peripheral artery disease 29
• Heart failure 46
• Coronary heart disease 49

Wong, et al. submitted for publication
22
Barriers to defining and managing cardiovascular
risk
1.Focusing on DBP rather than SBP and pulse
pressure goals
23

• A rise in systolic blood pressure is part of the
  normal aging process. Therefore, an estimate of
  normal systolic blood pressure is 100 plus you
  age in years.

Source Anonymous.
Who is at greater cardiovascular risk? Those with
BP of 135/95 vs 150/80?
24
1970
25
SHEP TrialDesign

• N 4736 43 male
• Age gt60
• BP SBP 160-219 and DBP lt90
• Design Placebo control, double blind
• Active Rx Chlorthalidone (atenolol as step 2)
• SBP difference 12 mm Hg
• Duration 4.5 years

JAMA 19912653255
26
SHEP TrialCardiovascular Disease Endpoints
JAMA 19912653255
27
Cardiovascular Risk Associated with Increasing
SBP at Fixed Values of DBP
EWPHE (n 840) SYST-EUR (n 4695) SYST-CHINA (n
2394)
75 80 85 90 95
DBP (mm Hg)
2-year risk of endpoint
SBP (mm Hg)

• Two-year risk adjusted for active treatment, sex,
  age, previous CV complications, and smoking by
  multiple Cox regression.

Staessen, et al. Lancet. 2000355865872.
28
2. Failure to consider all CV risk factors
in calculating global absolute risk
29
Risk Factor Clustering With Hypertension
30
Men
25
Women
27
26
25
24
20
22
RiskFactors()
20
19
17
15
10
12
8
5
0
0
1
2
3
4
Number of Risk Factors
Risk factor clustering with hypertension, ages
1874 years. Framingham offspring.
Kannel WB. Am J Hypertens. 2000.
30
The Metabolic Syndrome
NCEP-ATP III Definition 3 of the Following
Diagnosis is established when 3 of these risk
factors are present.Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
31
Adults With Diagnosed Diabetes
7.3 DM Prevalence
4.9 DM Prevalence
Includes women with a history of gestational
diabetes.
Mokdad AH, et al. JAMA. 2001286(10)1195-1200.
32
Framingham Heart Study (1983)
CV Risk Gradient Profile
703
700
600
500
459
400
8 Year Probability Per 1,000
326
300
210
200
100
46
Systolic BPCholesterolGlucose
Intol.Cigaretes ECG-LVH

• gtgtgt 185
• 185
• 0
• 0
• 0

• gtgtgt 185
• 335
• 0
• 0
• 0

• gtgtgt 185
• 335
• 0
• 0

• gtgtgt 185
• 335
• 0

• gtgtgt 185
• 335

Kannel, 1983
33
ESH/ESC Guidelines - 10 Year Risk of CVD
Low added Moderate added High added Very high
added
lt 15 15-20 20-30 gt 30
Like the 1999 WHO/ISH Guidelines, except for
use of word added
6410 M
34
ESH/ESC Guidelines Stratification of Risk to
Quantify Prognosis
Blood Pressure (mmHg)
Grade 1 SBP 140-159 or DBP 90-99
Grade 2 SBP 160-179 or DBP 100-109
Grade 3 SBP 180 or DBP 110
Normal SBP 120-129 or DBP 80-84
High Normal SBP 130-139 or DBP 85-89
Other Risk Factors and Disease History No other
risk factors 1-2 risk factors ACC
High added risk
Moderate added risk
Low added risk
Average risk
Average risk
Very high added risk
Moderate added risk
Moderate added risk
Low added risk
Low added risk
Very high added risk
High added risk
High added risk
High added risk
Moderate added risk
3 or more risk factors or TOD or diabetes
Very high added risk
Very high added risk
Very high added risk
Very high added risk
High added risk
ACC associated clinical conditions TOD target
organ damage SBP systolic blood pressure DBP
diastolic blood pressure
6252 M
35
Clinical Silos
Cardiovascular Disease Risk
Blood Pressure JNC 7
Lipids NCEP ATP III
Diabetes ADA
Courtesy of Bryan Williams, MD.
36
3. Failure to strongly advocate lifestyle
modifications
37
Lifestyle Interventions for Prevention or
Treatment of Hypertension

