3 ACC Prevention Blood Pressure

The Evidence for Current Cardiovascular
Disease Prevention Guidelines:

Blood Pressure Control
Evidence and Guidelines
American College of Cardiology
Best Practice Quality Initiative Subcommittee
and Prevention Committee
Classification of Recommendations
and Levels of Evidence
*Data available from clinical trials or
registries about the
usefulness/efficacy in different
subpopulations, such as gender, age,
history of diabetes, history of prior
myocardial infarction, history of heart
failure, and prior aspirin use. A
recommendation with Level of
Evidence B or C does not imply that
the recommendation is weak. Many
important clinical questions addressed
in the guidelines do not lend
themselves to clinical trials. Even
though randomized trials are not
available, there may be a very clear
clinical consensus that a particular
test or therapy is useful or effective.
†In 2003, the ACC/AHA Task Force

on Practice Guidelines developed a
list of suggested phrases to use when
writing recommendations. All
guideline recommendations have
been written in full sentences that
express a complete thought, such that
a recommendation, even if separated
and presented apart from the rest of
the document (including headings
above sets of recommendations),
would still convey the full intent of the
recommendation. It is hoped that this
will increase readers’ comprehension
of the guidelines and will allow queries
at the individual recommendation
level.
Icons Representing the Classification and Evidence
Levels for Recommendations
I IIa IIb III I IIa IIb III I IIa IIb III

Evidence for Current Cardiovascular Disease
Prevention Guidelines
Blood Pressure Evidence

High Blood Pressure*:
Prevalence Increases with Age
National Health and Nutrition Examination Survey (NHANES) III
Hypertension* Prevalence (%)
72%
66%
51%
38%
18%
9%
3%
18-29 30-39 40-49 50-59 60-69 70-79 80+

Age
The prevalence of high blood pressure increases with age
*Hypertension defined as blood pressure >140/90 mmHg or treatment

Source: JNC-VI. Arch Intern Med 1997;157:2413-2446
High Blood Pressure*:
Prevalence in Different Patient Groups
National Health and Nutrition Examination Survey (NHANES)
*High blood pressure defined as blood pressure 140/90 mmHg or treatment

Source: Yoon SS et al. NCHS Data Brief 2012;107:1-7
High Blood Pressure:
Lifetime Risk*
Framingham Heart Study
Risk of hypertension (%)
Men Women
Years
*Residual lifetime risk of developing hypertension among people
with blood pressure <140/90 mmHg starting at age 55-65 years
Source: Vasan RS et al. JAMA 2002; 287:1003-1010
Change in Blood Pressure Levels in
the United States Over Time
National Health and Nutrition Examination Survey (NHANES)
age-adjusted percentage
Blood pressure
Source: Ford ES et al. Figure 2b, Circulation 2009;120:1181-1188

Blood Pressure Treatment

JNC VII Guidelines:
Measurement of Blood Pressure
Method Brief Description
In-office Two readings, 5 minutes apart, sitting in chair

Confirm elevated reading in contralateral arm
Ambulatory BP Indicated for evaluation of “white-coat” HTN.

monitoring Absence of 10–20% BP decrease during sleep
indicates increased CVD risk
Self-measurement Provides information on response to treatment.

May help improve adherence to treatment and
evaluate “white-coat” HTN
BP=Blood pressure, CVD=Cardiovascular

disease, HTN=Hypertension
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
JNC VII Guidelines:
Causes of Secondary Hypertension
Medical Conditions Drugs
Chronic kidney disease NSAIDs
Primary hyperaldosteronism Oral contraceptives
Renovascular disease Adrenal steroids
Chronic steroid therapy Sympathomimetics
Cushing’s syndrome Cyclosporine or tacrolimus
Pheochromocytoma Erythropoietin
Aortic coarctation Ephedra, mu huang, bitter orange
Thyroid or parathyroid disease Cocaine or amphetamines
Sleep apnea Alcohol
NSAIDs=Non-steroidal anti-inflammatory drugs

Resistant Hypertension
Diagnostic and Treatment Algorithm
Confirm Treatment Resistance Identify/Reverse Contributing Lifestyle Factors
Obesity
Office BP >140/90 or 130/80 mm Hg in patients with DM Physical inactivity
or chronic kidney disease Excessive alcohol ingestion
and High salt, low fiber diet
Patient prescribed 3 or more antihypertensive
medications at optimal doses, including if possible a
diuretic
or
Office BP at goal but patient requiring 4 or more Discontinue/Minimize Interfering Substances
antihypertensive medications
Non-steroidal anti-inflammatory agents

Sympathomimetics (diet pills, decongestants)
Stimulants
Exclude Pseudoresistance Oral contraceptives
Licorice
Ephedra
Is patient adherent with prescribed reigmen?
Obtain home, work, or ambulatory BP readings to exclude

white coat effect
BP=Blood pressure, DM=Diabetes mellitus

Source: Calhoun DA et al. Circulation 2008;117:e510-526
Resistant Hypertension (Continued)
Diagnostic and Treatment Algorithm
Screen for Secondary Causes of Hypertension Pharmacologic Treatment
Maximize diuretic therapy, including possible addition of

mineralocorticoid receptor antagonist
Combine agents with different mechanisms of action
Obstructive sleep apnea (snoring, witnessed Use loop diuretics in patients with chronic kidney
apena, excessive daytime sleepiness) disease and/or those receiving potent vasodilators (e.g.,
Primary aldosteronism (elevated aldosterone/renin minoxidil)
ratio)
Chronic kidney disease (CrCl <30 ml/min)
Renal artery stenosis (young female, known
atherosclerotic disease, worsening renal function)
Pheochromocytoma (episodic hypertension,
palpitations, diaphoresis, headache) Refer to Specialist
Cushing’s syndrome (moon facies, central obesity,
abdominal striae, inter-scapular fat deposition)
Refer to appropriate specialist for known or suspected
Aortic coarctation (differential in brachial or
secondary cause(s) of hypertension
femoral pulses, systolic bruit)
Refer to hypertension specialist if blood pressure remains
uncontrolled after 6 months of treatment
CrCl=Creatinine clearance
Source: Calhoun DA et al. Circulation 2008;117:e510-526
High Blood Pressure Evidence:
Increased Risk with Increased Levels
Ischemic heart disease mortality and blood pressure
Age at Risk (Y) Age at Risk (Y)
80-89 80-89
Ischemic Heart Disease Mortality
256 256
Ischemic Heart Disease Mortality

