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Practical Approaches to Managing
Hypertension: Reducing Global
Cardiovascular Risk
John S. Banas, MD
Professor Emeritus of Clinical Medicine
Columbia University College of Physicians and Surgeons
New York, New York
Dorothy and Lloyd Huck Chairman Emeritus
Department of Cardiovascular Medicine
Morristown Memorial Hospital
Morristown, New Jersey
Key Question
Which class of agents do you presently
consider first-line treatment for patients
with hypertension?
1. Diuretics
2. β-Blockers (BBs)
3. Calcium channel blockers (CCBs)
4. Angiotensin-converting enzyme inhibitors (ACEIs)
5. Angiotensin receptor blockers (ARBs)
6. All of the above
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Faculty Disclosure
 Dr Banas: speakers bureau: Bristol-Myers Squibb
Company, Pfizer Inc, sanofi-aventis Group; speakers
bureau, consultant: King Pharmaceuticals, Inc.
Learning Objectives
 State the prevalence of hypertension and its role
in the cardiovascular disease continuum
 Formulate hypertension management according
to risk stratification
 Describe the importance of targeting improvement
in vascular function in patients with hypertension
Progression of Cardiovascular Disease:
The Cardiovascular Continuum
Myocardial infarction
Myocardial
ischemia
SD
Ventricular
dysfunction
PAD
Endothelial
dysfunction and
atherothrombosis
Ventricular
dilation and
hypertrophy
Stroke
Hyperlipidemia,
HTN, diabetes, smoking,
obesity, etc
Adapted from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.
Congestive
heart failure
and death
Progression From Hypertension
to Heart Failure/Sudden Death
Obesity
Diabetes
LVH
Diastolic
dysfunction
Hypertension
Smoking
Dyslipidemia
Risk Factors
HF
ACS
Systolic
dysfunction
Atherothrombosis,
left ventricular
remodeling
Subclinical
left ventricular
dysfunction
Time
Adapted from Vasan RS, Levy D. Arch Intern Med. 1996;156:1789-1796.
Overt heart
failure
Death/
Sudden
Death
Development and Progression
of Vascular Disease
RISK FACTORS
LDL
BP
Diabetes
Smoking
Oxidative Stress
Endothelial Dysfunction and
Smooth Muscle Activation
NO •  Local Mediators •  Tissue ACE, AII
Endothelin
Catecholamines
PAI-1, Platelet
Aggregation,
Tissue Factor
Vasoconstriction
Thrombosis
VCAM/ICAM
Cytokines
Proteolysis
Inflammation
Inflammation
Plaque
Rupture
CLINICAL SEQUELAE
Dzau V. Hypertension. 2001;37:1047-1052.
Growth Factors
Cytokines
Matrix
Vascular Lesion
and Remodeling
Hypertension and Global CV Risk
What Is Global CV Risk?
 Treating hypertension to goal is good
 Addressing all CV risk factors is better
 Achieve
optimal BP level
 Avoid CV and renal morbidity and mortality
Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
JNC 7 Cardiovascular Risk Factors
 Hypertension
 Microalbuminuria
 Cigarette smoking
or estimated GFR
<60 mL/min
 Age (men >55 yr;
women >65 yr)
 Family history of
premature CVD
 Obesity (BMI ≥30 kg/m2)
 Physical inactivity
 Dyslipidemia
 Diabetes mellitus
Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
NCEP/Framingham Risk Scores: Estimate
of 10-yr CHD Risk in Men Without CHD
Age (y)
Points
20–34
–9
35–39
–4
40–44
0
45–49
3
50–54
6
Total-C
(mg/dL)
20–39
40–49
<160
160–199
200–239
240–279
≥280
0
4
7
9
11
0
3
5
6
8
0
2
3
4
5
Age (y)
20–39
40–49
50–59
60–69
0
8
0
5
0
3
0
1
Point total:
<0
10-yr risk (%) <1
0
1
1 2
1 1
3
1
4
1
65–69 70–74 75–79
11
12
13
HDL-C (mg/dL)
Points
Age (y)
50–59
Nonsmoker
Smoker
55–59 60–64
8
10
5
2
60–69
70–79
0
1
1
2
3
0
0
0
1
1
6
2
Reilly MP, Rader DJ. Circulation. 2003;108:1546-51.
–1
0
1
2
Systolic BP
Points
(mm Hg) Untreated Treated
<120
0
0
120–129
0
1
130–139
1
2
0
140–159
1
2
1
≥160
2
3
9 10 11 12 13 14 15 16 >17
5 6 8 10 12 16 20 25 ≥30
70–79
7 8
3 4
≥60
50–59
40–49
<40
Points
Key Question
What percentage of patients with hypertension
have 2 or more additional CV risk factors?
