Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

1
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
2
Key Question

• Which class of agents do you presently
• consider first-line treatment for patients
• with hypertension?
• Diuretics
• ß-Blockers (BBs)
• Calcium channel blockers (CCBs)
• Angiotensin-converting enzyme inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs)
• All of the above
• Use your keypad to vote now!

3
Faculty Disclosure

• Dr Banas speakers bureau Bristol-Myers Squibb
  Company, Pfizer Inc, sanofi-aventis Group
  speakers bureau, consultant King
  Pharmaceuticals, Inc.

4
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

5
Progression of Cardiovascular Disease The
Cardiovascular Continuum
Myocardial infarction
Myocardialischemia
Ventricular dysfunction
SD
PAD
Endothelialdysfunction and atherothrombosis
Ventricular dilation and hypertrophy
Stroke
Hyperlipidemia,HTN, diabetes, smoking, obesity,
etc
Congestive heart failure and death
Adapted from Dzau V, Braunwald E. Am Heart
J. 19911211244-1263.
6
Progression From Hypertension to Heart
Failure/Sudden Death
Obesity Diabetes
Hypertension
Smoking Dyslipidemia
Risk Factors
Time
Adapted from Vasan RS, Levy D. Arch Intern Med.
19961561789-1796.
7
Development and Progression of Vascular Disease
RISK FACTORS
Smoking
?BP
Diabetes
?LDL
Oxidative Stress
Endothelial Dysfunction andSmooth Muscle
Activation
?NO ? Local Mediators ? Tissue ACE, AII
EndothelinCatecholamines
PAI-1, PlateletAggregation, Tissue Factor
VCAM/ICAMCytokines
Proteolysis Inflammation
Growth Factors Cytokines Matrix
Inflammation
PlaqueRupture
Vasoconstriction
Thrombosis
Vascular Lesionand Remodeling
CLINICAL SEQUELAE
Dzau V. Hypertension. 2001371047-1052.
8
Hypertension and Global CV Risk
9
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/hyperte
nsion/jnc7full.pdf.
10
JNC 7 Cardiovascular Risk Factors

• Microalbuminuria or estimated GFR lt60 mL/min
• Age (men gt55 yr women gt65 yr)
• Family history of premature CVD

• Hypertension
• Cigarette smoking
• 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/hyperte
nsion/jnc7full.pdf.
11
NCEP/Framingham Risk Scores Estimate of 10-yr
CHD Risk in Men Without CHD
Reilly MP, Rader DJ. Circulation.
20031081546-51.
12
Key Question

• What percentage of patients with hypertension
• have 2 or more additional CV risk factors?
• 20
• 30
• 40
• 50
• gt50
• Use your keypad to vote now!

