St

1
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007

2
Blood Pressure and Beyond Important
Considerations in Managing Your Patients
Cardiovascular Risk
Joshua Furman, MD, FACC Division of
Cardiology Mount Sinai Medical Center Miami
Beach, Florida
3
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

4
Faculty Disclosure

• Dr Furman has no relevant financial relationships
  with any commercial interests to disclose.

5
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

6
65 Million Americans Require Treatment for
Hypertension
Nearly 1 in 3 adults (31) in the United States
has hypertension
Fields LE et al. Hypertension. 200444398-404.
7
JNC 7 Cardiovascular Risk Factors

• Hypertension
• Cigarette smoking
• Obesity (BMI 30 kg/m2)
• Physical inactivity
• Dyslipidemia
• Diabetes mellitus

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

BMI body mass index CVD cardiovascular
disease GFR glomerular filtration rate.
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.
8
Microalbuminuria and Hypertension Increase the
Risk of Ischemic Heart Disease
N 2085, 10-year follow-up
Relative Risk of Ischemic Heart Disease
Adapted from Borch-Johnsen et al. Arterioscler
Thromb Vasc Biol. 1999191992-1997.
9
Progression of Cardiovascular Disease The
Cardiovascular Continuum
Myocardial infarction
Myocardialischemia
Ventricular dysfunction
Sudden death
Peripheral arterial disease
Endothelialdysfunction and atherothrombosis
Ventricular dilation and hypertrophy
Stroke
Hyperlipidemia,hypertension, diabetes, smoking,
obesity, etc
Congestive heart failure and death
Adapted from Dzau V, Braunwald E. Am Heart
J. 19911211244-1263.
10
Development and Progression of CVD

HYPERTENSION Age, gender, smoking, inactivity,
obesity, cholesterol, diabetes mellitus
Risk factors
? Oxidative stress
? Endothelial function? EPCs
Genetic factors
Functional alterations
Structural alterations
Clinical sequelae
EPC endothelial progenitor cell.
Adapted from Pepine CJ. Am J Cardiol.
200188(suppl)5K-9K.
11
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.
12
Renal Continuum of Risk
Adapted from Braunwald E, ed. Heart Disease A
Textbook of Cardiovascular Medicine. 6th ed.
Philadelphia, Pa WB Saunders 2001.
13
US Adult Population at Risk
Hypertensive (gt139/89 mm Hg)
Normal(lt120/80 mm Hg)
65 M1
98 M
45 M2
Prehypertensive(120-139/80-89 mm Hg)

• Fields LE et al. Hypertension. 200444398-404.
• American Heart Association. Heart Disease and
  Stroke Statistics-2004 Update. 2003.

14
Lifestyle Modifications to Manage Hypertension

The effects of implementing these modifications
are dose and time dependent. DASH Dietary
Approaches to Stop Hypertension.1. The Trials of
Hypertension Prevention Collaborative Research
Group. Arch Intern Med. 1997157657-667. 2. He
J et al. Hypertension. 200035544-549. 3. Sacks
FM et al. N Engl J Med. 20013443-10. 4.
Vollmer WM et al. Ann Intern Med.
20011351019-1028. 5. Chobanian AV, Hill M.
Hypertension. 200035858-863. 6. Kelley GA,
Kelley KS. Hypertension. 200035838-843. 7.
Whelton SP et al. Ann Intern Med.
2002136493-503. 8. Xin X et al. Hypertension.
2001381112-1117. Table adapted with permission
from Chobanian V et al. JAMA. 20032892560-2572.
15
TROPHY Kaplan-Meier Curves of New Onset
Clinical Hypertension
90
Candesartan Placebo
80
70
60
Cumulative Incidence ()
50
40
30
20
10
0
0
1
2
3
Years in Study
TROPHY Trial of Preventing Hypertension.
Julius S et al. N Engl J Med. 20063541685-1697.