1. 20%
2. 30%
3. 40%
4. 50%
5. >50%
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CV Risk Factor Clustering With Hypertension:
Framingham Offspring, Aged 18 to 74 Years
>50% of Hypertension Occurs in Presence
of 2 or More Risk Factors
Men
Women
1 RF
2 RFs
1 RF
25%
26%
12%
3 RFs
4 or
More RFs
20%
17%
8%
No
Additional
RFs
24%
27%
22%
19%
2 RFs
No
Additional
RFs
RF = risk factor.
Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.
3 RFs
4 or
More RFs
10-Year Probability of
Event (%)
Risk of CHD in Mild Hypertension by
Intensity of Associated Risk Factors
Risk Factors
40
42
36
30
21
24
18
10
12
6
4
14
6
0
SBP 150-160 mm Hg
TC 240-262 mg/dL
HDL-C 33-35 mg/dL
Diabetes
Cigarette smoking
ECG-LVH
+
−
−
−
−
−
+
+
−
−
−
−
+
+
+
−
−
−
Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.
+
+
+
+
−
−
+
+
+
+
+
−
+
+
+
+
+
+
JNC 7 Classification of Blood Pressure
STAGE 2
SBP 160 mm Hg or
DBP 100 mm Hg
Treatment
recommended
STAGE 1
SBP 140-159 mm Hg or
DBP 90-99 mm Hg
PREHYPERTENSION
SBP 120-139 mm Hg or
DBP 80-89 mm Hg
NORMAL
Consider treatment in
those with diabetes or
renal disease who fail
lifestyle modification
SBP <120 mm Hg and
DBP <80 mm Hg
Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
JNC 7: Algorithm for Hypertension
LIFESTYLE MODIFICATIONS
Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients
with diabetes or chronic kidney disease)
INITIAL DRUG CHOICES
Without Compelling Indications
Stage 1 Hypertension
Thiazide-type diuretics
for most; may consider
ACEI, ARB, BB, CCB,
or combo
Stage 2 Hypertension
2-drug combos for most
(usually thiazide-type
diuretics and ACEI,
or ARB, or BB, or CCB)
With Compelling Indications
Compelling Indications
Other drugs
(diuretic, ACEI, ARB,
BB, CCB) as needed
If not at goal BP, optimize dosages or add drugs until
goal BP achieved; consider consultation with hypertension specialist
Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230.
Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
Nonpharmacologic Interventions
and BP Reduction
Weight Loss
(19.4 lb)
0
Low-Salt
Diet
Exercise
Alcohol
Reduction
BP Decrease
(mm Hg)
1
2
3
4
5
6
SBP
DBP
7
Adapted from: Stevens VJ et al. Ann Intern Med. 2001;134:1-11; Messerli FH et al. In: Griffin BP et al,
eds. 2004. Manual of Cardiovascular Medicine. 2nd ed; Whelton SP et al. Ann Intern Med.
2002;136:493-503; Cutler JA et al. Am J Clin Nutr. 1997;65(suppl):643S-651S; Xin X et al. Hypertension.
2001;38:1112-1117; Whelton PK et al. JAMA. 1997;277:1624-1632.
Antihypertensive Medications:
Mechanism of Action
Drug Class
Mechanism of Action
Diuretics
 Rid body of excess fluids and sodium
 May enhance effect of other BP medications
ACEIs
 Lower levels of angiotensin II
 Dilate blood vessels
ARBs
 Block angiotensin II receptors
 Dilate blood vessels
BBs
 Decrease heart rate and cardiac output
CCBs
 Interrupt movement of calcium into heart and vessel cells
Aldosterone Receptor
Blockers
 Decrease salt and water retention
Renin Inhibitors
 Block action of renin, decreasing formation of angiotensin I
American Heart Association. December 11, 2006. Available
at:http://www.americanheart.org/presenter.jhtml?identifier=3038158.
JNC 7: Compelling Indications
for Antihypertensive Drug Classes
Recommended Drugs
Compelling Indication
Heart failure
Post MI
High coronary
disease risk
Diabetes
Chronic kidney disease
Recurrent stroke
prevention
Diuretic ACEI
•
•
•
•
•
•
•
•
•
•
BB
•
•
Aldo
ARB CCB ANT
•
•
•
•
•
•
•
•
•
Aldo ANT = aldosterone antagonist. Chobanian AV et al, for the NHBPEPCC. Bethesda, Md: NHLBI;
2004. NIH Publication No. 04-5230. Available at:
www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.
Key Question
On average, how many drugs will a patient
need to control hypertension?
1. 1
2. 2
3. 3
4. 4
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Multiple Antihypertensive Agents Frequently
Required to Achieve BP Goal
UKPDS (<150/85 mm Hg)
MDRD (<92 mm Hg, MAP)
HOT (<80 mm Hg, diastolic)
AASK (<92 mm Hg, MAP)
RENAAL (<140/90 mm Hg)
IDNT (135/85 mm Hg)
1
2
3
Average No. of BP Medications
Patients had either diabetes or renal impairment.
Bakris GL et al. Am J Kidney Dis. 2000;36:646-661; Brenner BM et al. N Engl J Med. 2001;345:861869; Lewis EJ et al. N Engl J Med. 2001;345:851-860.