128 70-79 128 70-79
(Floating absolute risk)
(Floating absolute risk)

64 60-69 64 60-69
32 50-59 32 50-59
16 40-49 16 40-49
8 8
4 4
2 2
1 1
0 0
120 140 160 180 70 80 90 100 110
Usual Systolic BP (mm Hg) Usual Diastolic BP (mm Hg)
BP=Blood pressure
Source: Prospective Studies Collaboration. Lancet 2002;360:1903-1913
Risk of CHD with Treatment
Veterans Administration, 1967

Veterans Administration, 1970
Hypertension Stroke Study, 1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study, 1991
MRC Study, 1992
Syst-Eur Study, 1997
0.79
(0.69 to 0.90)
Total
0 0.5 1.0 1.5 2.0
Better than placebo Worse than placebo
CHD=Coronary heart disease

Source: He J et al. Am Heart J 1999;138:211-219
Number of Medications Needed
Trial (SBP Achieved)

UKPDS (144 mm Hg)
ABCD (127 mm Hg)
MDRD (132 mm Hg)
HOT (138 mm Hg)
AASK (127 mm Hg)
1 1.5 2 2.5 3 3.5 4

Number of BP Meds
AASK=African American Study of Kidney Disease and Hypertension,

ABCD=Appropriate Blood Pressure Control in Diabetes, BP=Blood pressure,
HOT=Hypertension Optimal Treatment, MDRD=Modification of Dietary Protein in Renal
Disease, SBP=Systolic blood pressure, UKPDS=UK Prospective Diabetes Study
Source: Abbott K et al. J Clin Pharmacology 2004;44:431-438
Blood Pressure Lowering Therapy Evidence:
Primary Prevention
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT)
33,357 patients with HTN and >1 CHD risk factor randomized to
chlorthalidone, amlodipine, or lisinopril for 5 years
.20
Chlorthalidone
.16 Amlodipine
Rate of MI or
Lisinopril
fatal CHD
.12
.08 RR (95% CI) P-value

A/C 0.98 (0.90-1.07) 0.65
.04
L/C 0.99 (0.91-1.08) 0.81
0
0 1 2 3 4 5 6 7
Years to CHD Event
All three BP lowering agents provide similar efficacy
BP=Blood pressure, CHD=Coronary heart disease,
HTN=Hypertension, MI=Myocardial infarction
Source: ALLHAT Investigators. JAMA 2002;288:2981-2997
Primary Prevention
Losartan Intervention for Endpoint (LIFE) Reduction in
Hypertension Study
9,193 high-risk hypertensive* patients with LVH randomized to losartan
(100 mg) or atenolol (100 mg) for 5 years
death, MI, or stroke (%)
16
Proportion with CV
12
Atenolol
8 Losartan
4
13% RRR, P=0.021
0
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
An ARB provides greater efficacy in patients with LVH

*Defined by SBP=160-200 mmHg or DBP=95-115 mmHg
ARB=Angiotensin receptor blocker, CV=Cardiovascular,
DBP=Diastolic blood pressure, LVH=Left ventricular hypertrophy,
MI=Myocardial infarction, SBP=Systolic blood pressure
Source: Dahlöf B et al. Lancet 2002;359:995-1003
Primary Prevention
Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure
Lowering Arm (ASCOT-BPLA)
19,342 high-risk hypertensive patients with 3 additional CV risk factors
randomized to amlodipine (10 mg) & perindopril (8 mg) or atenolol (100 mg)
& bendroflumethiazide (2.5 mg) for 5.5 years
6
Nonfatal MI and
Atenolol-based regimen
fatal CHD (%)
4
Amlodipine-based regimen
2
RRR=10%, P=0.1052
0
0 1 2 3 4 5 6
Time since randomization (years)
Both BP lowering regimens provide similar efficacy
BP=Blood pressure, CV=Cardiovascular,

CHD=Coronary heart disease, MI=Myocardial infarction
Primary Prevention
Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure
Lowering Arm (ASCOT-BPLA)
Amlodipine- Atenolol-based
based rate/1000 Amlodipine- Atenolol-
rate/1000 patient years based based
Secondary endpoints patient years better better P
Nonfatal MI + fatal CHD 7.4 8.5 <0.05
Total coronary endpoint 14.6 16.8 <0.01
Total CV events/procedures 27.4 32.8 <0.0001
All-cause mortality 13.9 15.5 <0.05
CV mortality 4.9 6.5 0.001
Fatal/nonfatal stroke 6.2 8.1 <0.001
Fatal/nonfatal HF 2.5 3.0 NS
0.50 0.70 1.00 1.45 2.00
An amlodopine-based regimen appears to reduce the rate of other CV events
CHD=Coronary heart disease, CV=Cardiovascular,

HF=Heart failure, MI=Myocardial infarction
Primary Prevention
Avoiding Cardiovascular Events Through Combination Therapy in
Patients Living with Systolic Hypertension (ACCOMPLISH)
11,506 high-risk hypertensive patients randomized to benazepril (40 mg) and
amlodipine (10 mg) or benazepril (40 mg) and HCTZ (25 mg) for 36 months*
0.16
for angina, sudden cardiac
MI, stroke, hospitalization
Composite of CV death,
0.14
revascularization (%)
arrest, and coronary
0.12
Benazepril/HCTZ
0.10
0.08
Benazepril/Amlodipine
0.06
0.04
0.02
20% RRR, HR=0.80, P=0.0002
0.00
0 200 400 600 800 1000 1200 1400
An amlodipine-based regimen provides greater benefit

