practical approaches to managing hypertension: reducing global cardiovascular risk randall m....

Practical Approaches to Managing Hypertension: Reducing Global

Cardiovascular Risk

Randall M. Zusman, MDAssociate Professor of Medicine

Harvard Medical School Director

Division of Hypertension and Vascular MedicineMassachusetts General Hospital

Boston, Massachusetts

Key Question

Which class of agents do you presently consider first-line treatment for patients with hypertension? 1. Diuretics2. β-Blockers (BBs)3. Calcium channel blockers (CCBs)4. Angiotensin-converting enzyme inhibitors (ACEIs)5. Angiotensin receptor blockers (ARBs)6. All of the above

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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.

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

Hypertension and Global CV Risk

What Is Global CV Risk?

Treating hypertension to goal is good Addressing all CV risk factors is better

Achieve optimal BP levelAvoid 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/hypertension/jnc7full.pdf.

JNC 7 Cardiovascular Risk Factors

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

Microalbuminuria or estimated GFR <60 mL/min

Age (men >55 yr; women >65 yr)

Family history of premature CVD


Key Question

What percentage of patients with hypertension have 2 or more additional CV risk factors?

1. 20%

2. 30%

3. 40%

4. 50%

5. >50%


?

26% 25%

8%

RF = risk factor. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

Men Women

2 RFs

3 RFs

1 RF

No Additional

RFs 4 or More RFs

27% 24%

12%

2 RFs

3 RFs

1 RF

No Additional

RFs 4 or More RFs

>50% of Hypertension Occurs in Presenceof 2 or More Risk Factors

CV Risk Factor Clustering With Hypertension: Framingham Offspring, Aged 18 to 74 Years

19% 22% 17% 20%

Risk of CHD in Mild Hypertension by Intensity of Associated Risk Factors

SBP 150-160 mm Hg + + + + + +TC 240-262 mg/dL − + + + + + HDL-C 33-35 mg/dL − − + + + +Diabetes − − − + + +Cigarette smoking − − − − + +ECG-LVH − − − − − +

42

36

30

24

18

12

6

0

46

1014

21

4010

-Yea

r P

rob

abil

ity

of

Eve

nt

(%)

Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

Risk Factors

LIFESTYLE MODIFICATIONS

Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease)

Without Compelling Indications With Compelling Indications

Stage 1 Hypertension Thiazide-type diuretics for most; may consider ACEI, ARB, BB, CCB,

or combo

Stage 2 Hypertension 2-drug combos for most

(usually thiazide-type diuretics and ACEI,

or ARB, or BB, or CCB)

Compelling IndicationsOther drugs

(diuretic, ACEI, ARB, BB, CCB) as needed

If not at goal BP, optimize dosages or add drugs until goal BP achieved; consider consultation with hypertension specialist

INITIAL DRUG CHOICES

JNC 7: Algorithm for Hypertension


Adapted from: Stevens VJ et al. Ann Intern Med. 2001;134:1-11; Messerli FH et al. In: Griffin BP et al, eds. 2004. Manual of Cardiovascular Medicine. 2nd ed; Whelton SP et al. Ann Intern Med. 2002;136:493-503; Cutler JA et al. Am J Clin Nutr. 1997;65(suppl):643S-651S; Xin X et al. Hypertension. 2001;38:1112-1117; Whelton PK et al. JAMA. 1997;277:1624-1632.