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
Increased Stroke Risk With ?-blockers Shown in
Meta-Analysis
N 105,951
RR(95 CI)
Favors ß-blocker
Favors other drug
Stroke
1.29 (1.12-1.49)
ASCOT-BPLA
0.87 (0.68-1.12)
CONVINCE
1.58 (0.69-3.64)
ELSA
0.77 (0.49-1.23)
HAPPHY
1.14 (0.93-1.39)
INVEST
1.34 (1.13-1.58)
LIFE
1.22 (0.83-1.79)
MRC Old
1.22 (0.99-1.50)
NORDIL
1.12 (0.96-1.30)
STOP-2
0.90 (0.48-1.69)
UKPDS
0.56 (0.21-1.48)
Yurenev
2.28 (1.31-3.95)
MRC
1.16 (1.04-1.30)
Total events
Test for heterogeneity ?2 22.39 (P .02)
0.5
0.7
1.0
1.5
2.0
Lindholm LH et al. Lancet. 20053661545-53.
18
Key Points for Optimal Hypertension Management
lt130/80 mm Hg in patients with diabetes or renal
disease
lt140/90 mm Hg
JNC 7BPGoals
JNC 7 recommends If SBP gt20 mm Hg or DBP gt10 mm
Hg over goal, consider initiating with 2-drug
combination
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.
19
JNC 7 Highlights Key Risk-Related Messages

• Certain high-risk conditions are compelling
  indications for the initial use of specific
  antihypertensive drug classes

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.
20
Compelling Indications for Therapy in Complex
Hypertension
Compelling indications are based on benefits
from outcomes studies or existing clinical
guidelines. High-risk condition is managed
simultaneously with BP combination of agents may
be required.
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.
21
Hypertension and Global CV Risk
22
HypertensionThe Disease Continuum
Natural History of CVD Progression
Early Paradigm
Elevated BP
Target Organ Damage
More Recent Paradigm
Vascular Dysfunction
Elevated BP
Target Organ Damage
A Proposed Future Paradigm
Elevated BP
Target OrganDamage
VascularDysfunction
EndothelialDysfunction
Anginapectoris
LVH
Renaldamage
Stroke
MI
LVH left ventricular hypertrophy MI
myocardial infarction.
23
IDNT Systolic BP, Mean Arterial Pressure, and
Diastolic BP Response
SBP
Irbesartan Amlodipine Control
BP (mm Hg)
MAP
DBP
0
6
12
18
24
30
36
42
48
54
Follow-up Visit (mo)
Control defined as placebo plus permitted
adjunctive antihypertensive therapy. Patients
received an average of 3.0 concomitant
antihypertensive agents in the irbesartan and
amlodipine groups and 3.3 concomitant agents in
the control group. IDNT Irbesartan Diabetic
Nephropathy Trial MAP mean arterial pressure.
Adapted from Lewis EJ et al. N Engl J Med.
2001345851-860.
24
IDNT Primary End Point Time to Doubling of
Serum Creatinine, ESRD, or Death
Irbesartan Amlodipine Control
Subjects ()
0
6
12
18
24
30
36
42
48
54
60
Follow-up (mo)
Control defined as placebo. ESRD end-stage
renal disease RRR relative risk reduction
SeCr serum creatinine. Lewis EJ et al. N Engl
J Med. 2001345851-860.
25
LIFE Blood Pressure Results Follow-up
Atenolol
Losartan
Atenolol 145.4 mm Hg
Systolic
Losartan 144.1 mm Hg
BP (mm Hg)
Mean Arterial
Losartan 81.3 mm Hg
Diastolic
Atenolol 80.9 mm Hg
Study Month
Dahlof B et al. Lancet. 2002359995-1003.
26
LIFE Primary Outcome (CV Death, MI, stroke)
9193 Patients With Hypertension and ECG-LVH
16
13.0 adjusted risk reduction, P .021(losartan
vs atenolol)
14
12
10
Proportion of Patients With First Event ()
8
Primary Outcome
6
Atenolol Losartan
4
?BP from baseline (mm Hg) 29.1/16.8 30.2/16.6 Pati
ents with BP 140/90 mm Hg 46 49
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Time (mo)
No. at risk Losartan 4605 4524 4460 4392 4312 4247
4189 4112 4047 3897 1889 901 Atenolol 4588 4494 4
414 4349 4289 4205 4135 4066 3992 3821 1854 876
LIFE Losartan Intervention For Endpoint
reduction in hypertension study.Dahlof B et al.
Lancet. 2002359995-1003.
27
VALUE Comparison of CCB and ARB
Population 15,245 patients with high-risk
hypertension Treatment Amlodipine 5-10 mg ?
HCTZ 12.5-25 mgValsartan 80-160 mg ? HCTZ
12.5-25 mg Primary outcome Composite of cardiac
mortality, MI, HF Secondary outcomes MI, HF,
stroke Follow-up 4.2 years
VALUE Valsartan Antihypertensive Long-term Use
Evaluation. Julius S et al. Lancet.
20043632022-2031.
28
VALUE Similar Treatment Effectson Primary
Outcome at Study End
N 15,245
14
HR 1.03(95 CI, 0.94-1.14) P .49
12
10
Valsartan-based regimen (n 7649)
Main outcome of cardiac disease did not differ
between treatment groups. Unequal reductions in
BP might account for differences.
8
Proportion of Patients With First Event ()
6
4
Amlodipine-based regimen (n 7596)
2
0
0
30
18
54
66
6
42
Time (mo)
Julius S et al. Lancet. 20043632022-2031.
29
VALUE Hazard Ratios for Prespecified Analyses in
Patients With Hypertension at High CV Risk
Patients had hypertension and were at high CV
risk. Julius S et al, for the VALUE trial group.
Lancet. 20043632022-2031.
30
What percentage of patients with hypertension
have 2 or more additional CV risk factors?