4
Hypertension and Diabetes:
Global CV Risk Reduction With
Evidence-Based Intervention
DM Approximately Doubles CVD Risk
in Patients With Hypertension
Study
Patients With Patients Without
Diabetes
Diabetes
(events per 1000 pt-yr)
Ratio
SHEP
CV events
63.0
36.8
1.71
Stroke
28.8
15.0
1.92
CHD events
32.2
15.2
2.12
CV events
55.0
28.9
1.90
Stroke
26.6
12.3
2.16
CHD events
23.1
12.4
1.87
24.0
9.8
2.45
Syst-Eur
HOT (DBP <90 mm Hg)
CV events
Adapted from Curb JD et al. JAMA. 1996;276:1886-1892; Hansson L et al. Lancet.
1998;351:1755-1762; Tuomilehto J et al. N Engl J Med. 1999:340:677-684.
Syst-Eur: CV Protection Resulting From BP
Lowering Was Greatest in Patients With Diabetes
Reduction in Event Rate for
Active Treatment Group (%)
Diabetic
0
–10
–20
Overall
Mortality
8%
P = .55
–30
–40
–50
Nondiabetic
All CV
CVD
Events
Mortality
16%
P = .37
41%
P = .09
–60
–70
25%
P = .02
70%
P = .01
62%
P = .002
Fatal and
Nonfatal
Stroke
36%
P = .02
69%
P = .02
Fatal and
Nonfatal
Cardiac Events
22%
P = .10
57%
P = .06
Patients with hypertension received nitrendipine  enalapril or HCTZ. N = 4695. DM = 492.
Syst-Eur = Systolic Hypertension in Europe; CV = cardiovascular.
Adapted from Tuomilehto J et al. N Engl J Med. 1999;340:677-684.
HOT Study: Fewer Major CV Events in Patients
With Diabetes Randomized to Lower BP Goal
P = .005
(per 1000 patient-years)
Stroke, MI, or CV Death
25
20
15
10
5
0
80
85
90
Target DBP (mm Hg)
Patients with hypertension and diabetes were given baseline felodipine, plus other agents in
a 5-step regimen. Study N = 18790; diabetes n = 1501.
HOT = Hypertension Optimal Treatment; MI = myocardial infarction.
Adapted from Hansson L et al, for the HOT Study Group. Lancet. 1998;351:1755-1762.
Relative Risk Reduction (%)
UKPDS: Tight Glucose Versus Tight
BP Control and CV Outcomes
0
-10
Tight glucose control (goal <6.0 mmol/L or 108 mg/dL)
Tight BP control (average 144/82 mm Hg)
Any Diabetic
DM
Microvascular
Stroke
Endpoint
Deaths
Complications
5%
10%
12%
-20
24%
*
-30
32%
*
-40
-50
44%
*
32%
*P <.05 compared to tight glucose control
37%
*
Patients had hypertension and Type 2 diabetes. N = 1148.
UKPDS = United Kingdom Prospective Diabetes Study.
Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.
Antihypertensive Medications:
Mechanism of Action
Drug Class
Mechanism of Action
Diuretics
 Rid body of excess fluids and sodium
 May enhance effect of other BP medications
ACEIs
 Lower levels of angiotensin II
 Dilate blood vessels
ARBs
 Block angiotensin II receptors
 Dilate blood vessels
BBs
 Decrease heart rate and cardiac output
CCBs
 Interrupt movement of calcium into heart and vessel cells
Aldosterone Receptor
Blockers
 Decrease salt and water retention
Renin Inhibitors
 Block action of renin, decreasing formation of angiotensin 1
American Heart Association. December 11, 2006. Available at:
http://www.americanheart.org/presenter.jhtml?identifier=3038158.
The Renin-Angiotensin-Aldosterone
System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Renin
Bradykinin
Angiotensin I
ACE
Inactive Peptides
 Blood Pressure
 Vascular Proliferation
 Oxidative Stress
 Vascular Inflammation
 Thrombogenesis
 Aldosterone
Angiotensin II
AT1
Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH.
J Am Soc Nephrol. 2004;15:1983-1992.
The Renin-Angiotensin-Aldosterone
System (RAAS)
Angiotensinogen
Kininogen
Renin
Inhibitors
Renin 
Kallikrein
Bradykinin
Angiotensin I
ACE
Inactive Peptides
Angiotensin II
ARBs
 Blood Pressure
 Vascular Proliferation
 Oxidative Stress
 Vascular Inflammation
 Thrombogenesis
 Aldosterone
AT1
Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH.
J Am Soc Nephrol. 2004;15:1983-1992.
The Renin-Angiotensin-Aldosterone
System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Renin
Bradykinin
Angiotensin I
ACE
Angiotensin II
Inactive Peptides
AT2
AT2
 Blood Pressure
 Vascular Proliferation
 Oxidative Stress
 Vascular Inflammation
 Thrombogenesis
 Aldosterone

ARBs
ARBs
AT1
Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH.