BP

Dec

reas

e(m

m H

g)

SBP DBP

ExerciseLow-Salt

DietAlcohol

ReductionPotassium

Supplement

Nonpharmacologic Interventionsand BP Reduction

5

4

3

2

1

0

6

7

Weight Loss(19.4 lb)

NORMAL

PREHYPERTENSION

STAGE 1

STAGE 2

SBP <120 mm Hg andDBP <80 mm Hg

SBP 120-139 mm Hg orDBP 80-89 mm Hg

SBP 140-159 mm Hg orDBP 90-99 mm Hg

SBP 160 mm Hg orDBP 100 mm Hg

Treatment recommended

Consider treatment in those with diabetes or renal disease who fail lifestyle modification

JNC 7 Classification of Blood Pressure


Goal BP Recommendations for Patients With DM or Renal Disease

Organization YearGoal BP

(mm Hg)

Canadian Hypertension Society 2007 <130/80

American Diabetes Association 2006 <130/80

National Kidney Foundation 2004 <130/80

British Hypertension Society 2004 130/80

JNC 7 2003 <130/80

World Health Organization/International Society of Hypertension

2003 <130/80


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 strokeprevention • 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.

Hypertension and Diabetes: Global CV Risk Reduction With Evidence-Based Intervention

Key Question

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

1. 1

2. 2

3. 3

4. 4


?

Patients had hypertension and at least 1 other CHD risk factor. N = 33357.Adapted from Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

Baseline 6 Months 3 Years 5 Years

1 Drug 2 Drugs 3 Drugs % Controlled <140/90 mm Hg

Pat

ien

ts (

%)

0

20

40

60

80

100

1 Year

Multiple Antihypertensive Agents Needed to Achieve BP Goal: ALLHAT

Multiple Antihypertensive Agents Needed to Achieve BP Goal: Diabetes/Renal Impairment

Patients had either diabetes or renal impairment.Bakris GL et al. Am J Kidney Dis. 2000;36:646-661; Brenner BM et al. N Engl J Med. 2001;345:861-869; Lewis EJ et al. N Engl J Med. 2001;345:851-860.

Average No. of BP Medications

UKPDS (<150/85 mm Hg)

MDRD (<92 mm Hg, MAP)

HOT (<80 mm Hg, diastolic)

AASK (<92 mm Hg, MAP)

RENAAL (<140/90 mm Hg)

IDNT (135/85 mm Hg)

4321

Adapted from Curb JD et al. JAMA. 1996;276:1886-1892; Hansson L et al. Lancet. 1998;351:1755-1762; Tuomilehto J et al. N Engl J Med. 1999:340:677-684.

DM Approximately Doubles CVD Risk in Patients With Hypertension

Study

Patients With Diabetes

Patients Without Diabetes

Ratio(events per 1000 pt-yr)

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

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 <90 mm Hg)

CV events 24.0 9.8 2.45

Target DBP (mm Hg)

Str

oke

, M

I, o

r C

V D

eath

(per

100

0 p

atie

nt-

year

s)

80 85 900

5

10

15

20

25 P = .005

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. 1998;351:1755-1762.

HOT Study: Fewer Major CV Events in Patients

With Diabetes Randomized to Lower BP Goal

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. 1999;340:677-684.

Syst-Eur: CV Protection Resulting From BP

Lowering Was Greatest in Patients With Diabetes R

educ

tion

in E

vent

Rat

e fo

r A

ctiv

e Tr

eatm

ent G

roup

(%)

Overall Mortality

CVDMortality

All CVEvents

Fatal and NonfatalStroke

Fatal and Nonfatal

Cardiac Events0

–10

–20

–30

–70

–40

–5041%

P = .09

8%P = .55

70%P = .01

16%P = .37

62%P = .002

25%P = .02

69%P = .02

36%P = .02

–60 57%P = .06

22%P = .10

With Diabetes Without Diabetes

UKPDS: Tight Glucose Versus Tight BP Control and CV Outcomes

Tight glucose control (goal <6.0 mmol/L or 108 mg/dL)

Tight BP control (average 144/82 mm Hg)

*P <.05 compared to tight glucose control

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

Rel

ativ

e R

isk

Red

uct

ion

(%

)

32%37%

10%

32%

12%

24%

5%

44%*

*

**

Patients had hypertension and type 2 diabetes. N = 1148. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.

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.jhtml?identifier=159.

Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420.Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

The Renin-Angiotensin-Aldosterone System (RAAS)

ACEI

Blood Pressure Vascular Proliferation Oxidative Stress Vascular Inflammation Thrombogenesis

ARB

ACE

ACEIs

Angiotensinogen

Renin

Angiotensin I

Angiotensin II

AT1

ARBs ARBs

Kininogen

Kallikrein

Bradykinin

Inactive Peptides

NitricOxide

Adapted with permission from Brown NJ et al. Circulation. 1998;97:1411-1420; Endemann DH. J Am Soc Nephrol. 2004;15:1983-1992.

The Renin-Angiotensin-Aldosterone System (RAAS)

Blood Pressure Vascular Proliferation Oxidative Stress Vascular Inflammation Thrombogenesis

ACE

Angiotensinogen

Renin

Angiotensin I

Angiotensin II

AT1

ARBs

Kininogen

Kallikrein

Bradykinin

Inactive Peptides

Renin

Inhibitors

VALUE: Hazard Ratios for Prespecified Analyses in Patients With Hypertension at High CV Risk

Favors Valsartan Favors Amlodipine

Hazard RatioValsartan/Amlodipine

Primary cardiac composite endpoint

Cardiac mortality

Cardiac morbidity

All myocardial infarction

All congestive heart failure

All stroke

All-cause death

New-onset diabetes

0.5 1 2.0

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. 2004;363:2022-2031.

Val-HeFT: HF Morbidity With ARB in Patients Not Receiving ACEIs

Valsartan (n = 185)Placebo (n = 181)

Eve

nt-

Fre

e P

rob

abil

ity

(%)

Months

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27

Risk Reduction 44% (P <.001)

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure. Maggioni AP et al. J Am Coll Cardiol. 2002;40:1414-1421.

VALIANT: ARBs in Secondary Prevention

0.0

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Valsartan

Valsartan and captopril

Captopril

All-

Cau

se M

ort

alit

y (p

rob

abili

ty)

Months

Valsartan vs captopril: HR = 1.00; P = .982

Valsartan + captopril vs captopril: HR = 0.98; P = .726

Patients had post-MI HF or LVSD (EF <0.40). 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. 2003;349:1893-1906.

Acute dual RAS blockade provides no significant benefit

Carvedilol n = 1511; metoprolol n = 1518.COMET = Carvedilol or Metoprolol European Trial.Poole-Wilson PA et al. Lancet. 2003;362:7-13.

Time (years)

COMET: Primary Endpoint of MortalityA

ll-C

ause

Mo

rtal

ity

(%)

0

10

20

30

40

0 1 2 3 4 5

HR = 0.83 95% CI, 0.74-0.93P = .0017

Metoprolol

Carvedilol

ACEI Versus Placebo: Effect on MI

Patients had HF and/or LVD. Strauss MD, Hall A. Circulation. 2006;114:838-854.

CONSENSUS II

AIRETRACE

SOLVD-Treatment

SOLVD-Prevention

SAVETotal (9

5% CL)

1.5

1.0

0.7

0.5

OR

(95

% C

L)

for

the

Occ

urr

ence

of

MI

1.3 3.0 3.1 3.4 3.5

Years

EUROPA Investigators. Lancet. 2003;362:782-788; HOPE Study Investigators. N Engl J Med. 2000;342:145-153; PEACE Trial Investigators. N Engl J Med. 2004;351:2058-2068; Pitt B, et al. Am J Cardiol. 2001;87:1058-1063.