13
CV Risk Factor Clustering With Hypertension
Framingham Offspring, Aged 18 to 74 Years
gt50 of Hypertension Occurs in Presenceof 2 or
More Risk Factors
Men
Women
2 RFs
1 RF
2 RFs
1 RF
25
24
26
27
20
22
19
17
8
12
No Additional RFs
No Additional RFs
3 RFs
3 RFs
4 or More RFs
4 or More RFs
RF risk factor. Adapted from Kannel WB. Am J
Hypertens. 2000133S-10S.
14
Risk of CHD in Mild Hypertension by Intensity of
Associated Risk Factors
40
42
36
30
21
10-Year Probability of Event ()
24
18
14
10
12
6
4
6
0
Risk Factors
SBP 150-160 mm Hg TC 240-262 mg/dL -
HDL-C 33-35 mg/dL - - Diabete
s - - - Cigarette smoking - - - -
ECG-LVH - - - - -
Adapted from Kannel WB. Am J Hypertens.
2000133S-10S.
15
JNC 7 Classification of Blood Pressure
Chobanian AV et al, for the NHBPEPCC. Bethesda,
Md NHLBI 2004. NIH Publication No. 04-5230.
Available at www.nhlbi.nih.gov/guidelines/hyperte
nsion/jnc7full.pdf.
16
JNC 7 Algorithm for Hypertension
LIFESTYLE MODIFICATIONS
Not at Goal BP (lt140/90 mm Hg, or lt130/80 mm Hg
for patients with diabetes or chronic kidney
disease)
INITIAL DRUG CHOICES
Without Compelling Indications
With Compelling Indications
Stage 2 Hypertension 2-drug combos for most
(usually thiazide-type diuretics and ACEI, or
ARB, or BB, or CCB)
Compelling Indications Other drugs (diuretic,
ACEI, ARB, BB, CCB) as needed
Stage 1 Hypertension Thiazide-type diuretics
for most may consider ACEI, ARB, BB, CCB, or
combo
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/hyperte
nsion/jnc7full.pdf.
17
Nonpharmacologic Interventionsand BP Reduction
Low-SaltDiet
Weight Loss(19.4 lb)
Alcohol Reduction
Exercise
0
1
2
3
BP Decrease(mm Hg)
4
5
6
SBP
DBP
7
Adapted from Stevens VJ et al. Ann Intern Med.
20011341-11 Messerli FH et al. In Griffin BP
et al, eds. 2004. Manual of Cardiovascular
Medicine. 2nd ed Whelton SP et al. Ann Intern
Med. 2002136493-503 Cutler JA et al. Am J Clin
Nutr. 199765(suppl)643S-651S Xin X et al.
Hypertension. 2001381112-1117 Whelton PK et
al. JAMA. 19972771624-1632.
18
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 athttp//www.americanheart.org/presente
r.jhtml?identifier3038158.
19
JNC 7 Compelling Indications for
Antihypertensive Drug Classes

Recommended Drugs
AldoCompelling Indication Diuretic ACEI
BB ARB CCB ANT Heart failure   Post
MI       High coronary disease risk
    Diabetes   Chronic kidney
disease         Recurrent
stroke prevention
       
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.
20
Key Question

• On average, how many drugs will a patient
• need to control hypertension?
• 1
• 2
• 3
• 4
• Use your keypad to vote now!

21
Multiple Antihypertensive Agents Frequently
Required to Achieve BP Goal
UKPDS (lt150/85 mm Hg) MDRD (lt92 mm Hg, MAP) HOT
(lt80 mm Hg, diastolic) AASK (lt92 mm Hg,
MAP) RENAAL (lt140/90 mm Hg) IDNT (?135/85 mm Hg)
4
3
2
1
Average No. of BP Medications
Patients had either diabetes or renal
impairment. Bakris GL et al. Am J Kidney Dis.
200036646-661 Brenner BM et al. N Engl J Med.
2001345861-869 Lewis EJ et al. N Engl J Med.
2001345851-860.
22
Hypertension and Diabetes Global CV Risk
Reduction With Evidence-Based Intervention
23
DM Approximately Doubles CVD Risk in Patients
With Hypertension
Study Patients With Diabetes Patients Without Diabetes Ratio
Study (events per 1000 pt-yr) (events per 1000 pt-yr) Ratio
SHEP SHEP SHEP SHEP
CV events 63.0 36.8 1.71
Stroke 28.8 15.0 1.92
CHD events 32.2 15.2 2.12
Syst-Eur Syst-Eur Syst-Eur Syst-Eur
CV events 55.0 28.9 1.90
Stroke 26.6 12.3 2.16
CHD events 23.1 12.4 1.87
HOT (DBP lt90 mm Hg) HOT (DBP lt90 mm Hg) HOT (DBP lt90 mm Hg) HOT (DBP lt90 mm Hg)
CV events 24.0 9.8 2.45
Adapted from Curb JD et al. JAMA.
19962761886-1892 Hansson L et al. Lancet.
19983511755-1762 Tuomilehto J et al. N Engl J
Med. 1999340677-684.
24
Syst-Eur CV Protection Resulting From BP
Lowering Was Greatest in Patients With Diabetes
Diabetic
Nondiabetic
Fatal and Nonfatal Stroke
Fatal and Nonfatal Cardiac Events
Overall Mortality
CVD Mortality
All CV Events
0
10
8 P .55
16 P .37
20
22 P .10
Reduction in Event Rate for Active Treatment
Group ()
25 P .02
30
36 P .02
40
41 P .09
50
57 P .06
60
62 P .002
70
69 P .02
70 P .01
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. 1999340677-684.
25
HOT Study Fewer Major CV Events in Patients With
Diabetes Randomized to Lower BP Goal
P .005
25
20
15
Stroke, MI, or CV Death (per 1000 patient-years)
10
5
0
?80
?90
?85
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.
19983511755-1762.
26
UKPDS Tight Glucose Versus Tight BP Control and
CV Outcomes
Tight glucose control (goal lt6.0 mmol/L or 108
mg/dL)
Tight BP control (average 144/82 mm Hg)
Stroke
Any Diabetic Endpoint
DM Deaths
Microvascular Complications
0
5
-10
10
12
-20
Relative Risk Reduction ()
24