• Intervention
• Exercise
• Weight reduction
• Alcohol intake reduction
• Sodium intake reduction
• DASH diet

• Blood Pressure Effect
• 5-10 mm Hg (gt30 min gt3x/wk)
• 1-2 mm Hg/Kg?
• 1 mm Hg/drink/d?
• 1-3 mm Hg/40 mmol/d?
• 3-10 mm Hg ?

Adapted from Cushman et al. Endocrine Practice
19973106 Sacks, et al. NEJM 20013343
38
Lifestyle Treatment Measures

• Nonpharmacologic treatments are used for
• Lowering blood pressure
• Reducing need for antihypertensive agents
• Minimizing associated risk factors
• Primary prevention of hypertension

39
4. Failure to use Polypharmacy
40
Rationale for Combination Drug Therapy in
Hypertension

• Necessary for Good Control
• ? Approx. 2/3 of mild/ moderate hypertension
• Almost all patients with complicated HTN
• All resistant, severe, or secondary hypertension
• Maximizes Efficacy
• Supplementary mechanisms of action
• Blockade of contra regulatory mechanisms
• Minimizes Side Effects
• Lower doses of each drug
• ? May antagonize adverse pharm. actions of other
  drug

41
Multiple Antihypertensive Agents Are Most Often
Needed to Achieve Target BP
No. of Antihypertensive Agents
Target BP (mm Hg)
Trial
1
2
3
4
DBP ?85
UKPDS1
DBP ?75
ABCD2
MAP ?92
MDRD3
DBP ?80
HOT4
MAP ?92
AASK5
SBP ?135/DBP ?85
IDNT6
ALLHAT7
SBP ?140/DBP ?90
1. UK Prospective Diabetes Study Group. BMJ.
1998317703-713. 2. Estacio RO et al. Am J
Cardiol. 1998829R-14R. 3. Lazarus JM et al.
Hypertension. 199729641-650.4. Hansson L et
al. Lancet. 19983511755-1762.
5. Kusek JW et al. Control Clin Trials.
19961640S-46S. 6. Lewis EJ et al. N Engl J Med.
2001345851-860. 7. ALLHAT. JAMA.
20022882998-3007.
42
Rule of TENS for SBP

• 1 Additional Drug for Every Additional
• 10 mmHg Reduction in Blood Pressure

Cushman W and Basile J. of Clinical Hypertension
(submitted for publication)
43
5. Failure to use a diuretic as part of
polypharmacy
44
The greatest breakthrough in the history of
drug treatment of hypertension came with the
discovery of the orally effective diuretic,
chlorothiazide in 1957 Edward
D Freis
45
Physiological Effects of Diuretics
Diuretics
? Plasma volume
Initially
? Cardiac Output
Long-term
? Blood Pressure
? Arterial Resistance
Counter-regulatory Mechanisms
? Renal Perfusion ? Renin/Angiotensin
Activity ? Arterial Resistance ? Blood Pressure
Adapted from Moser and Setaro, Med Clin N Am
200488167-187.
46
Primary Outcome (Fatal CHD or Nonfatal MI) by
Treatment Group
Chlorthalidone Amlodipine Lisinopril

47
SBP Response to 2-Drug Combo With or Without a
Diuretic
SBP lt140 mm Hg
100
P 0.002
77
80
60
Patients ()
46
40
20
0
With HCTZ
Without HCTZ
HCTZ hydrochlorothiazide Materson BJ, et al. J
Hum Hypertens. 19959791-796.
48
Conclusions (1)

• Diuretics are good first choice agents for
• older patients, isolated systolic
  hypertension Blacks.
• Diuretics are questionable first choice
  single-agents for
• the young, salt-resistant, and the
  metabolic syndrome.
• Diuretics/beta blocker combinations lower BP,
  but
• increase dyslipidemia and insulin
  resistance.