J Am Soc Nephrol. 2004;15:1983-1992.
VALUE: Hazard Ratios for Prespecified Analyses
in Patients With Hypertension at High CV Risk
Hazard Ratio
Valsartan/Amlodipine
Primary cardiac composite endpoint
Cardiac mortality
Cardiac morbidity
All myocardial infarction
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
0.5
1
Favors Valsartan
2.0
Favors Amlodipine
Patients had hypertension and were at high CV risk.
VALUE = Valsartan Antihypertensive Long-term Use Evaluation.
Julius S et al, for the VALUE trial group. Lancet. 2004;363:2022-2031.
The Renin-Angiotensin-Aldosterone
System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Nitric
Oxide
Bradykinin
Inactive Peptides
Renin
ACEIs
 ACE
 Blood Pressure
 Vascular Proliferation
 Oxidative Stress
 Vascular Inflammation
 Thrombogenesis
 Aldosterone
Angiotensin I
Angiotensin II
AT1
Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH.
J Am Soc Nephrol. 2004;15:1983-1992.
EUROPA: CV Death/MI/Cardiac Arrest
Placebo
20% Risk Reduction
HR = 0.80 (0.71–0.91)
P = .0003
Perindopril
8 mg
Time (years)
Percent
15
10
5
Time (years)
0
0
30
25
20
15
10
5
0
HOPE: CV Death/MI/Stroke
Placebo
22% Risk Reduction
HR = 0.78 (0.70–0.86)
Ramipril
P <.001
10 mg
20
Percent
14
12
10
8
6
4
2
0
1
2
3
4
5
0
PEACE: CV Death/MI/CABG/PCI
4% Risk Reduction Placebo
HR = 0.96 (0.88–1.06)
P = .43
Trandolapril
4 mg
Time (years)
1
2
3
4
5
6
1
2
3
QUIET: All CV Events
4% Risk Increase
HR = 1.04 (0.89–1.22)
P = .6
50
Percent
Percent
ACEI Trials in CAD Without HF:
Primary Outcomes
40
30
4
Quinapril
20 mg
Placebo
20
10
Time (years)
0
0
1
2
EUROPA Investigators. Lancet. 2003;362:782-788; HOPE Study Investigators. N Engl J Med.
2000;342:145-153; PEACE Trial Investigators. N Engl J Med. 2004;351:2058-2068; Pitt B, et al.
Am J Cardiol. 2001;87:1058-1063.
3
Primary Outcome (%)
MICRO-HOPE, PERSUADE:
CV Events in Patients With Diabetes
MICRO-HOPE
(n = 3577)
CV death/MI/stroke
25
25
PERSUADE
(n = 1502)
CV death/MI/cardiac arrest
Placebo
20
Placebo
20
25% RRR
P = .0004
15
19% RRR
P = .13
15
10
5
Perindopril
8 mg
10
Ramipril
10 mg
5
0
0
0
1
2
3
4
Follow-Up (years)
5
0
1
2
3
4
Follow-Up (years)
5
MICRO-HOPE = Microalbuminuria, Cardiovascular, and Renal Outcomes (Heart Outcomes Prevention
Evaluation); PERSUADE = Perindopril Substudy in Coronary Artery Disease and Diabetes.
HOPE Study Investigators. Lancet. 2000;355:253-259; Daly CA et al. Eur Heart J. 2005;26:1369-1378.
MICRO-HOPE: Albuminuria in Patients
With Diabetes
Mean Albumin/Creatinine
Ratio (urine)
3.0
Placebo
2.5
Ramipril
2.0
P = .02
1.5
P = .001
1.0
0.5
0.0
0
1
2
Time (y)
HOPE Study Investigators. Lancet. 2000;355:253-259.
3
4-5
Multiple Mechanisms of ACEI
in Cardiovascular Disease
Blood pressure lowering
Cardioprotective effects
  Preload and afterload
  LV mass
  Sympathetic stimulation
  Reperfusion injury
 Improved myocardial remodeling
Metabolic syndrome
 Lipid neutral
 Improved glucose metabolism
 Increases adiponectin
 Decreased insulin resistance
Vasculoprotective effects
 Direct antiatherogenic
 Enhance endogenous fibrinolysis
 Inhibit platelet aggregation
 Antimigratory for mononuclear cells
  Matrix formation
 Improve endothelial function
 Antioxidant
 Anti-inflammatory
 Protection from plaque rupture
 Improved arterial compliance
and tone
Modified from: Lonn E et al. Eur Heart J Suppl. 2003;5:A43-A48.