-30
32
32

37
-40

P lt.05 compared to tight glucose control
44

-50
Patients had hypertension and Type 2 diabetes. N
1148.
UKPDS United Kingdom Prospective Diabetes
Study. Bakris GL et al. Am J Kidney Dis.
200036646-661.
27
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/present
er.jhtml?identifier3038158.
28
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Renin
Angiotensin I
Bradykinin
ACE
Angiotensin II
Inactive Peptides

• Blood Pressure
• Vascular Proliferation
• Oxidative Stress
• Vascular Inflammation
• Thrombogenesis
• Aldosterone

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
29
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Renin Inhibitors
?
Renin
ACEIs
Angiotensin I
?
ACE
Angiotensin II
ARBs
?
ARBs

• Blood Pressure
• Vascular Proliferation
• Oxidative Stress
• Vascular Inflammation
• Thrombogenesis
• Aldosterone

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
30
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Kininogen
Renin Inhibitors
Kallikrein
?
Renin
Angiotensin I
Bradykinin
ACE
Angiotensin II
Inactive Peptides
ARBs

• Blood Pressure
• Vascular Proliferation
• Oxidative Stress
• Vascular Inflammation
• Thrombogenesis
• Aldosterone

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
31
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Renin
Angiotensin I
Bradykinin
ACE
Angiotensin II
Inactive Peptides
ARBs
?
ARBs
AT2
AT2

• Blood Pressure
• Vascular Proliferation
• Oxidative Stress
• Vascular Inflammation
• Thrombogenesis
• Aldosterone

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
32
VALUE Hazard Ratios for Prespecified Analyses in
Patients With Hypertension at High CV Risk
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. 20043632022-2031.
33
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Renin
ACEIs
Angiotensin I
?
ACE
Angiotensin II

• Blood Pressure
• Vascular Proliferation
• Oxidative Stress
• Vascular Inflammation
• Thrombogenesis
• Aldosterone