49
Conclusions (2)

• A diuretic should be part of the
  antihypertensive drug combination, especially in
  those in whom SBP is difficult to control.
• ACEI/ARB-diuretic combinations are favored for
  therapy in diabetes, renal disease, and heart
  failure.
• Hypertension treatment is less about which drug
  you start with and more about which combination
  is most effective in controlling blood pressure
  to target

50
6. Failure in selecting effective combinations
of antihypertensive classes
51
Choices for Uncomplicated Hypertension
Younger (lt55 years) and non-black
Older (lt55 years) or black
(1)
(2)
Step 1
D or C
A (or B)
Step 2
A (or B) D or C
Step 3
A (or B) D C
Step 4
Add spironolactone (or Alpha Blocker)
Resistant hypertension
A ACE inhibitor or angiotensin receptor
blocker C Calcium channel blocker
B ß blocker D Diuretic (thiazide and
thiazide-like)
Dickerson, et al. Lancet 19993532008-2013.
52
7. Failure to titrate doses upward
53
3020100
HCTZ
3020100
ß- Blocker
Prevalence () of people reporting symptoms
(treated placebo)
3020100
Proportions of people reporting one or more
symptoms attributable to treatment (treated
minus placebo with 95 confidence interval)
according to category of drug and dose as
a proportion of standard (designated 1).
CCB
1/4
1/2
1
2
4
Law, M R et al. BMJ 20033261427
54
8. Fear of reaching excessively low DBP
55
Is there a J curve for increased CV events?
CV events
DBP
56

• This relationship is not related to
  antihypertensive treatmentat least not until DBP
  lt 60-70 mm Hg.
• Poor health conditions leading to ? BP and ?
  mortality probably explain some of the J-shaped
  curve.
• Increased arterial stiffness explains most of the
  J-shaped curve.

57
9. Behavioral barriers to controlling
hypertension
58
The Initial Confrontation of the HTN Problem

• Upon making a diagnosis of HTN, tell patient the
  BP reading and what it should be (provide a
  written copy).
• Prepare patient for the probable necessity for
  polypharmacy to control BP with a minimum of
  side effects
• Advise Home BP measurement (135/85 mmHg is
  considered to be hypertensive).

Table 28. JNC 7 Report. Hypertension.
200342(6)1240.
59
Self-Measurement of BP

• Provides information useful for
• assessing response to antihypertensive Rx
• improving adherence with therapy
• evaluating white-coat HTN
• Home BP is more strongly related to target organ
  damage and has better prognostic accuracy than
  office BP.

60
The Non- or Poor- Compliance Patient

• Consider non-adherence as a cause of
• Failure to reach goal BP.
• Resistant hypertension.
• Sudden loss of control.
• Encourage patients to bring in all medications
  from all physicians and other sources, whether
  prescription, complementary, or over-the-counter,
  to each visit for review and to rule out
  iatrogenic causes of elevated BP.

Table 26. JNC 7 Report. Hypertension.
200342(6)1240.
61
10. The truly resistant Patient with hypertension
62
Differential Diagnosis of Refractory (Resistant)
Hypertension

• Physiologic
• Morbid obesity
• Excess dietary sodium
• Excessive alcohol

Secondary hypertension renal
parenchymal disease renovascular
hypertension sleep apnea
mineralocorticoid hypertension Increased artery
stiffness isolated systolic hypertension

• Concurrent medication
• NSAIDs (low GFR)
• Sympathomimetics
• Illicit drugs

63
Philosophy for Successful Treatment of HTN
--- Huang Dee Nai-Chang --- (2600 BC 1st
Chinese Medical Text) Superior doctors prevent
the disease. Mediocre doctors treat the disease
before evident. Inferior doctors treat the
full-blown disease.