• 20
• 30
• 40
• 50
• gt50

31
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.
32
On average, how many drugs will a patient need
to control hypertension?

• 1
• 2
• 3
• 4

33
Number of Antihypertensive Agents Needed to
Achieve Systolic BP Control
SBP achieved(mm Hg)
Trial
Number of BP Medications
50 patients required 3 medications. Average
per patient. Bakris et al. Am J Kidney Dis.
200036646-661 ALLHAT. JAMA. 20022882981-2997
Berl et al. Ann Intern Med. 2003138542-549
Bakris et al. Arch Intern Med. 20031631555-1565
Wright et al. JAMA. 20022882421-2431 Pepine
et al. JAMA. 20032902805-2816.
34
Hypertension and Diabetes Global CV Risk
Reduction With Evidence-Based Intervention
35
Diabetes Approximately Doubles CVD Risk in
Patients With Hypertension
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.
36
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.
37
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
Relative Risk Reduction ()
-20
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.
38
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.
39
Adherence
40
Factors Contributing 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.

41
Practical Tips to Improve Adherence

• Talk to your patient
• Explain the condition and why 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
• Ways to approach patients based on individual
  attitudes
• Allies in patient carefamily, friends
• Ways to simplify the regimen
• Refill dates (no refill no adherence)

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 appointments offering 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)
• Patient assistance programs
• Support when medication costs are a barrier

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
Antihypertensive Medications Mechanism of Action
American Heart Association. December 11, 2006.
Available at http//www.americanheart.org/present
er.jhtml?identifier3038158.
44
Antihypertensive Drugs Hemodynamic Mechanism of
BP Reduction
BP (MAP)
SVR
CO

