St

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Fall 2007Symposia Series

• St

• Melville Marriott Long IslandMelville, New
  YorkDecember 1, 2007

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Blood Pressure and Beyond Important
Considerations in Managing Your Patients
Cardiovascular Risk
Jeffrey L. Probstfield, MD Director, Clinical
Trials Service Unit Professor of Medicine
(Cardiology) and Epidemiology University of
Washington Schools of Medicine and Public Health
and Community Medicine Seattle, Washington
3
Which class of agents do you presently consider
first-line treatment for patients with
hypertension?

1. Diuretics
2. ß-Blockers (BBs)
3. Calcium channel blockers (CCBs)
4. Angiotensin-converting enzyme inhibitors (ACEIs)
5. Angiotensin receptor blockers (ARBs)
6. All of the above

Use your keypad to vote now!
4
Faculty Disclosure

• Dr Probstfield grant support Abbott
  Laboratories, Boehringer-Ingelheim Corporation,
  sanofi-aventis.

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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

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Hypertension and Global CV Risk
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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.
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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.
9
What percentage of patients with hypertension
have 2 or more additional CV risk factors?

1. 20
2. 30
3. 40
4. 50
5. gt50

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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.
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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.
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INTERHEART Risk of AMI Associated With Multiple
Risk Factors (N 29,972)
2.9
2.4
42.3
1.9
3.3
13.0
68.5
182.9
333.7
512
256
128
64
32
Odds Ratio (99 CI)
16
8
4
2
1
Current Smoking(1)
DM (2)
HTN (3)
?ApoB/A1 (4)
123
1-4
1-4Obesity
1-4PS
All 9RFs
Individual RFs
Combined RFs
AMI acute myocardial infarction PS
psychosocial stressors. All 6 RFs no daily
fruits/veg, weekly alcohol consumption, or
regular exercise Yusuf S et al. Lancet.
2004364937-952.
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INTERHEART Decreased Risk of AMI Associated With
Risk Factor Reduction
0.35
0.70
0.21
0.86
0.91
0.24
0.19
1.0
0.5
Odds Ratio (99 CI)
0.25
0.125
NoSmoking(1)
Frt/Veg (2)
Exer (3)
Alc(4)
12
13
14
Individual Risk Factors
Combined Risk Factors
Exercise 4 hr/week alcohol consumption
3x/week Yusuf S et al. Lancet. 2004364937-952.
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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.
15
More Compelling Evidence Against Beta Blockers
for Uncomplicated Hypertension

• Little support for BBs as monotherapy or
  first-line agents
• Increased stroke risk and less LVH regression
  compared with other antihypertensives
• No effect on endothelial dysfunction or central
  aortic pressure
• Numerous adverse effects
• BBs remain effective for
• Heart failure
• Some arrhythmias
• Hypertrophic obstructive cardiomyopathy
• Patients with previous MI
• Efficacy of newer BBs (nebivolol, carvedilol) in
  reducing morbidity and mortality yet to be
  determined

Bangalore S, et al. J Am Coll Cardiol.
200750563-572.
16
Nonpharmacologic Interventionsand BP Reduction
Low-SaltDiet
Alcohol Reduction
PotassiumSupplement
Weight Loss(19.4 lb)
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.
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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.
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Goal BP Recommendations for Patients With DM or
Renal Disease
Organization Year Goal BP (mm Hg)
Canadian Hypertension Society 2007 lt130/80
American Diabetes Association 2006 lt130/80
National Kidney Foundation 2004 lt130/80
British Hypertension Society 2004 ?130/80
JNC 7 2003 lt130/80
World Health Organization/ International Society of Hypertension 2003 lt130/80
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.
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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 and
       
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.
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Hypertension and Diabetes Global CV Risk
Reduction With Evidence-Based Intervention
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On average, how many drugs will a patient need
to control hypertension?