Definition of the Metabolic Syndrome
Abdominal Obesity
Waist Circumference
Men:
>40 in (>102 cm); (>94 cm [37 in])
Women: >35 in (>88 cm); (>80 cm [32 in])
Plus Two Risk Factors
 Triglycerides ≥150 mg/dL (1.7 mmol/L)
 HDL cholesterol
Men: <40 mg/dL (<1.0 mmol/L)
Women: <50 mg/dL (<1.3 mmol/L)
 BP ≥30/85 mm/Hg
 Glucose ≥110 mg/dL (>6.1 mmol/L);
(≥100 mg/dl) (≥5.6 mmol/L)
Grundy SM et al. Circulation. 2004;109:433-438.
IDF Consensus. Berlin 2005.
Metabolic Syndrome (cont’d)
Large (Visceral/Peritoneal)
Insulin-Resistant
Adipocytes
Relationship Between Visceral
Adipose Tissue and Insulin Action
Decreased Adiponectin*
Resistin
FFA*
TNF-alpha*
Leptin*
IL-6 (CRP)*
Tissue Factor*
PAI-1*
Retinol-binding protein
Adipsin
Angiotensinogen*
Acylation-stimulating protein
*Probable CAD Risk Factor
Banerji M et al. Am J Physiol. 1997;273:E425-E432.
Characteristics of the Metabolic
Syndrome: NCEP-ATP III
Abdominal obesity
Glucose intolerance/
Insulin resistance
Diabetes
Hypertension
CVD
Atherogenic dyslipidemia
Proinflammatory/
Prothrombotic state
National Cholesterol Educational Program (NCEP); Adult Treatment Panel (ATP) III; 2001.
AHA/ACC Guidelines Update in Patients
With Atherosclerotic CV Disease
Medication Recommendations as Supplements* to Lifestyle Modification
(TLC) (DASH, weight loss, exercise, smoking cessation):
 Lipid-lowering therapy to achieve LDL-C of <100 mg/dL
(optional: <70 mg/dL); non-HDL <130 mg/dL (optional: <100 mg/dL)
 Antiplatelet therapy, aspirin and/or clopidogrel
 Antihypertensive therapy to achieve BP of <140/90 mm Hg
 <130/80 mm Hg in the patient with diabetes
 Ideal BP 120/80 (JNC 7)
 Hypoglycemic therapy to achieve near normal fasting glucose (HbA1C <7%)
(ADA: <6.5)
 ACE inhibitor
 Beta-blocker
 Influenza vaccine
*In the absence of specific contraindications
Updated from: AHA/ACC. Circulation. 2001;104:1577-1579; Braunwald E et al. J Am Coll Cardiol.
2002;40:1366-1374; Grundy SM et al. Circulation. 2004;110:227-239; Krumholz HM et al. Circulation.
2006;113:732-761; Smith S et al. J Am Coll Cardiol. 2006;47:2130-2139.
Adherence
CV Risk Factor Control Among Adults
With Diagnosed Diabetes
Fewer than half of adults with diabetes achieve
treatment goals for CV risk factors
NHANES III, 1988-1994 (n = 1204)
NHANES 1999-2000 (n = 370)
60
Adults (%)
50
40
48.2
44.3
37.0
35.8
33.9
29.0
30
20
10
0
5.2
A1C Level
<7%
7.3
Blood Pressure Total Cholesterol* Achieved All 3
<130/80 mm Hg
<200 mg/dL
Treatment Goals
*LDL-C and TG not evaluated.
Saydah SH, et al. JAMA. 2004;291:335-342.
Factors Which Contribute
to Poor Adherence
 Lack of understanding
 Dementia/senility
 Side effects
 Lack of discharge planning
 Cost
 Lack of symptoms
 Complexity of Rx regimen
 Poor mobility
 Little or no support system
Modified from: Vermeire E, et al. J Clin Pharm and Ther. 2001;26:331-342; Cheng JWM, et al.
Pharmacotherapy. 2001;21:828-841.
Practical Tips to Improve Adherence
 Talk to your patient






Explain the condition and why specific therapy is important
Ask about adherence
Involve the patient as a partner in treatment
Provide clear written and oral instructions
Tailor the regimen to the patient’s lifestyle and needs
Use motivational interviewing techniques
 Look for
 Different ways to approach patients based on individual
patient attitudes
 Allies in patient care—family, friends
 Ways to simplify the regimen
 Refill dates (if the patient has not refilled the prescription,
the medication is not being taken)
Ockene IS et al. J Am Coll Cardiol. 2002;40:630-640.
Practical Tips to Improve Adherence
 Use systematic approaches


Disease management programs
Periodic review of electronic medical records or manual
chart audits
 Group/shared medical appointments blend care, education,
social support
 Other techniques
 Follow-up (telephone/mail/e-mail) and reminder cards
 Signed agreements/contracts
 Self-monitoring tools (eg, tape measure, pedometer,
home testing devices)
 Patient assistance programs
 Support patients where medication costs are a barrier
to adherence
Fonarow GC et al. Am J Cardiol. 2001;87:819-822; Ockene IS et al. J Am Coll Cardiol. 2002;40:
630-640; NCEP ATP III. September 2002. NIH publication no. 02-5215;
Pfizer Helpful Answers Web site. Available at: http://www.pfizerhelpfulanswers.com.