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
34
ACEI Trials in CAD Without HF Primary Outcomes
EUROPA CV Death/MI/Cardiac Arrest
HOPE CV Death/MI/Stroke
14
20
Placebo
12
Placebo
15
22 Risk Reduction HR 0.78 (0.700.86) P lt.001
20 Risk Reduction HR 0.80 (0.710.91) P .0003
10
Percent
8
Ramipril 10 mg
10
6
Perindopril 8 mg
Percent
4
5
2
Time (years)
Time (years)
0
0
1
3
4
0
5
2
0
2
4
1
3
QUIET All CV Events
PEACE CV Death/MI/CABG/PCI
50
30
Quinapril 20 mg
Placebo
4 Risk Increase HR 1.04 (0.891.22) P .6
40
25
4 Risk Reduction HR 0.96 (0.881.06) P .43
20
30
Percent
Percent
Trandolapril 4 mg
15
Placebo
20
10
10
Time (years)
Time (years)
5
0
0
1
2
3
4
5
6
0
1
2
3
EUROPA Investigators. Lancet. 2003362782-788
HOPE Study Investigators. N Engl J Med.
2000342145-153 PEACE Trial Investigators. N
Engl J Med. 20043512058-2068 Pitt B, et al.
Am J Cardiol. 2001871058-1063.
35
MICRO-HOPE, PERSUADE CV Events in Patients With
Diabetes
MICRO-HOPE(n 3577)CV death/MI/stroke
PERSUADE(n 1502)CV death/MI/cardiac arrest
25
25
Placebo
Placebo
20
20
25 RRRP .0004
19 RRRP .13
15
15
Primary Outcome ()
Perindopril8 mg
10
10
Ramipril10 mg
5
5
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Follow-Up (years)
Follow-Up (years)
MICRO-HOPE Microalbuminuria, Cardiovascular,
and Renal Outcomes (Heart Outcomes Prevention
Evaluation) PERSUADE Perindopril Substudy in
Coronary Artery Disease and Diabetes. HOPE Study
Investigators. Lancet. 2000355253-259 Daly CA
et al. Eur Heart J. 2005261369-1378.
36
MICRO-HOPE Albuminuria in Patients With Diabetes
3.0
Placebo
2.5
Ramipril
2.0
P .02
Mean Albumin/Creatinine Ratio (urine)
1.5
P .001
1.0
0.5
0.0
1
0
4-5
2
3
Time (y)
HOPE Study Investigators. Lancet.
2000355253-259.
37
Multiple Mechanisms of ACEIin 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.
20035A43-A48.
38
Definition of the Metabolic Syndrome

• Abdominal Obesity
• Waist Circumference
• Men gt40 in (gt102 cm) (gt94 cm 37 in)
• Women gt35 in (gt88 cm) (gt80 cm 32 in)
• Plus Two Risk Factors
• Triglycerides 150 mg/dL (1.7 mmol/L)
• HDL cholesterol Men lt40 mg/dL (lt1.0 mmol/L)
  Women lt50 mg/dL (lt1.3 mmol/L)
• BP 30/85 mm/Hg
• Glucose 110 mg/dL (gt6.1 mmol/L) (100
  mg/dl) (5.6 mmol/L)

Grundy SM et al. Circulation. 2004109433-438. ID
F Consensus. Berlin 2005.
39
Metabolic Syndrome (contd)
40
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 Ang
iotensinogen Acylation-stimulating protein
Probable CAD Risk Factor
Banerji M et al. Am J Physiol.
1997273E425-E432.
41
Characteristics of the Metabolic Syndrome
NCEP-ATP III
National Cholesterol Educational Program (NCEP)
Adult Treatment Panel (ATP) III 2001.
42
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 lt100
  mg/dL (optional lt70 mg/dL) non-HDL lt130 mg/dL
  (optional lt100 mg/dL)
• Antiplatelet therapy, aspirin and/or clopidogrel
• Antihypertensive therapy to achieve BP of lt140/90
  mm Hg
• lt130/80 mm Hg in the patient with diabetes
• Ideal BP ?120/80 (JNC 7)
• Hypoglycemic therapy to achieve near normal
  fasting glucose (HbA1C lt7) (ADA lt6.5)
• ACE inhibitor
• Beta-blocker
• Influenza vaccine

In the absence of specific contraindications
Updated from AHA/ACC. Circulation.
20011041577-1579 Braunwald E et al. J Am Coll
Cardiol. 2002401366-1374 Grundy SM et al.
Circulation. 2004110227-239 Krumholz HM et al.
Circulation. 2006113732-761 Smith S et al. J
Am Coll Cardiol. 2006472130-2139.
43
Adherence
44
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)
60
NHANES 1999-2000 (n 370)
50
40
Adults ()
30
20
10
0
Blood Pressure lt130/80 mm Hg
Total Cholesterol lt200 mg/dL
Achieved All 3 Treatment Goals
A1C Levellt7
LDL-C and TG not evaluated. Saydah SH, et al.
JAMA. 2004291335-342.
45
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. 200126331-342 Cheng JWM, et al.
  Pharmacotherapy. 200121828-841.