PEACE: CV Death/MI/CABG/PCI

HOPE: CV Death/MI/Stroke

15

5

10

0

20

0

Placebo

Ramipril 10 mg

Time (years)

Per

cen

t

2 41

22% Risk ReductionHR = 0.78 (0.70–0.86)P <.001

3

Time (years)

12

4

10

01 3 4

14

0

Placebo

Perindopril 8 mg

86

2

52

EUROPA: CV Death/MI/Cardiac Arrest

20% Risk ReductionHR = 0.80 (0.71–0.91)P = .0003

40

20

30

0

50

0

Placebo

Quinapril 20 mg

Time (years)

1

4% Risk IncreaseHR = 1.04 (0.89–1.22)P = .6

10

2 3

QUIET: All CV Events

Time (years)

Trandolapril4 mg

Placebo30

20

1015

5

1 2 3 4 5

25

06

4% Risk ReductionHR = 0.96 (0.88–1.06)P = .43

Per

cen

tP

erce

nt

Per

cen

t

ACEI Trials in CAD Without HF: Primary Outcomes

MICRO-HOPE, PERSUADE: CV Events in Patients With Diabetes

HOPE Study Investigators. Lancet. 2000;355:253-259; Daly CA et al. Eur Heart J. 2005;26:1369-1378.

0 1 2 3 4 5

0

5

10

15

20

25

Follow-Up (years)

Pri

mar

y O

utc

om

e (%

)

MICRO-HOPE(n = 3577)

CV death/MI/stroke

Ramipril10 mg

Placebo

25% RRRP = .0004

0 1 2 3 4

0

5

10

15

20

25

Follow-Up (years)

PERSUADE(n = 1502)

CV death/MI/cardiac arrest

Perindopril8 mg

Placebo

19% RRRP = .13

5

MICRO-HOPE: Albuminuria in Patients With Diabetes

0.0

0.5

1.0

1.5

2.0

2.5

3.0

HOPE Study Investigators. Lancet. 2000;355:253-259.

4-51 2 30

P = .001

P = .02

Placebo

Ramipril

Mea

n A

lbu

min

/Cre

atin

ine

Rat

io (

uri

ne)

Time (y)

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 cluster—and 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

Adherence

CV Risk Factor Control Among Adults With Diagnosed Diabetes

*LDL-C and TG not evaluated.Saydah SH, et al. JAMA. 2004;291:335-342.

Fewer than half of adults with diabetes achieve treatment goals for CV risk factors

A1C Level<7%

Blood Pressure <130/80 mm Hg

Total Cholesterol* <200 mg/dL

Achieved All 3 Treatment Goals

44.3

37.0

29.0

35.8 33.9

48.2

5.2 7.3

0

10

20

30

40

50

60

Ad

ult

s (%

)

NHANES III (n = 1204)

NHANES 1999-2000 (n = 370)

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 patient’s lifestyle and needs Use motivational interviewing techniques

Look for: Different ways to approach patients based on individual

patient attitudes Allies in patient care—family, 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. 2002;40:630-640.

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 adherenceFonarow GC et al. Am J Cardiol. 2001;87:819-822; Ockene IS et al. J Am Coll Cardiol. 2002;40:630-640; NCEP ATP III. September 2002. NIH publication no. 02-5215; Pfizer Helpful Answers Web site. Available at: http://www.pfizerhelpfulanswers.com.

Case Study

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

Decision Point

What is the JNC 7 goal for this patient who has hypertension, diabetes, and renal disease?1. <120/80 mm Hg

2. <130/80 mm Hg

3. <140/80 mm Hg

4. <140/90 mm Hg


?

Decision Point

The patient’s BP is 148/96 mm Hg whiletaking HCTZ 25 mg/d and glyburide 5 mg/d. To bring BP down to <130/80 mm Hg, you wouldadd a(n):

1. BB

2. CCB

3. ARB

4. ACE


?

PCE Takeaways

PCE Takeaways

1. Patients with hypertension often present with multiple cardiac risk factors

2. Be vigilant in your investigation of all clinical indicators

3. Creatively address patient adherence; not everyone responds to the same interventions

4. Clinical inertia is the enemy—don't settle for "close enough"

Key Question

How important is using an antihypertensive agent with proven risk reduction (reducing morbidityand mortality) when choosing medications foryour patients with hypertension?1. Not important2. Slightly important3. Somewhat important4. Extremely important


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