SV
HR
BB, ARB, ACEI, Central acting, CCB, Diuretic,
VasoD
Preload
Contractility
BB
Diuretic
BB, CCB
Nondihydropyridine CCBs. CO cardiac output
HR heart rate SV stroke volume SVR
systemic vascular resistance. 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 Houston MC. Primary Care. 199118713-753.
45
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.
46
Deleterious Effects of Angiotensin II
?PAI-1/thrombosis
Abnormalvasoconstriction
Angiotensin II
Plateletaggregation
ActivateSNS
Superoxideproduction
Vascularsmooth musclegrowth
?Aldosterone
Myocytegrowth
?Collagen
?Vasopressin
?Endothelin
Remodeling
SNS sympathetic nervous system. Burnier M et
al. Lancet. 2000355637-645 Brown NJ et al. Adv
Intern Med. 200045419-429.
47
Possible Consequences of Angiotensin II on
Target Organs
Stroke
Atherosclerosis1 Vasoconstriction2 Vascular
hypertrophy2 Endothelial dysfunction2
Hypertension
LVH2 Fibrosis2 Remodeling2 Apoptosis3
AII AT1 receptor
DEATH
Heart failure, MI
?GFR4 ?Proteinuria4 ?Aldosterone
release2 Glomerular sclerosis4
Renal failure
Preclinical data.
1. Daugherty A et al. J Clin Invest.
20001051605-1612 2. Dahlöf B. J Hum Hypertens.
19959(suppl 5)S37-S44 3. Booz GW et al. Heart
Failure Rev. 19983125-130 4. Anderson S. Exp
Nephrol. 19964(suppl 1)34-40.
48
The Renin-Angiotensin-Aldosterone System (RAAS)
Angiotensinogen
Kininogen
Kallikrein
Renin
ACEIs
Nitric Oxide
Bradykinin
Angiotensin I
?
?
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.
49
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.
50
HOPE Landmark Outcomes With Ramipril
Effects Beyond Baseline Therapy

• Aspirin
• BBs
• Lipid-lowering agents

• Diuretics
• Other antiplatelets
• CCBs

HOPE Heart Outcomes Prevention
Evaluation.Yusuf et al, for the HOPE Study
Investigators. N Engl J Med. 2000342145-153.
51
HOPE Stroke Reduction Independent of BP
Reduction
9297 High-Risk Patients
0.06
32 risk reductionP .0002
0.05
0.04
Placebo(?BP 0.66/1.1 mm Hg)
Incidence of Stroke ()
0.03
0.02
Ramipril 10 mg(?BP 3.8/2.8 mm Hg)
0.01
0
0
500
1000
1500
Follow-up (days)
Bosch J et al, and the HOPE Investigators. BMJ.
2002324699-702.
52
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.
53
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.
54
Comparison of Studies in Hypertensive Renal
Disease
AML amlodipine HT hypertension IRB
irbesartan IRMA 2 Irbesartan in Patients with
Type 2 Diabetes and Microalbuminuria LOS
losartan MARVAL Microalbuminuria Reduction
with Valsartan PLA placebo RENAAL Reduction
of Endpoints in NIDDM (non-insulin-dependent
diabetes mellitus) with Angiotensin II Antagonist
Losartan UAER elevated urine albumin
excretion VAL valsartan.
55
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.
56
Direct Renin Inhibitor Therapy Efficacy at 8
Weeks
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.

57
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

58
Case Study
59
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

60
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

61
The patients BP is 148/96 mm Hg whiletaking
HCTZ 25 mg/d and glyburide 5 mg/d. To further
reduce BP, you would add a(n)

• BB
• CCB
• ARB
• ACE

62
Q A
63
PCE Takeaways
64
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"

65
How important is using an antihypertensive agent
with proven risk reduction (reducingmorbidity
and mortality) when choosing medications for
your patients with hypertension?

• Not important
• Slightly important
• Somewhat important
• Extremely important

66
Thank You
67
BackupStudy Design Slides
68
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.
69
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
HOPE Heart Outcomes Prevention
Evaluation. Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med.
2000342145-153.
70
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.
71
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
HOPE Heart Outcomes Prevention Evaluation.
Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med. 2000342145-153.
72
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.
73
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.
74
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.
75
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.
76
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.
77
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.
78
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.
79
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007