46
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 patients lifestyle and
  needs
• Use motivational interviewing techniques
• Look for
• Different ways to approach patients based on
  individual patient attitudes
• Allies in patient carefamily, 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.
200240630-640.
47
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. 200187819-822
Ockene IS et al. J Am Coll Cardiol.
200240 630-640 NCEP ATP III. September 2002.
NIH publication no. 02-5215 Pfizer Helpful
Answers Web site. Available at
http//www.pfizerhelpfulanswers.com.
48
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 factorsand
  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

49
Case Study
50
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

51
NCEP/Framingham Risk Scores Estimate of 10-yr
CHD Risk in Men Without CHD
VBWG
Reilly MP, Rader DJ. Circulation.
20031081546-51.
52
Decision Point

• What is the JNC 7 goal for this patient who has
• hypertension, diabetes, and renal disease?
• lt120/80 mm Hg
• lt130/80 mm Hg
• lt140/80 mm Hg
• lt140/90 mm Hg
• Use your keypad to vote now!

53
Decision Point

• The patients BP is 148/96 mm Hg while
• taking HCTZ 25 mg/d and glyburide 5 mg/d.
• To bring BP down to lt130/80 mm Hg, you would
• add a(n)
• BB
• CCB
• ARB
• ACE
• Use your keypad to vote now!

54
PCE Takeaways
55
PCE Takeaways

• Patients with hypertension often present with
  multiple cardiac risk factors
• Be vigilant in your investigation of all clinical
  indicators
• Creatively address patient adherence not
  everyone responds to the same interventions
• Clinical inertia is the enemydon't settle for
  "close enough"

56
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?
• Not important
• Slightly important
• Somewhat important
• Extremely important
• Use your keypad to vote now!

57
(No Transcript)
58
Estimate of 10-Year Risk for Men (Framingham
Point Scores)
1
5
3
Age Age Age Age Age 20-39 40-49 50-59 60-69 70-7
9
Systolic BP If If mm
Hg Untreated Treated
Age, y Points
20-34 -9 35-39 -4 40-44 0 45-49 3 50-54 6 55-59 8
60-64 10 65-69 11 70-74 12 75-79 13
Nonsmoker 0 0 0 0 0Smoker 8 5 3 1 1
lt120 0 0 120-129 0 1 130-139 1 2 140-159 1 2
?160 2 3
Point Total 10-Year Risk,
6
lt0 lt1 0 1 1 1 2 1 3 1 4 1 5 2 6 2 7 3 8
4 9 5 10 6 11 8 12 10 13 12 14 16 15 20 16
25 ?17 ?30
4
HDL mg/dL Points
?60 -1 50-59 0 40-49 1 lt40 2
2
Total Age Age Age Age Age Cholesterol 20-39 40-4
9 50-59 60-69 70-79
lt160 0 0 0 0 0 160-199 4 3 2 1 0 200-239 7 5 1
3 0 240-279 9 6 4 2 1 ?280 11 8 5 3 1
NCEP-ATP-III. JAMA. 20012852486-2497.
59
Estimate of 10-Year Risk for Women(Framingham
Point Scores)
1
5
3
Age Age Age Age Age 20-39 40-49 50-59 60-69 70-7
9
Systolic BP If If mm
Hg Untreated Treated
Age, y Points
20-34 -7 35-39 -3 40-44 0 45-49 3 50-54 6 55-59 8
60-64 10 65-69 12 70-74 14 75-79 16
Nonsmoker 0 0 0 0 0Smoker 9 7 4 2 1
lt120 0 0 120-129 1 3 130-139 2 4 140-159 3 5
?160 4 6
Point Total 10-Year Risk,
6
lt9 lt1 9 1 10 1 11 1 12 1 13 2 14 2 15 3 1
6 4 17 5 18 6 19 8 20 11 21 14 22 17 23 22
24 27 ?25 ?30
4
HDL mg/dL Points
?60 -1 50-59 0 40-49 1 lt40 2
2
Total Age Age Age Age Age Cholesterol 20-39 40-4
9 50-59 60-69 70-79
lt160 0 0 0 0 0 160-199 4 3 2 1 1 200-239 8 6 4
2 1 240-279 11 8 5 3 2 ?280 13 10 7 4 2
NCEP-ATP-III. JAMA. 20012852486-2497.
60
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/dayn 6110
placebon 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.
2003362782-788.
61
Study Design HOPE
STUDY N 9297 Aged ?55 yearsPatients 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/dayn 651
Placebon 826
Randomized 2x2 factorial study also evaluated
effects of vitamin E
RESULTS CV DEATH MI STROKE ALL-CAUSE DEATH
PLACEBO GROUP 8.1 12.3 4.9 12.2
TREATMENT GROUP 6.1 9.9 3.4 10.4
HOPE Heart Outcomes Prevention Evaluation.
Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med. 2000342145-153.
62
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.
19983511755-1762.
63
Study Design MICRO-HOPE (a substudy of HOPE)
STUDY N 3577 Aged ?55 yearsPatients were at
high risk for CV events and at least 1 other CV
risk factor
Ramipril 10 mg/day n 1808
Placebo n 1760
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 REVASCULAR-IZATION
TREATMENT GROUP i 25 i 22 i 37 i 17
MI, stroke, or CV death MI, stroke, or CV death MI, stroke, or CV death MI, stroke, or CV death MI, stroke, or CV death
HOPE Heart Outcomes Prevention Evaluation.
Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med. 2000342145-153.
64
Study Design PEACE
STUDY N 8290 Patients had stable CAD and normal
or slightly reduced left ventricular function
Trandolapril 4 mg/dayn 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.
20043512058-2068.
65
Study Design PERSUADE (a substudy of EUROPA)
STUDY N 1502 Patients had diabetes with known
CAD and no HF
perindopril 8 mg/dayn 721
placebon 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. 2005261369-1378.
66
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. 2001871058-1063.
67
Study Design SHEP
STUDY N 4736 Aged ?60 years SBP ?160 mm Hg
DBP lt90 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
patients 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. 19962761886-1892.
68
Study Design Syst-Eur
STUDY N 4695 Aged ?60 years SBP 160-219 mm
Hg DBP lt95 mm Hg patients with diabetes n 492
Placebo
Nitrendipine 10-40 mg/day with addition or
substitution of enalapril 5-20 mg/day
or hydrochlorothiazide 12.5-25 mg/day or both