*The study was prematurely stopped
CV=Cardiovascular, MI=Myocardial infarction
Source: Jamerson K et al. NEJM 2008;359:2417-2428
Primary Prevention
Hypertension in the Very Elderly (HYVET) Trial
3,845 patients >80 years with SBP >160 mm Hg randomized to treatment to
indapamide (1.5 mg) and perindopril (2-4 mg if needed) vs. placebo for 2 years
P=0.02
Rate/1000 patient years (%)
P<0.001
Indapamide +
perindopril
Placebo
P=0.06
P=0.05 P<0.001
(Primary end point)

Blood pressure control in patients >80 years of age provides benefit
CV=Cardiovascular, CVA=Cerebrovascular accident

Source: Beckett NS et al. NEJM 2008;358:1887-1898
Secondary Prevention
International Verapamil-Trandolapril Study (INVEST)
22,576 patients with HTN and CAD randomized to a BP lowering
strategy with verapamil SR (240 mg) or atenolol (50 mg) for 2.7 years
Calcium antagonist strategy (CAS)*

Incidence of all cause
death, nonfatal MI, or
20 Non-calcium antagonist strategy (NCAS)*

nonfatal stroke
15
10
5
RR=0.98, P=0.57
0
0 6 12 18 24 30 36 42 48 54 60
Months
Both a CAS and NCAS provide similar efficacy
*Trandolapril (up to 4 mg) was added in those with diabetes
mellitus, chronic kidney disease, or heart failure
BP=Blood pressure, CAS=Calcium antagonist strategy, HTN=Hypertension,
MI=Myocardial infarction, NCAS=Non-calcium antagonist strategy
Source: Pepine CJ et al. JAMA 2003;290:2805-2816
Valsartan Antihypertensive Long-Term Use
Evaluation (VALUE) Trial
15,245 patients with untreated HTN and high CV risk randomized to a BP
lowering strategy with valsartan (160 mg) or amlodipine (10 mg) for 4.2 years
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
Favors valsartan Favors amlodipine
Both blood pressure lowering regimens provide similar efficacy
BP=Blood pressure, CV=Cardiovascular, HTN=Hypertension

Source: Julius S et al. Lancet 2004;363:2022-2031
Comparison of Amlodipine vs Enalapril to Limit Occurrences of
Thrombosis (CAMELOT) Trial
1,991 patients with CAD and a DBP <100 mmHg randomized to amlodipine
(10 mg), enalapril (20 mg), or placebo for 2 years
0.25 130/78
Placebo Follow-up BP
CV event rate*
Enalapril
124/77
0.20 (mmHg)
Amlodipine 125/77
0.15
0.10
0.05
0
0 6 12 18 24
Months
Treatment with amlodipine results in reduced CV events
*Includes CV death, myocardial infarction, cardiac arrest, coronary
revascularization, hospitalization for heart failure or angina pectoris, stroke,
transient ischemic attack, development of peripheral arterial disease
BP=Blood pressure, CAD=Coronary artery disease,
CV=Cardiovascular, DBP=Diastolic blood pressure
Source: Nissen S et al. JAMA 2004;292:2217-2226
Effect of Intensive Blood Pressure Control
Hypertension Optimal Treatment (HOT) Study
18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized
to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg
Patients with Patients without

Diabetes Diabetes
Major CV events per
1000 patient-years
Diastolic BP goal Diastolic BP goal

More intensive blood pressure control provides greater benefit in diabetics
BP=Blood pressure, CV=Cardiovascular

Source: Hansson L et al. Lancet 1998;351:1755-1762
Cardio-SIS Trial
1,111 patients >55 years with SBP >150 mm Hg randomized to
treatment to achieve usual BP control (SBP <140 mm Hg) or intensive
BP control (SBP <130 mm Hg)
P=0.013
21 15 P=0.003
Incidence of LVH (%)
17.0
Composite of CV
events* (%)
14 10 9.4
11.4
4.8
7 5
0 0
Usual Control Tight Control Usual Control Tight Control
More intensive blood pressure control provides greater benefit
*Composite of death, MI, CVA, TIA, CHF, angina, new AF,
revascularization, aortic dissection, PAD, and ESRD
AF=Atrial fibrillation, ESRD=End stage renal disease, CHF=Congestive heart failure,
CVA=Cerebrovascular accident, LVH=Left ventricular hypertrophy, MI=Myocardial infarction,
PAD=Peripheral artery disease, SBP=Systolic blood pressure, TIA=Transient ischemic attack
Source: Verdecchia P et al. Lancet 2009;374:525-533
International Verapamil-Trandolapril Study (INVEST)—DM
Substudy
6,400 diabetic patients from the INVEST study grouped by tight (<130 mm Hg),
usual (>130 to <140 mm Hg), or uncontrolled (>140 mm Hg) blood pressure
HR=1.15, p=0.036
Tight BP control is not associated with reduced adverse CV events
BP=Blood pressure, CV=Cardiovascular

Source: Cooper-DeHoff RM et al. JAMA 2010;304:61-68
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Blood Pressure Trial
4,733 diabetic patients randomized to intensive BP control (target SBP <120
mm Hg) or standard BP control (target SBP <140 mm Hg) for 4.7 years
HR=0.88 HR=0.59
20 20
95% CI (0.73-1.06) 95% CI (0.39-0.89)

Nonfatal MI, nonfatal
stroke, or CV death
Patients with Events (%)
Patients with Events (%)