1. 1
2. 2
3. 3
4. 4

Use your keypad to vote now!
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Multiple Antihypertensive Agents Needed to
Achieve BP Goal ALLHAT
Controlled lt140/90 mm Hg
1 Drug
2 Drugs
?3 Drugs
100
80
60
Patients ()
40
20
0
Baseline
6 Months
3 Years
5 Years
1 Year
Patients had hypertension and at least 1 other
CHD risk factor. N 33357. Adapted from Cushman
WC et al. J Clin Hypertens. 20024393-404.
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Multiple Antihypertensive Agents Needed to
Achieve BP Goal Diabetes/Renal Impairment
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.
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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.
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
Syst-Eur CV Protection Resulting From BP
Lowering Was Greatest in Patients With Diabetes
With Diabetes
Without Diabetes
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
Reduction in Event Rate for Active Treatment
Group ()
22 P .10
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. Syst-Eur
Systolic Hypertension in Europe CV
cardiovascular. Adapted from Tuomilehto J et al.
N Engl J Med. 1999340677-684.
27
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. Bakris GL et al. Am J Kidney Dis.
200036646-661.
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Currently Available Antihypertensive Medications
Mechanism of Action
Drug Class Mechanism of Action
Diuretics Rid the body of excess fluids and sodium through urination May enhance the effect of other BP medications
ACEIs Lower levels of angiotensin II Expand blood vessels
ARBs Block angiotensin II receptors Expand blood vessels
BBs Decrease heart rate and cardiac output
CCBs Interrupt movement of calcium into heart and vessel cells
American Heart Association. December 11, 2006.
Available at http//americanheart.org/presenter.j
html?identifier159.
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The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Renin
ACEIs
Angiotensin I
?
ACE
Angiotensin II
ARBs
?
ARBs
Blood Pressure Vascular Proliferation
Oxidative Stress Vascular Inflammation
Thrombogenesis
AT1
ACEI
ARB
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420.Endemann DH. J Am
Soc Nephrol. 2004151983-1992.
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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.
31
Val-HeFT HF Morbidity With ARB in Patients Not
Receiving ACEIs
100
Valsartan (n 185) Placebo (n 181)
80
60
Event-Free Probability ()
40
Risk Reduction 44 (P lt.001)
20
0
0
3
6
9
12
15
18
21
24
27
Months
ACEI angiotensin-converting enzyme inhibitor
ARB angiotensin receptor blocker HF heart
failure. Maggioni AP et al. J Am Coll Cardiol.
2002401414-1421.
32
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.
33
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
Primary Outcome ()
15
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)
HOPE Study Investigators. Lancet.
2000355253-259 Daly CA et al. Eur Heart J.
2005261369-1378.
34
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.
35
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

AT1
Adapted with permission from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
36
Direct Renin Inhibitor Therapy Efficacy at 8
Weeks
Uresin et al Aliskiren 300 mgn 279 Tschoepe et al Aliskiren 300 mgn 282
Mean change in SBP (mm Hg) -14.7 -14.9
Mean change in DBP (mm Hg) -11.3 -11.5
Patients had diabetes and hypertension. Main
adverse effects of aliskiren include angioedema,
dose-related GI adverse effects, and cough.
Tschoepe D et al. Presented at European
Association for the Study of Diabetes September
17, 2006 Copenhagen, Denmark. Abstract 0217
Uresin Y et al. Presented at European Society of
Hypertension April 2006 Madrid, Spain Tekturna
(aliskiren) prescribing information. East
Hanover, NJ Novartis Pharmaceuticals Corp 2007.

37
Renin Inhibition in Patients With Diabetes

• Few studies of aliskiren in patients with
  diabetes exist
• AVOID will compare aliskiren with placebo in
  patients with type 2 diabetes and proteinuria
  already treated with an ARB results expected
  late 2007
• Aliskiren prescribing information includes
  precautions regarding impaired renal function and
  hyperkalemia
• Further research needed on aliskiren combination
  therapies
• Dual renin inhibition might find a niche in
  selected hypertensive patients at high risk with
  associated conditions or in treatment-resistant
  hypertension. -- Birkenhager and Staessen in a
  Lancet editorial, 2007

AVOID Aliskiren in the Evaluation of
Proteinuria in Diabetes. Birkenhager H, Staessen
JA. Lancet. 2007370195-196 Tekturna
(aliskiren) prescribing information. East
Hanover, NJ Novartis Pharmaceuticals Corp 2007.

38
The Data Support Global CV Risk Management

• CV disease remains the leading cause of death in
  both men and women in the United States
• Framingham data show that CV risk factors tend to
  clusterand that risk of death from CHD and
  stroke increases proportionately
• Endothelial dysfunction seems to be a key factor
  in the development of CV disease
• Recent clinical trials have given us a wealth of
  information with which to manage global CV risk

39
Adherence
40
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 (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.
41
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.
42
Practical Tips to Improve Adherence

• Use systematic approaches
• Disease management programs
• Periodic review of electronic medical records or
  manual chart audits
• Group/shared medical appointmentsblend 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.
43
Case Study
44
Case Study 55-Year-Old Asian Man With
Hypertension and Type 2 Diabetes

• 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

45
What is the JNC 7 goal for this patient who has
hypertension, diabetes, and renal disease?
Decision Point

1. lt120/80 mm Hg
2. lt130/80 mm Hg
3. lt140/80 mm Hg
4. lt140/90 mm Hg

Use your keypad to vote now!
46
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)
Decision Point
Use your keypad to vote now!

1. BB
2. CCB
3. ARB
4. ACE

47
Q A
48
PCE Takeaways
49
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"

50
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!
51
Fall 2007Symposia Series

• St

• Melville Marriott Long IslandMelville, New
  YorkDecember 1, 2007