Summary: The Case for Global
CV Risk Management
 CV disease remains the leading cause of death
in both men and women in the United States
 Data from the Framingham Heart Study have demonstrated
“clustering” of risk factors—and that risk of death from CHD
and stroke increases further with each added risk factor
 Hypertension, a pivotal risk factor for CV disease, should
prompt the search for the presence of additional risk factors
 Recent clinical trials have provided the “evidence” supporting
a “standard of care” for the management of global CV risk
Case Study
Case Study: 55-Year-Old Man From India
With Hypertension and Type 2 Diabetes
The patient is in for a checkup
 History
 Hypertension
 Type 2 diabetes
 Nonsmoker
 No symptoms
 Physical examination
 BP: 148/96 mm Hg
 Height: 64"
 Weight: 178 lb
 BMI: 30 kg/m2
 Waist circumference: 38"
 Cardiac dysfunction status:
normal ventricular function
(LVEF 68%)
 Laboratory values

Glucose: 148 mg/dL
(fasting)
 A1C: 8.8%
 Creatinine: 1.5 mg/dL
 Urinalysis: 1+ proteinuria
 Lipid profile (mg/dL):
TC: 268; LDL-C: 168;
HDL-C: 42; TG: 296
 Medications
 HCTZ 25 mg/d
 Glyburide 5 mg/d
VBWG
NCEP/Framingham Risk Scores: Estimate
of 10-yr CHD Risk in Men Without CHD
Age (y)
Points
20–34
–9
35–39
–4
40–44
0
45–49
3
50–54
6
55–59 60–64
8
10
HDL-C (mg/dL)
Total-C
(mg/dL)
20–39
40–49
Points
Age (y)
50–59
<160
160–199
200–239
240–279
≥280
0
4
7
9
11
0
3
5
6
8
0
2
3
4
5
Age (y)
20–39
40–49
50–59
60–69
70–79
0
8
0
5
0
3
0
1
0
1
Nonsmoker
Smoker
Point total:
<0
10-yr risk (%) <1
0
1
1 2
1 1
3
1
4
1
65–69 70–74 75–79
11
12
13
5
2
60–69
70–79
0
1
1
2
3
0
0
0
1
1
6
2
Reilly MP, Rader DJ. Circulation. 2003;108:1546-51.
7 8
3 4
≥60
50–59
40–49
<40
Points
–1
0
1
2
Systolic BP
Points
(mm Hg) Untreated Treated
<120
120–129
130–139
140–159
≥160
9 10 11 12
5 6 8 10
0
0
1
1
2
0
1
2
2
3
13 14 15 16 >17
12 16 20 25 ≥30
Decision Point
What is the JNC 7 goal for this patient who has
hypertension, diabetes, and renal disease?
1. <120/80 mm Hg
2. <130/80 mm Hg
3. <140/80 mm Hg
4. <140/90 mm Hg
Use your keypad to vote now!
?
Decision Point
The patient’s BP is 148/96 mm Hg while
taking HCTZ 25 mg/d and glyburide 5 mg/d.
To bring BP down to <130/80 mm Hg, you would
add a(n):
1. BB
2. CCB
3. ARB
4. ACE
Use your keypad to vote now!
?
PCE Takeaways
PCE Takeaways
1. Patients with hypertension often present with
multiple cardiac risk factors
2. Be vigilant in your investigation of all clinical
indicators
3. Creatively address patient adherence; not
everyone responds to the same interventions
4. Clinical inertia is the enemy—don't settle for
"close enough"
Key Question
How important is using an antihypertensive
agent with proven risk reduction (reducing
morbidity and mortality) when choosing
medications for your patients with hypertension?
1. Not important
2. Slightly important
3. Somewhat important
4. Extremely important
Use your keypad to vote now!
?
Estimate of 10-Year Risk for Men
(Framingham Point Scores)
1
2
Age, y
Points
20-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
-9
-4
0
3
6
8
10
11
12
13
Total
Cholesterol
<160
160-199
200-239
240-279
280
3
Systolic BP
mm Hg
If
If
Untreated Treated
<120
120-129
130-139
140-159
160
4
0
0
1
1
2
HDL mg/dL
60
50-59
40-49
<40
Age
20-39
0
4
7
9
11
Age
40-49
0
3
5
6
8
0
2
1
4
5
NCEP-ATP-III. JAMA. 2001;285:2486-2497.