15 15
Total stroke
10 10
5 5
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Years Post-Randomization Years Post-Randomization
Intensive BP control in DM does not reduce a composite of adverse CV

events, but does reduce the rate of stroke
BP=Blood pressure, DM=Diabetes mellitus,
HR=Hazard ratio, SBP=Systolic blood pressure
ACCORD study group. NEJM 2010;362:1575-1585
JNC VII Guidelines:
Management and Treatment
Initial drug therapy
BP SBP* DBP* Lifestyle Without compelling With compelling
classification mmHg mmHg modification indications indications
Normal <120 and <80 Encourage
Prehypertension 120–139 or 80–89 Yes No antihypertensive drug Drug(s) for compelling
indicated. indications.‡
Stage 1 140–159 or 90–99 Yes Thiazide-type diuretics for

Hypertension most. May consider ACE-I,
ARB, BB, CCB, or combination Drug(s) for compelling
of these. indications.‡
Stage 2 >160 or >100 Yes 2-drug combination for most† Other antihypertensive
Hypertension (usually thiazide-type diuretic drugs (as needed).
and ACE-I or ARB or BB or
CCB).
*Treatment determined by highest blood pressure category

†Initial combined therapy should be used cautiously
in those at risk for orthostatic hypotension

‡Treat patients with chronic kidney disease or diabetes
mellitus to blood pressure goal of <130/80 mmHg

ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor
blocker, BB=Beta-blocker, BP=Blood pressure, CCB=Calcium channel
blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure
JNC VII Guidelines:
Lifestyle Modifications for BP Control
Modification Recommendation Approximate SBP

Reduction Range
Weight reduction Maintain normal body weight (BMI=18.5- 5-20 mmHg/10 kg weight
25) lost
DASH eating plan Diet rich in fruits, vegetables, low fat dairy 8-14 mmHg
and reduced in fat
Restrict sodium <2.4 grams of sodium per day 2-8 mmHg

intake
Physical activity Regular aerobic exercise for at least 30 4-10 mmHg

minutes most days of the week
Moderate alcohol <2 drinks/day for men and <1 drink/day 2-4 mmHg
for women
BMI=Body mass index, BP=Blood pressure, SBP=Systolic blood pressure

JNC VII Guidelines:
Compelling Indications for Drug Classes
Compelling Indication Initial Therapy Options Clinical-Trial Basis
Heart Failure Diuretic, BB, ACE-I, MERIT-HF, COPERNICUS, CIBIS,
ARB, Aldo ANT SOLVD, AIRE, TRACE, Val-HeFT,
RALES
Post-MI BB, ACE-I, Aldo ANT ACC/AHA Post-MI Guidelines, BHAT,

SAVE, Capricorn, EPHESUS
High CAD Risk Diuretic, BB, ACE-I, CCB ALLHAT, HOPE, ANBP2,
LIFE, CONVINCE
Diabetes Mellitus Diuretic, BB, ACE-I, NKF-ADA Guideline,
ARB, CCB UKPDS, ALLHAT
Chronic Kidney Disease ACE-I, ARB NKF Guidelines, Captopril Trial,

RENAAL, IDNT, REIN, AASK
Recurrent Stroke Prevention Diuretic, ACE-I PROGRESS
ACE-I=Angiotensin converting enzyme inhibitor, Aldo ANT=Aldosterone

antagonist, ARB=Angiotensin receptor blocker, BB=Beta-blocker,
CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial
infarction
JNC VII Guidelines:
Blood Pressure Treatment Algorithm
Lifestyle modifications
Not at goal BP (<140/90 mm Hg)

(<130/80 mm Hg for those with diabetes mellitus
or chronic kidney disease)
Initial drug choices
WITHOUT compelling indications WITH compelling indications
Stage 1 hypertension Stage 2 hypertension

(SBP 140–159 mm Hg or DBP 90–99 mm Hg): (SBP 160 or DBP 100 mm Hg): Drugs for compelling
Thiazide-type diuretic for most. Two-drug combination for most indications:
May consider ACEI, ARB, BB, CCB, or combo. (usually thiazide-type diuretic and Other antihypertensive drugs
ACEI or ARB or BB or CCB). (diuretic, ACEI, ARB, BB, CCB)
as needed.
Not at goal BP
Optimize dosages or add additional drugs until goal BP is achieved.

Consider consultation with hypertension specialist.
ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor

blocker, BB=Beta-blocker, BP=Blood pressure, CCB=Calcium channel blocker,
DBP=Diastolic blood pressure, SBP=Systolic blood pressure
Blood Pressure Recommendations
Primary and Secondary Prevention
I IIa IIb III Counsel regarding the need for lifestyle modification: weight
control; increased physical activity; alcohol moderation;
sodium reduction; and emphasis on increased consumption
of fresh fruits, vegetables, and low-fat dairy products.
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

AHA Primary Prevention of CV Disease in DM
Primary Prevention
• BP should be measured at every routine visit. Patients with a SBP
>130 mm Hg or DBP >80 mm Hg should have BP confirmed on a
separate day.
• Patients should be treated to a SBP <130 mm Hg and a DBP <80

mm Hg.
• Patients with a SBP of 130-139 mm Hg or a DBP of 80-89 mm Hg

should initiate lifestyle modification* alone for a maximum of 3
months. If, after these efforts, targets are not achieved, treatment
with pharmacological agents should be initiated.
*Includes weight control, increased physical activity, alcohol moderation, sodium reduction, and
emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products
AHA=American Heart Association, BP=Blood pressure,
CV=Cardiovascular, DBP=Diastolic blood pressure,
DM=Diabetes mellitus, SBP=Systolic blood pressure
Source: Buse JB et al. Circulation 2007;115:114-126
Blood Pressure Recommendations (Continued)
Primary Prevention
• Multiple-drug therapy is generally required to achieve BP targets.
• In elderly hypertensive patients, BP should be lowered gradually to

avoid complications.
• Orthostatic measurement of BP should be performed when clinically

indicated.
• Patients not achieving target BP despite multiple-drug therapy should

be referred to a physician specializing in the care of patients with
hypertension.
AHA=American Heart Association, BP=Blood pressure,

