Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

1
Practical Approaches to Managing Hypertension
Reducing Global Cardiovascular Risk
Kenneth A. Jamerson, MD Professor of Internal
Medicine University of Michigan Medical
Director Program for Multicultural
Health University of Michigan Health Systems Ann
Arbor, Michigan
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 Jamerson consultant King Pharmaceuticals,
  Inc., Merck Co., Inc., Novartis Pharmaceuticals
  Corporation, sanofi-aventis Group, Sankyo Co.,
  Ltd. grants/research support King
  Pharmaceuticals, Inc., National Institutes of
  Health, National Institute of Diabetes
  Digestive Kidney Diseases, Novartis
  Pharmaceuticals Corporation, Speedel speakers
  bureau Abbott Laboratories, GlaxoSmithKline,
  Merck Co., Inc., Novartis Pharmaceuticals
  Corporation.

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
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.
6
Hypertension and Global CV Risk
7
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.
8
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
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!

10
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.
11
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.
12
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.
13
Key Question

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

14
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.
15
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.
16
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.
17
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.
18
Hypertension and Diabetes Global CV Risk
Reduction With Evidence-Based Intervention
19
Diabetes 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
Systolic Hypertension in the Elderly Program (SHEP) Systolic Hypertension in the Elderly Program (SHEP) Systolic Hypertension in the Elderly Program (SHEP) Systolic Hypertension in the Elderly Program (SHEP)
CV events 63.0 36.8 1.71
Stroke 28.8 15.0 1.92
CHD events 32.2 15.2 2.12
Systolic Hypertension in Europe (Syst-Eur) Systolic Hypertension in Europe (Syst-Eur) Systolic Hypertension in Europe (Syst-Eur) Systolic Hypertension in Europe (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
Hypertension Optimal Treatment (HOT) (DBP lt90 mm Hg) Hypertension Optimal Treatment (HOT) (DBP lt90 mm Hg) Hypertension Optimal Treatment (HOT) (DBP lt90 mm Hg) Hypertension Optimal Treatment (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.
20
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 18,790 diabetes n
1501. HOT Hypertension Optimal Treatment MI
myocardial infarction. Adapted from Hansson L et
al, for the HOT Study Group. Lancet.
19983511755-1762.
21
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.
22
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.
23
The Renin System, Angiotensin II, and End-Organ
Damage
Role of Angiotensin II in the Progression of
Cardiovascular Disease
Atherosclerosis Vasoconstriction Vascular
inflammation and hypertrophy Endothelial
dysfunction
Stroke
Brain
Hypertension
Vessels
Angiotensin II
Left ventricular hypertrophy Fibrosis Remodeling A
poptosis
Death
Heart Failure Myocardial Infarction
Heart
?Glomerular capillary pressure ?Proteinuria ?Aldos
terone release Glomerular sclerosis
Renal Failure
Kidney
Adapted from Willenheimer R et al. Eur Heart J.
199920997-1008 Dahlöf B. J Hum Hypertens.
19959(suppl 5)S37-S44 Fyhrquist F et al. J Hum
Hypertens. 19959(suppl 5)S19-S24 Booz GW et
al. Heart Fail Rev. 19983125-130 Beers MH,
Berkow R, eds. In The Merck Manual of Diagnosis
and Therapy. 19991417-1427 Anderson S. Exp
Nephrol. 19964(suppl 1)34-40.
24
Physiology and Pathophysiology of the Renin
System
Renin
Renin
Angiotensinogen
Angiotensinogen
Feedback Loop
Ang I
Ang I
ACE
ACE
Ang II
Ang angiotensin. Adapted from Brown NJ et al.
Circulation. 1998971411-1420 Endemann DH. J
Am Soc Nephrol. 2004151983-1992.
25
Most Agents Work After the Point of Activation
Renin activates the system by converting
angiotensinogen to angiotensin 1
Renin
Angiotensinogen
Feedback Loop
Ang I
AT1 Receptor
ACE
ARBs

• ACE cleaves Ang I to form Ang II
• ACEIs work at this point

Ang II

• Ang II binds to the AT1 receptor
• ARBs work at this point

Adapted from Brown NJ et al. Circulation.
1998971411-1420 Endemann DH. J Am Soc
Nephrol. 2004151983-1992.
26
Direct Renin Inhibitors

