Practical Approaches to Managing Hypertension: Reducing Global Cardiovascular Risk

1
Practical Approaches to Managing Hypertension
Reducing Global Cardiovascular Risk
Randall M. Zusman, MD Associate Professor of
Medicine Harvard Medical School
Director Division of Hypertension and Vascular
Medicine Massachusetts General Hospital Boston,
Massachusetts
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 Zusman advisory board member, research
  support, speakers bureau AstraZeneca,
  Bristol-Myers Squibb Company, Forest
  Pharmaceuticals, Inc., Novartis Pharmaceuticals
  Corporation, Pfizer Inc, sanofi-aventis Group,
  Sankyo Co., Ltd.

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
Hypertension and Global CV Risk
6
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.
7
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.
8
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!

9
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.
10
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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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.
12
Nonpharmacologic Interventionsand BP Reduction
Low-SaltDiet
Weight Loss(19.4 lb)
Alcohol Reduction
PotassiumSupplement
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.
13
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.
14
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.
15
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
17
Key Question

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

18
Clinical Trials

• AASK The African American Study of Kidney
  Disease and Hypertension
• AIRE Acute Infarction Ramipril Efficacy
• ALLHAT Antihypertensive and Lipid-Lowering
  Treatment to Prevent Heart Attack Trial
• COMET Carvedilol or Metoprolol European Trial
• CONSENSUS Cooperative North Scandinavian
  Enalapril Survival
• EUROPA European Trial on Reduction of Cardiac
  Events With Perindopril in Stable Coronary Artery
  Disease
• HOPE Heart Outcomes Prevention Evaluation
• HOT Hypertension Optimal Treatment
• IDNT Irbesartan in Diabetic Nephropathy Trial
• MDRD Modification of Diet in Renal Disease
• MICRO-HOPE Microalbuminuria, Cardiovascular,
  and Renal Outcomes (Heart Outcomes Prevention
  Evaluation)

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Clinical Trials (contd)

• PEACE Prevention of Events With
  Angiotensin-Converting Enzyme Inhibition
• PERSUADE Perindopril Substudy in Coronary
  Artery Disease and Diabetes
• QUIET Quinapril Ischemic Event Trial
• RENAAL Reduction in Endpoints With the
  Angiotensin Antagonist Losartan
• SAVE Survival and Ventricular Enlargement
• SHEP Systolic Hypertension in the Elderly
  Program
• SOLVD Studies of Left Ventricular Dysfunction
• Syst-Eur Systolic Hypertension in Europe
• TRACE Trandolapril Cardiac Elevation
• UKPDS United Kingdom Prospective Diabetes Study
• Val-HeFT Valsartan Heart Failure Trial
• VALIANT Valsartan in Acute Myocardial
  Infarction Trial
• VALUE Valsartan Antihypertensive Long-term Use
  Evaluation

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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.
21
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.
22
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.
23
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.
24
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
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. Syst-Eur
Systolic Hypertension in Europe CV
cardiovascular. Adapted from Tuomilehto J et al.
N Engl J Med. 1999340677-684.
25
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.
26
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.
27
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.
28
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.
29
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.
30
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.
31
VALIANT ARBs in Secondary Prevention
Acute dual RAS blockade provides no significant
benefit
0.4
Captopril
Valsartan
0.3
Valsartan and captopril
All-Cause Mortality (probability)
0.2
0.1
Valsartan vs captopril HR 1.00 P .982
Valsartan captopril vs captopril HR 0.98 P
.726
0.0
0
6
12
18
24
30
36
Months
Patients had post-MI HF or LVSD (EF lt0.40). N
14703. EF ejection fraction LVSD left
ventricular systolic dysfunction MI myocardial
infarction RAS renin-angiotensin system
VALIANT Valsartan in Acute Myocardial
Infarction Trial. Pfeffer M et al. N Engl J Med.
20033491893-1906.
32
COMET Primary Endpoint of Mortality
40
Metoprolol
Carvedilol
30
All-Cause Mortality ()
20
HR 0.83 95 CI, 0.74-0.93 P .0017
10
0
0
1
2
3
4
5
Time (years)
Carvedilol n 1511 metoprolol n 1518. COMET
Carvedilol or Metoprolol European
Trial. Poole-Wilson PA et al. Lancet.
20033627-13.
33
ACEI Versus Placebo Effect on MI
CONSENSUS II
SOLVD-Prevention
SOLVD-Treatment
Total (95 CL)
1.5
TRACE
AIRE
SAVE
OR (95 CL) for the Occurrence of MI
1.0
0.7
0.5
1.3
3.0
3.1
3.4
3.5
Years
Patients had HF and/or LVD. Strauss MD, Hall A.
Circulation. 2006114838-854.
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)
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
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

38
Adherence
39
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.
40
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.
41
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.
42
Case Study
43
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

44
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!

45
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!

46
PCE Takeaways
47
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"

48
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!