CV=Cardiovascular, DM=Diabetes Mellitus
ADA Blood Pressure Recommendations
for Patients with Diabetes Mellitus
Primary Prevention
• BP should be measured at every routine DM visit. Patients found to
have a SBP >130 mm Hg or a DBP >80 mm Hg should have BP
confirmed on a separate day. A repeat SBP >130 mm Hg or a repeat
DBP >80 mm Hg confirms a diagnosis of hypertension.
• Patients with DM should be treated to a SBP <130 mm Hg.
• Patients with DM should be treated to a DBP <80 mm Hg.
• Patients with a SBP 130-139 mm Hg or a DBP 80-89 mm Hg may be

given lifestyle therapy alone for a maximum of 3 months, and then if
targets are not achieved, patients should have pharmacologic agents
added.
ADA=American Diabetes Association, BP=Blood pressure, DBP=Diastolic

blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
for Patients with Diabetes Mellitus (Continued)
Primary Prevention
• Patients with more severe hypertension (SBP >140 mm Hg or DBP
>90 mm Hg) at diagnosis or follow-up should receive pharmacologic
therapy in addition to lifestyle therapy.
• Lifestyle therapy for hypertension consists of weight loss if

overweight, DASH-style dietary pattern including reducing sodium and
increasing potassium intake, moderation of alcohol intake, and
increased physical activity.
ACE=Angiotensin converting enzyme, ADA=American Diabetes Association,

BP=Blood pressure, DBP=Diastolic blood pressure, DM=Diabetes mellitus,
GFR=Glomerular filtration rate, SBP=Systolic blood pressure
Primary Prevention
• Pharmacologic therapy for patients with DM and hypertension
should be paired with a regimen that includes either an ACE inhibitor
or an ARB. If one class is not tolerated, the other should be
substituted. If needed to achieve BP targets, a thiazide diuretic
should be added to those with an estimated GFR >30 ml/min and a
loop diuretic with an estimated GFR <30 ml/min.
• Multiple drug therapy (two or more agents at maximal doses) is

generally required to achieve BP targets.
ACE=Angiotensin converting enzyme, ADA=American Diabetes

Association, ARB=Angiotensin receptor blocker, BP=Blood pressure,
DM=Diabetes mellitus, GFR=Glomerular filtrate rate
I IIa IIb III
Use of an ACE inhibitor and/or beta-blocker in those with BP
>140/90 mmHg*. Other drugs should be added in order to
achieve the desired BP.
*A BP >130/80 mmHg should be used for individuals with CKD or DM

ACE=Angiotensin converting enzyme, BP=Blood pressure,
CKD=Chronic kidney disease, DM=Diabetes mellitus

Angiotensin Converting
Enzyme Inhibitor Evidence
and Guidelines
ACE Inhibitor:
Mechanism of Action
Angiotensin II Inactive Fragments
ACE Inhibitor Kininase II

Angiotensin I
Bradykinin
Renin
Angiotensinogen
Kininogen
Sympathetic
Vasopressin Kallikrein
tPA
Aldosterone Vasodilation
Vasoconstriction Prostaglandins
ACE=Angiotensin converting enzyme

ACE Inhibitor Evidence:
Heart Outcomes Prevention and Evaluation (HOPE) Study
9,297 patients with DM or vascular disease plus an additional CV
risk factor, but without HF or known LVSD randomized to ramipril
(10 mg) or placebo for 5 years
0.20
CV death, MI, or
0.15 Placebo
stroke (%)
0.10 Ramipril
0.05
22% RRR, P<0.001
0.00
0 500 1000 1500
Days of Follow-Up
An ACE inhibitor provides benefit in high-risk individuals
ACE=Angiotensin converting enzyme, DM=Diabetes

mellitus, CV=Cardiovascular, HF=Heart failure, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction
Source: HOPE Investigators. NEJM 2000;342:145-153
European Trial on Reduction of Cardiac Events with Perindopril
in Stable Coronary Artery Disease (EUROPA)
12,218 patients with CAD and presumed normal LV function
randomized to perindopril (8 mg) or placebo for 4 years
Cardiovascular death (0.86; 0.72-1.03)
Non-fatal MI (0.78; 0.20-0.90)
Cardiac arrest (0.54; 0.20-1.47)
Combined endpoint (0.80; 0.71-0.91)
0 0.5 1 1.5 2
Favors Perindopril Favors Placebo
An ACE inhibitor provides benefit in intermediate-risk individuals
ACE=Angiotensin converting enzyme, CAD=Coronary artery

disease, CV=Cardiovascular, MI=Myocardial infarction
Source: EUROPA Investigators. Lancet 2003;362:782-788
Prevention of Events with Angiotensin Converting Enzyme
Inhibition (PEACE) Trial
8,290 patients with stable CAD and normal LV function randomized to
trandolapril (4 mg) or placebo for 5 years
30
Placebo
Primary End Point (%)*
25 Trandolapril
20
15
10
5
0
0 1 2 3 4 5 6
Years After Randomization

An ACE inhibitor does not provide benefit in lower-risk individuals
*Includes death from cardiovascular causes,
myocardial infarction, or coronary revascularization
ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, LV=Left ventricular
Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
Comparison between the HOPE and PEACE trials
HOPE, placebo
MI, Cardiac death,
HOPE, active drug

or Stroke (%)
(ramipril)
PEACE, placebo
Years
Patients enrolled in the PEACE trial were lower risk*
*Reflects better blood pressure control, revascularization,

and use of other risk-reducing medications (i.e., antiplatelet
therapy, beta-blocker, lipid-lowering medication)
CHD=Coronary heart disease, MI=Myocardial infarction
Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
Meta-Analysis of the HOPE, EUROPA, and PEACE Trials*
Clinical Trial N Deaths RR of Mortality
HOPE 9,297 1051 HR=0.84 P=0.005
EUROPA 12,218 795 HR=0.89 P=0.10
PEACE 8,290 633 HR=0.89 P=0.13
All Trials 33,960 >3000 HR=0.86 P<0.001
0.4 0.6 0.8 1.0 1.2 1.4 1.6
ACE-I Better Placebo Better