• 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 i69 in diabetic vs i26 in
  nondiabetic patients
• Fatal/nonfatal strokes i 73 in diabetic vs i
  38 in nondiabetic patients

Syst-Eur Systolic Hypertension in Europe
Tuomilehto J, et al. New Engl J Med.
1999340677-684.
69
Study Design UKPDS
STUDY N 1148 Type 2 diabetes Mean age 56 years,
mean BP 160/94 mm Hg
Less-tight BP control n 390
Tight BP control n 758
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.
1998317703-713 Bakris GL, et al. Am J Kidney
Dis. 200036646-661.
70
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/dayStep 2 valsartan 160
mg/dayn 7649
Step 1 amlodipine 5 mg/dayStep 2 amlodipine 10
mg/dayn 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 i 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 i 4.0/2.1 mm Hg in amlodipine after 1 month

VALUE Valsartan Antihypertensive Long-term Use
Evaluation. Julius S, et al. Lancet.
20043632022-2031.
71

• Abdominal Obesity
• Waist Circumference
• Men gt40 in (gt102 cm) (gt94 cm 37in)
• Women gt35 in (gt88 cm) (gt80 cm 32in)
• Plus Two Risk Factors
• Triglycerides gt150 mg/dL (1.7 mmol/L)
• HDL cholesterol Men lt40 mg/dL (lt1.0 mmol/L)
  Women lt50 mg/dL (lt1.3mmol/L)
• BP gt130/85 mm/Hg
• Glucose gt110 mg/dL (gt6.1 mmol/L) (100
  mg/dl) (gt5.6 mmol/L)

Grundy SM et al. Circulation. 2004109433-438. ID
F Consensus. Berlin 2005
72
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