0
8
Point Total
6
Points
Age Age
60-69 70-79
0
1
3
2
3
Age
20-39
Nonsmoker
Smoker
0
1
2
2
3
-1
0
1
2
Age
50-59
5
0
0
0
1
1
<0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Age
40-49
0
5
Age
50-59
Age Age
60-6970-79
0
3
0
1
10-Year Risk, %
<1
1
1
1
1
1
2
2
3
4
5
6
8
10
12
16
20
25
30
0
1
Estimate of 10-Year Risk for Women
(Framingham Point Scores)
1
2
Age, y
Points
20-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
-7
-3
0
3
6
8
10
12
14
16
Total
Cholesterol
<160
160-199
200-239
240-279
280
3
Systolic BP
mm Hg
If
If
Untreated Treated
<120
120-129
130-139
140-159
160
4
0
1
2
3
4
HDL mg/dL
60
50-59
40-49
<40
Age
40-49
Age
50-59
0
4
8
11
13
0
3
6
8
10
0
2
4
5
7
6
Points
NCEP-ATP-III. JAMA. 2001;285:2486-2497.
Age Age
60-69 70-79
0
1
2
3
4
Age
20-39
Age
40-49
Age
50-59
0
9
0
7
0
4
Nonsmoker
Smoker
0
3
4
5
6
-1
0
1
2
Age
20-39
5
0
1
1
2
2
Point Total
<9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Age Age
60-6970-79
0
2
10-Year Risk, %
<1
1
1
1
1
2
2
3
4
5
6
8
11
14
17
22
27
30
0
1
Study Design: EUROPA
STUDY N = 13,655
Patients had previous MI, angiographic evidence of CAD, coronary
revascularization, or a positive stress test
perindopril 8 mg/day
n = 6110
placebo
n = 6108
Randomized; mean follow-up 4.2 years
RESULTS
• Patients experiencing the primary endpoint (CV death, MI, or cardiac
arrest):
• 10% of patients in the placebo group
• 8% of patients in the perindopril group
• Among patients with stable CHD without apparent HF, perindopril can
significantly improve outcome
EUROPA = EURopean trial On reduction of cardiac events with Perindopril in stable
coronary Artery disease.
EUROPA Trial Investigators. Lancet. 2003;362:782-788.
Study Design: HOPE
STUDY N = 9297
Aged 55 years
Patients were at high risk for CV events (evidence of vascular disease or
diabetes + 1 other CV risk factor) but did not have LVD or HF
Ramipril 10 mg/day
n = 651
Placebo
n = 826
Randomized 2x2 factorial study also evaluated effects of vitamin E
RESULTS
CV DEATH
MI
STROKE
PLACEBO GROUP
8.1%
12.3% 4.9%
12.2%
TREATMENT GROUP
6.1%
9.9%
10.4%
3.4%
ALL-CAUSE DEATH
HOPE = Heart Outcomes Prevention Evaluation.
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med.
2000;342:145-153.
Study Design: HOT
STUDY N = 18,790
Aged 50-80 years, DBP 100-115 mm Hg
Randomized to DBP goals
90 mm Hg
n = 6264
85 mm Hg
n = 6264
80 mm Hg
n = 6262
Patients received the CCB felodipine 5 mg/day
To reach randomized BP goal, patients were also given ACE
inhibitors or beta-blockers; doses were increased as necessary
RESULTS
• CV events per 1000 pt/yrs, nondiabetic patients:
• 9.9 for DPB goal 90 mm Hg; 9.3 for DPB goal 80 mm Hg
• CV events per 1000 pt/yrs, diabetic patients:
• 24.4 for DPB goal 90 mm Hg; 11.9 for DPB goal 80 mm Hg
• BP lowering is particularly beneficial in patients with DM
HOT = Hypertension Optimal Treatment.
Hansson L, et al, for the HOT Study Group. Lancet. 1998;351:1755-1762.
Study Design: MICRO-HOPE
(a substudy of HOPE)
STUDY N = 3577
Aged 55 years
Patients were at high risk for CV events and
at least 1 other CV risk factor
Placebo n = 1760
Ramipril 10 mg/day n = 1808
2x2 factorial study also evaluated the effects of vitamin E
Follow-up 4.5 years; study stopped early because of consistent benefit
RESULTS
COMBINED
PRIMARY
OUTCOME*
MI
CV
DEATH
REVASCULARIZATION
TREATMENT GROUP
 25%
 22%
 37%
 17%
*MI, stroke, or CV death
HOPE = Heart Outcomes Prevention Evaluation.
Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145153.
Study Design: PEACE
STUDY N = 8290
Patients had stable CAD and normal
or slightly reduced left ventricular function
Trandolapril 4 mg/day
n = 4158
Placebo
n = 4132
Double blind, randomized, placebo controlled
Follow-up 4.8 years
RESULTS
• Patients experiencing the primary endpoint (CV death, MI, or coronary
revascularization):
• 22.5% of patients in the placebo group
• 21.9% of patients in the trandolapril group
PEACE = Prevention of Events with Angiotensin-Converting Enzyme Inhibition
PEACE Trial Investigators. N Engl J Med. 2004;351:2058-2068.