*7 RCTs, 33,960 randomized patients, and 4.4 years of mean follow-up.
Other findings include a CV mortality HR=0.81, MI HR=0.82, and stroke HR=0.77
ACE-I=Angiotensin converting enzyme inhihbitor, MI=Myocardial infarction
Sources:
Danchin N et al. Arch Intern Med 2006;166:787-796
The HOPE Trial Investigators. NEJM 2000;342:145-153
The EUROPA Study. Lancet 2003; 362: 782-788
The PEACE Trial Investigators. NEJM 2004;351:2058-2068
SAVE AIRE TRACE
Radionuclide Clinical and/or Echocardiogram
EF <40% radiographic EF <35%
signs of HF
0.4
Probability of Event
0.35
Placebo
0.3
0.25 ACE-I
0.2
0.15
0.1
0.05 OR 0.74 (0.66–0.83)
0
0 1 2 3 4
Years
An ACE-I provides substantial benefit in post-MI LVSD
ACE-I=Angiotensin converting enzyme inhibitor, EF=Ejection fraction, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio
Source: Flather MD et al. Lancet 2000;355:1575–1581
ACE Inhibitor Recommendations
I IIa IIb III An ACE inhibitor should be started and continued indefinitely
in all patients with left ventricular ejection fraction <40% and
in those with hypertension, DM, or CKD, unless
contraindicated
I IIa IIb III

An ACE inhibitor in all other patients
ACE=Angiotensin converting enzyme, CKD=Chronic kidney disease,

DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction
Primary Prevention
• Patients with a SBP >140 mm Hg or DBP >90 mm Hg should
receive drug therapy in addition to lifestyle and behavioral therapy.
• All patients with hypertension should be treated with a regimen that

includes an ACE inhibitor or an ARB. If one class is not tolerated,
the other should be substituted. Other drug classes* that have been
demonstrated to reduce CVD events should be added as needed to
achieve BP targets.
• If ACE inhibitors, ARBs, or diuretics are used, renal function and

serum potassium levels should be monitored within the first 3
months. If stable, follow-up could occur every 6 months.
*Includes beta-blockers, thiazide diuretics, and calcium channel blockers

ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker,
BP=Blood pressure, CV=Cardiovascular, CVD=Cardiovascular disease,
DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure
Primary Prevention
• If an ACE inhibitor, ARB, or diuretic is used, kidney function and
serum potassium levels should be closely monitored.
• In pregnant patients with DM and chronic hypertension, BP target

goals of 110-129/65-79 mm Hg are suggested in the interest of
long-term maternal health and minimizing impaired fetal growth.
• An ACE inhibitor and ARB are contraindicated during pregnancy.

ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus

Angiotensin Receptor Blocker

Angiotensin Receptor Blocker:
Mechanism of Action
Renin
Angiotensinogen Angiotensin I
ACE
Other Pathways Angiotensin II AT II
Receptor
AT I
Blocker
Receptor
Blocker ATI Receptors ATII
Vasoconstriction Proliferative Vasodilation Antiproliferative

Action Action
Angiotensin Receptor Blocker Evidence:
Candesartan in Heart Failure Assessment of Reduction in Mortality
and Morbidity (CHARM) Alternative Trial
2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to
ACE inhibitor randomized to candesartan (32 mg) or placebo for 34 months
50
Placebo
Hospitalization
40
CV Death or
30
for HF
Candesartan
20
10
HR 0.77 p=0.0004
0
0 1 2 3
Years
An ARB provides benefit in those intolerant of an ACE inhibitor
ACE=Angiotensin converting enzyme, ARB=Angiotensin

receptor blocker, CV=Cardiovascular, EF=Ejection fraction,
HF=Heart failure, LVSD=Left ventricular systolic dysfunction
Source: Granger CB et al. Lancet 2003;362:772-777
Valsartan in Acute Myocardial Infarction Trial (VALIANT)
14,703 patients with post-MI HF or LVSD (EF <0.40) randomized to captopril (50
mg tid), valsartan (160 mg bid), or captopril (50 mg tid) plus valsartan (80 mg
bid) for 2 years
0.4 Captopril
All Cause Mortality
0.3 Valsartan
Valsartan and Captopril
0.2
0.1 Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
0.0
0 6 12 18 24 30 36
Months
An ARB provides similar efficacy to an ACE inhibitor in Post-MI LVSD
ACE=Angiotensin converting enzyme,
ARB=Angiotensin receptor blocker, EF=Ejection
fraction, LVSD=Left ventricular systolic dysfunction
Source: Pfeffer M et al. NEJM 2003;349:1893-1906
Candesartan in Heart Failure Assessment of Reduction in Mortality
and Morbidity (CHARM) Added Trial
2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to
candesartan (32 mg) or placebo in addition to an ACE inhibitor for 34 months
50
Hospitalization
40 Placebo
CV Death or
30
for HF
Candesartan
20
10
HR 0.85, p=0.011
0
0 1 2 3
Years
Addition of an ARB to an ACE inhibitor may provide benefit in those with LVSD

receptor blocker, EF=Ejection fraction, HF=Heart failure,
LVSD=Left ventricular systolic dysfunction
Source: McMurray JJ et al. Lancet 2003;362:767-771
Ongoing Telmisartan Alone and in Combination with Ramipril
Global Endpoint Trial (ONTARGET)
25,620 patients with CVD or DM randomized to ramipril (10 mg),
telmisartan (80 mg), or a combination of both for 56 months
Non-inferiority Margin
Primary Composite (p = 0.003)
CV Death / MI / Stroke /
Hospitalization for Heart Failure
CV Death / MI / Stroke (p = <0.001)