• Direct renin inhibitors (DRIs) are currently in
  development
• To date, there is no clinical evidence that DRIs
  have a benefit in morbidity and mortality

27
DRIs Target the Point of Activation
DRIs prevent renin from converting
angiotensinogen to angiotensin 1
Renin
Angiotensinogen
DRI
Feedback Loop
ACE
Adapted from Brown NJ et al. Circulation.
1998971411-1420 Endemann DH. J Am Soc
Nephrol. 2004151983-1992.
28
Definition of the Metabolic Syndrome
Risk factor Categorical Cut-points
? Waist circumference 102 cm (40 in) in men 88 cm (35 in) in women
? TG 150 mg/dL (or drug treatment for)
? HDL-C lt40 mg/dL in men (or drug treatment for) lt50 mg/dL in women (or drug treatment for)
? BP 130 mm Hg SBP or 85 mm Hg DBP (or drug treatment for)
? Fasting glucose 100 mg/dL (or drug treatment for)
Presence of 3 or more of these factors
identifies the metabolic syndrome. Lower
threshold can be used for patients especially
prone to insulin resistance, particularly Asian
Americans. Grundy SM, et al. Circulation.
20051122735-2752. NOTE The ADA recently issued
a statement calling for a critical appraisal of
the metabolic syndrome. Kahn R, et al.
Diabetologia. 2005481684-1699.
29
Characteristics of the Metabolic Syndrome NCEP
ATP III
National Cholesterol Educational Program (NCEP)
Adult Treatment Panel (ATP) III 2001.
30
Management of the Metabolic Syndrome

• Weight reduction
• Increased physical activity
• Modification of atherogenic diet
• Drug therapy for dyslipidemia
• Drug therapy for hypertension
• Aspirin or clopidogrel for prothrombotic state
• Lifestyle changes to lower serum glucose (if
  diabetes has developed, drug therapy may also be
  needed to reduce A1C to ADA goal of lt7)

Grundy SM, et al. Circulation. 20051122735-2752.
31
Adherence
32
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.
33
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.

34
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.
35
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.
36
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 evidence
  supporting a standard of care for the management
  of global CV risk

37
Case Study
38
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

39
10-Year NCEP/Framingham Risk Scores for Fatal or
Nonfatal CHD in Men
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
SBP (mm Hg) Untreated Treated
lt120 0 0
120-129 0 1
130-139 1 2
140-159 1 2
?160 2 3
Smoking status Age (y) Age (y) Age (y) Age (y) Age (y)
Smoking status 20-39 40-49 50-59 60-69 70-79
Nonsmoker 0 0 0 0 0
Smoker 8 5 3 1 1
Point Total 10-Year Risk ()
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
HDL (mg/dL) Points
?60 -1
50-59 0
40-49 1
lt40 2
TC (mg/dL) Age 20-39 y Age 40-49 y Age 50-59 y Age 60-69 y Age 70-79 y
lt160 0 0 0 0 0
160-199 4 3 2 1 0
200-239 7 5 3 1 0
240-279 9 6 4 2 1
?280 11 8 5 3 1
A separate Framingham risk calculator exists for
women. NCEP ATP III. 2002. NIH Publication No.
02-5215. Available at http//www.nhlbi.nih.gov/gu
idelines/cholesterol/.
40
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!

41
Decision Point

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

42
Q A
43
PCE Takeaways
44
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"

45
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!

46
Supporting Studies
47
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. Diabetes n 492.
Syst-Eur Systolic Hypertension in Europe CV
cardiovascular. Adapted from Tuomilehto J et al.
N Engl J Med. 1999340677-684.
48
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.
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
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.
51
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.
52
HOPE StudyPrevention of Diabetes With Ramipril
0.10 0.08 0.06 0.04 0.02 0
Placebo Ramipril
Kaplan-Meier Rates
200 400 600 800 1000 1200 1400 1600
Days of Follow-Up (no diabetes at baseline)
The occurrence of self-reported diabetes was
reduced by 34 (95 CI, 15-49 P lt.001) in the
HOPE study. This effect was observed early and
maintained consistently throughout the trial.
HOPE Study Investigators. Lancet.
2000355253-259.