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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. ?. Key Question. - PowerPoint PPT Presentation
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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
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.
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%
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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
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.
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
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.
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
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: 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
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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)
Clinical Trials (cont’d)
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
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
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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
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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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