(HOPE Composite)
Telmisartan better Ramipril better

0.8 0.9 1.0 1.1 1.2
RR (95% CI)
An ARB provides similar efficacy to an ACE-I in high risk patients

ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker,
CVD=Cardiovascular disease, DM=Diabetes mellitus, MI=Myocardial infarction
Source: ON TARGET Investigators. NEJM 2008;358:1547-1559
Ongoing Telmisartan Alone and in Combination with Ramipril
Global Endpoint Trial (ONTARGET)
25,620 patients with CVD or DM randomized to ramipril (10 mg),
telmisartan (80 mg), or a combination of both for 56 months
0.20 Telmisartan plus ramipril*
CV Death, MI, Stroke,
or Hospitalization for
Telmisartan
0.15
Heart Failure
Ramipril
0.10
0.05 *Dual RAS blockade leads

to greater renal impairment
HR=1.33 (p<0.001)
0.00
0 1 2 3 4 5
Follow-up (years)
Dual RAS blockade provides no additional benefit but leads to greater
renal impairment
CVD=Cardiovascular disease, DM=Diabetes mellitus,
MI=Myocardial infarction, RAS=Renin angiotensin system
Source: ON TARGET Investigators. NEJM 2008;358-1547-1559
Telmisartan Randomized Assessment Study in ACE Intolerant
Subjects with Cardiovascular Disease (TRANSCEND)
5,926 high risk patients intolerant to ACE inhibitors randomized to
telmisartan (80 mg) or placebo for 56 months
P=0.055
Percent of patients
P=0.216
P=0.048
An ARB is well tolerated in those unable to take an ACE inhibitor

*Primary endpoint is a composite of CV death, MI,
stroke or heart failure hospitalization
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor
blocker, CV=Cardiovascular, MI=Myocardial infarction
Source: TRANSCEND Investigators. Lancet. 2008;372:1174-83
Angiotensin Receptor Blocker Recommendations
I IIa IIb III
An ARB in patients who have HF or who have had a MI
with left ventricular ejection fraction <40% and who are
ACE-inhibitor intolerant
I IIa IIb III

An ARB in other patients who are intolerant of an ACE
inhibitor
I IIa IIb III

Use of an ARB in combination with an ACE inhibitor is not
well established in those with systolic heart failure

receptor blocker, HF=Heart failure, MI=Myocardial infarction
Primary Prevention
• Patients with a SBP >140 mm Hg or DBP >90 mm Hg should
receive drug therapy in addition to lifestyle and behavioral therapy.
• All patients with hypertension should be treated with a regimen that

includes an ACE inhibitor or an ARB. If one class is not tolerated,
the other should be substituted. Other drug classes* that have been
demonstrated to reduce CVD events should be added as needed to
achieve BP targets.
• If ACE inhibitors, ARBs, or diuretics are used, renal function and

serum potassium levels should be monitored within the first 3
months. If stable, follow-up could occur every 6 months.
*Includes beta-blockers, thiazide diuretics, and calcium channel blockers

ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker,
BP=Blood pressure, CV=Cardiovascular, CVD=Cardiovascular disease,
DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure
Primary Prevention
• If an ACE inhibitor, ARB, or diuretic is used, kidney function and
serum potassium levels should be closely monitored.
• In pregnant patients with DM and chronic hypertension, BP target

goals of 110-129/65-79 mm Hg are suggested in the interest of
long-term maternal health and minimizing impaired fetal growth.
• An ACE inhibitor and ARB are contraindicated during pregnancy.

ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus

Beta-blocker Evidence and

Guidelines
Beta-blocker:
Targets and Receptor Selectivity
Heart a2 a2
Blood Vessel
+ b1 _ _ a2 Vasoconstriction
Inotropy
+ b2 NE
_
NE NE a1 Vasoconstriction
Chronotropy
+ +
_ a1 b2 Vasodilation
Dromotropy M2 b2
M2 M2 Vasodilation
Sympathetic
b1 selective blocker Nerve Terminal
b non-selective blocker
ACh
b non-selective blocker
with a1 blocking
activity
Parasympathetic Sympathetic Cholinergic Nerve
Nerve Terminal Terminal
a=Alpha receptor, Ach=Acetylcholine, b=Beta receptor,

M=Muscarinic receptor, NE=Norepinephrine
Source: Klabunde, RE (ed) Cardiovascular Physiology Concepts LWW 2001
Beta-blocker Evidence:
Placebo-controlled post-MI trials* using oral beta-blockers
Patient
s Treatment Duration of Effect on Effect on
Study (N) Groups Follow-Up Mortality Reinfarction
Metoprolol  36%
Göteborg Study† 1,395 3 months PNS
tartrate (P.03)
Timolol Trial  39%  28%

1,884 Timolol 17 months
(Norwegian) (P.003) (P.0005)
Lopressor
Metoprolol
Intervention 2,395 12 months PNS NA
tartrate
Trial
Beta-blocker Heart  26%

3,837 Propranolol 25 months PNS
Attack Trial (P.005)
 23%  40%
CAPRICORN Trial 1,959 Carvedilol 15 months
(P=.03) (P.01)
*Includes the largest trials performed to date

†Patients received IV followed by oral metoprolol
MI=Myocardial infarction, NA=Not applicable, NS=Not significant
Summary of secondary prevention trials of beta-blocker therapy
Phase of Total #
Treatment Patients RR (95% CI)
Acute 28,970 0.87 (0.77-0.98)

treatment
Secondary 24,298 0.77 (0.70-0.84)

prevention
Overall 53,268 0.81 (0.75-0.87)
0.5 1.0 2.0

RR of death
Beta-blocker Placebo
better better
CI=Confidence interval, RR=Relative risk