Study Design: PERSUADE
(a substudy of EUROPA)
STUDY N = 1502
Patients had diabetes with known CAD and no HF
perindopril 8 mg/day
n = 721
placebo
n = 781
Randomized, double-blind
Follow-up was a median of 4.3 years
RESULTS
• Patients experiencing the primary endpoint (CV death, nonfatal MI, or
resuscitated cardiac arrest):
• 15.5% of patients in the placebo group
• 12.6% of patients in the perindopril group (nonsignificant)
• Relative magnitude was similar to the 20% risk reduction in EUROPA
PERSUADE = PERindopril SUbstudy in coronary Artery Disease and diabEtes.
Daly CA, et al. Eur Heart J. 2005;26:1369-1378.
Study Design: QUIET
STUDY N = 1750
Patients did not have systolic left ventricular dysfunction
quinapril 20 mg/day
Placebo
Study duration a mean of 27  0.3 months
RESULTS
• Quinapril did not significantly affect the overall frequency of ischemic
events or the progression of coronary atherosclerosis
QUIET = Quinapril Ischemic Event Trial.
Pitt B, et al. Am J Cardiol. 2001;87:1058-1063.
Study Design: SHEP
STUDY N = 4736
Aged 60 years; SBP 160 mm Hg; DBP <90 mm Hg
Pts with noninsulin-dependent diabetes n = 583; nondiabetic pts n = 4149
Active treatment:
Chlorthalidone 12.5-25 mg/d with
step-up to atenolol 25-50 mg/d or
reserpine .05-.10 mg/d if needed
Placebo (or antihypertensive
drugs prescribed by patient’s
private physician for persistently
high BP)
Trial was double blind, randomized, placebo controlled
Follow-up 5 years
RESULTS:
• 5-year major CVD rate was lower by 34% for active treatment
compared with placebo for both diabetic and nondiabetic patients
• Absolute risk reduction with active treatment compared with placebo
was twice as great for diabetic vs nondiabetic patients
SHEP = Systolic Hypertension in the Elderly Program.
Curb JD et al. JAMA. 1996;276:1886-1892.
Study Design: Syst-Eur
STUDY N = 4695
Aged 60 years; SBP 160-219 mm Hg;
DBP <95 mm Hg; patients with diabetes n = 492
Nitrendipine 10-40 mg/day
with addition or substitution of
enalapril 5-20 mg/day or
hydrochlorothiazide 12.5-25 mg/day or both
Placebo
RESULTS
• In patients receiving active treatment, reductions in overall mortality,
mortality from CVD, and all CV events were significantly larger among
diabetic vs nondiabetic patients
• All CV events: 69% in diabetic vs 26% in nondiabetic patients
• Fatal/nonfatal strokes:  73% in diabetic vs  38% in nondiabetic patients
Syst-Eur = Systolic Hypertension in Europe
Tuomilehto J, et al. New Engl J Med. 1999;340:677-684.
Study Design: UKPDS
STUDY N = 1148
Type 2 diabetes
Mean age 56 years, mean BP 160/94 mm Hg
Tight BP control
n = 758
Less-tight BP control
n = 390
Randomized; median follow-up 8.4 years
RESULTS
• Risk reductions in group assigned to tight control vs less-tight control:
• 24% in diabetes-related end points
• 32% in deaths related to diabetes
• 44% in strokes
• 37% in microvascular end points
UKPDS = United Kingdom Prospective Diabetes Study.
UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713; Bakris GL, et al. Am J Kidney Dis.
2000;36:646-661.
Study Design: VALUE
STUDY N = 15,245
Aged 50 years;
With treated or untreated hypertension and high risk of cardiac events
Step 1: valsartan 80 mg/day
Step 2: valsartan 160 mg/day
n = 7649
Step 1: amlodipine 5 mg/day
Step 2: amlodipine 10 mg/day
n = 7596
Both regimens included HCTZ in steps 3 and 4
Further drugs could be given to achieve BP control
Randomized, double-blind, parallel group comparison
RESULTS
• BP  with both treatments
• Primary endpoint (composite of cardiac mortality and morbidity)
occurred in valsartan 10.6% vs amlodipine 10.4%, HR 1.04
• Amlodipine effects were more pronounced in the early period
•BP  4.0/2.1 mm Hg in amlodipine after 1 month
VALUE = Valsartan Antihypertensive Long-term Use Evaluation.
Julius S, et al. Lancet. 2004;363:2022-2031.
Metabolic
Syndrome
Abdominal Obesity
Waist Circumference
Men:
>40 in (>102 cm); (>94 cm [37in])
Women: >35 in (>88 cm); (>80 cm [32in])
Plus Two Risk Factors
 Triglycerides >150 mg/dL (1.7 mmol/L)
 HDL cholesterol
Men: <40 mg/dL (<1.0 mmol/L)
Women: <50 mg/dL (<1.3mmol/L)
 BP >130/85 mm/Hg
 Glucose >110 mg/dL (>6.1 mmol/L);
(≥100 mg/dl) (>5.6 mmol/L)
ICD-9 Code 277.7
Grundy SM et al. Circulation. 2004;109:433-438.
IDF Consensus. Berlin 2005
Large (Visceral / Peritoneal)
Insulin-Resistant
Adipocytes