Source: Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald
E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular
Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
Benefit in HF and/or LVSD
Study Drug HF Patients Follow-up Mean Dosage Effects on
Severity (n) Outcomes
CIBIS Bisoprolol* Moderate- 641 1.9 Years 3.8 All cause mortality
Severe mg/day (p=NS)
CIBIS-II Bisoprolol* Moderate- 2,647 1.3 Years 7.5 All cause mortality
Severe mg/day 34% (P<0.0001)
BEST Bucindolol* Moderate- 2,708 2.0 Years 152 All cause mortality
Severe mg/day (p=NS)
MERIT-HF Metoprolol Mild- 3,991 1.0 Years 159 All cause mortality
succinate# Moderate mg/day 34% (P=0.0062)
MDC Metoprolol Mild- 383 1.0 Years 108 Death or Need for TX
tartrate* Moderate mg/day (P=NS)
CAPRICORN Carvedilol Mild 1,989 1.3 Years 40 All cause mortality
mg/day 23% (P =0.03)
US Carvedilol Carvedilol Mild- 1,094 0.5 Years 45 All-cause mortality†
Moderate mg/day 65% (P=.0001)
COPERNICUS Carvedilol Severe 2,289 0.9 Years 37 All-cause mortality
mg/day 35% (P =0.0014)
SENIORS Nebivolol Moderate 2,128 3.0 Years 7.7 All-cause mortality or
mg/day CV hospitalization
14% (P =0.039)
*Not an approved indication,

†Not a planned end point
#Not approved for severe HF/mortality reduction alone
HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NS=Not significant, TX=Transplant

Beta-Blocker Recommendations
Beta-blocker should be used in all patients with LVSD
I IIa IIb III
(ejection fraction <40%) with HF or prior MI, unless
contraindicated*. (Use should be limited to carvedilol,
metoprolol succinate, or bisoprolol, which have been shown
to reduce mortality.)
I IIa IIb III
Beta-blocker for 3 years in all patients with normal left
ventricular function who have had a MI or ACS
I IIa IIb III
Beta-blocker beyond 3 years as chronic therapy in all
patients with normal left ventricular function who have had a
MI or ACS
*Relative contraindications include asthma, chronic obstructive
pulmonary disease, insulin dependent diabetes mellitus, severe
peripheral arterial disease, and a PR interval >0.24 seconds
ACS=Acute coronary syndrome, HF=Heart failure, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction
Beta-Blocker Recommendations (Continued)
I IIa IIb III
Beta-blocker in patients with LVSD (ejection fraction <40%)
without HF or prior MI
I IIa IIb III
Beta-blocker as chronic therapy for all other patients with
coronary or other vascular disease
HF=Heart failure, LVSD=Left ventricular systolic

dysfunction, MI=Myocardial infarction

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The Evidence for Current Cardiovascular

Disease Prevention Guidelines:

†In 2003, the ACC/AHA Task Force

I IIa IIb III I IIa IIb III I IIa IIb III

I IIa IIb III I IIa IIb III I IIa IIb III

I IIa IIb III I IIa IIb III I IIa IIb III

Blood Pressure Evidence

18-29 30-39 40-49 50-59 60-69 70-79 80+

*Hypertension defined as blood pressure >140/90 mmHg or treatment

*High blood pressure defined as blood pressure 140/90 mmHg or treatment

Source: Ford ES et al. Figure 2b, Circulation 2009;120:1181-1188

Blood Pressure Treatment

In-office Two readings, 5 minutes apart, sitting in chair

Ambulatory BP Indicated for evaluation of “white-coat” HTN.

Self-measurement Provides information on response to treatment.

BP=Blood pressure, CVD=Cardiovascular

NSAIDs=Non-steroidal anti-inflammatory drugs

Confirm Treatment Resistance Identify/Reverse Contributing Lifestyle Factors

Non-steroidal anti-inflammatory agents

Obtain home, work, or ambulatory BP readings to exclude

BP=Blood pressure, DM=Diabetes mellitus

Screen for Secondary Causes of Hypertension Pharmacologic Treatment

Maximize diuretic therapy, including possible addition of

Ischemic Heart Disease Mortality

(Floating absolute risk)

Veterans Administration, 1967

CHD=Coronary heart disease

Trial (SBP Achieved)

ABCD (127 mm Hg)

MDRD (132 mm Hg)

HOT (138 mm Hg)

AASK (127 mm Hg)

1 1.5 2 2.5 3 3.5 4

AASK=African American Study of Kidney Disease and Hypertension,

.08 RR (95% CI) P-value

An ARB provides greater efficacy in patients with LVH

Both BP lowering regimens provide similar efficacy

BP=Blood pressure, CV=Cardiovascular,

0.50 0.70 1.00 1.45 2.00

An amlodopine-based regimen appears to reduce the rate of other CV events

CHD=Coronary heart disease, CV=Cardiovascular,

An amlodipine-based regimen provides greater benefit

(Primary end point)

CV=Cardiovascular, CVA=Cerebrovascular accident

Calcium antagonist strategy (CAS)*

20 Non-calcium antagonist strategy (NCAS)*

BP=Blood pressure, CV=Cardiovascular, HTN=Hypertension

Patients with Patients without

Diastolic BP goal Diastolic BP goal

BP=Blood pressure, CV=Cardiovascular

Tight BP control is not associated with reduced adverse CV events

BP=Blood pressure, CV=Cardiovascular

95% CI (0.73-1.06) 95% CI (0.39-0.89)

Patients with Events (%)

Years Post-Randomization Years Post-Randomization

Intensive BP control in DM does not reduce a composite of adverse CV

Stage 1 140–159 or 90–99 Yes Thiazide-type diuretics for

*Treatment determined by highest blood pressure category

in those at risk for orthostatic hypotension

mellitus to blood pressure goal of <130/80 mmHg

Modification Recommendation Approximate SBP

Restrict sodium <2.4 grams of sodium per day 2-8 mmHg

Physical activity Regular aerobic exercise for at least 30 4-10 mmHg

BMI=Body mass index, BP=Blood pressure, SBP=Systolic blood pressure