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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 Classification of Recommendations and Levels Recommendations and Levels of Evidenceof 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.
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
I IIa IIb III
I IIa IIb III
I IIa IIb III
Icons Representing the Classification and Icons Representing the Classification and Evidence Levels for RecommendationsEvidence Levels for Recommendations
Blood Pressure EvidenceBlood Pressure Evidence
Evidence for Current Cardiovascular Evidence for Current Cardiovascular DiseaseDisease
Prevention GuidelinesPrevention Guidelines
Hypert
ensi
on*
Pre
vale
nce
(%
)
18-29
National Health and Nutrition Examination Survey (NHANES) III
30-39 40-49 50-59 60-69 70-79 80+
Age
3%9%
18%
Source: JNC-VI. Arch Intern Med 1997;157:2413-2446
51%
66%72%
38%
*Hypertension defined as blood pressure >140/90 mmHg or treatment
High Blood Pressure*: High Blood Pressure*: Prevalence Increases Prevalence Increases with Agewith Age
The prevalence of high blood pressure increases with age
High Blood Pressure*: High Blood Pressure*: Prevalence in Different Patient GroupsPrevalence in Different Patient Groups
National Health and Nutrition Examination Survey (NHANES)
Source: Yoon SS et al. NCHS Data Brief 2012;107:1-7
*High blood pressure defined as blood pressure 140/90 mmHg or treatment
Ris
k of
hyp
erte
nsio
n (%
)
*Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg starting at age 55-65 years
Years
Men Women
Source: Vasan RS et al. JAMA 2002; 287:1003-1010
Framingham Heart Study
High Blood Pressure: High Blood Pressure: Lifetime Risk*Lifetime Risk*
National Health and Nutrition Examination Survey (NHANES)
Bloo
d pr
essu
reag
e-ad
just
ed p
erce
ntag
e
Change in Blood Pressure Change in Blood Pressure Levels in the United States Levels in the United States Over TimeOver Time
Source: Ford ES et al. Figure 2b, Circulation 2009;120:1181-1188
Blood Pressure Treatment Blood Pressure Treatment Evidence and GuidelinesEvidence and Guidelines
Evidence for Current Cardiovascular Evidence for Current Cardiovascular DiseaseDisease
Prevention GuidelinesPrevention Guidelines
Provides information on response to treatment. May help improve adherence to treatment and evaluate “white-coat” HTN
Self-measurement
Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep indicates increased CVD risk
Ambulatory BP monitoring
Two readings, 5 minutes apart, sitting in chair
Confirm elevated reading in contralateral arm
In-office
BP=Blood pressure, CVD=Cardiovascular disease, HTN=Hypertension
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
JNC VII Guidelines: JNC VII Guidelines: Measurement of Blood Measurement of Blood PressurePressure Method Brief Description
Medical Conditions
Chronic kidney disease
Primary hyperaldosteronism
Renovascular disease
Chronic steroid therapy
Cushing’s syndrome
Pheochromocytoma
Aortic coarctation
Thyroid or parathyroid disease
Sleep apnea
Drugs
NSAIDs
Oral contraceptives
Adrenal steroids
Sympathomimetics
Cyclosporine or tacrolimus
Erythropoietin
Ephedra, mu huang, bitter orange
Cocaine or amphetamines
Alcohol
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
NSAIDs=Non-steroidal anti-inflammatory drugs
JNC VII Guidelines: JNC VII Guidelines: Causes of Secondary Causes of Secondary HypertensionHypertension
Source: Calhoun DA et al. Circulation 2008;117:e510-526
Diagnostic and Treatment Algorithm
Confirm Treatment Resistance Confirm Treatment Resistance
Office BP >140/90 or 130/80 mm Hg in patients with DM or chronic kidney disease
andPatient prescribed 3 or more antihypertensive
medications at optimal doses, including if possible a diuretic
orOffice BP at goal but patient requiring 4 or more
antihypertensive medications
Exclude Pseudoresistance Exclude Pseudoresistance
Is patient adherent with prescribed reigmen?
Obtain home, work, or ambulatory BP readings to exclude white coat effect
Identify/Reverse Contributing Lifestyle Factors
Identify/Reverse Contributing Lifestyle Factors
ObesityPhysical inactivity
Excessive alcohol ingestionHigh salt, low fiber diet
BP=Blood pressure, DM=Diabetes mellitus
Discontinue/Minimize Interfering Substances
Discontinue/Minimize Interfering Substances
Non-steroidal anti-inflammatory agentsSympathomimetics (diet pills, decongestants)
StimulantsOral contraceptives
LicoriceEphedra
Resistant HypertensionResistant Hypertension
Diagnostic and Treatment Algorithm
Screen for Secondary Causes of Hypertension
Screen for Secondary Causes of Hypertension
Obstructive sleep apnea (snoring, witnessed apena, excessive daytime sleepiness)
Primary aldosteronism (elevated aldosterone/renin 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)Cushing’s syndrome (moon facies, central obesity,
abdominal striae, inter-scapular fat deposition)Aortic coarctation (differential in brachial or
femoral pulses, systolic bruit)
Pharmacologic TreatmentPharmacologic Treatment
Maximize diuretic therapy, including possible addition of mineralocorticoid receptor antagonist
Combine agents with different mechanisms of actionUse loop diuretics in patients with chronic kidney
disease and/or those receiving potent vasodilators (e.g., minoxidil)
Refer to SpecialistRefer to Specialist
Refer to appropriate specialist for known or suspected secondary cause(s) of hypertension
Refer to hypertension specialist if blood pressure remains uncontrolled after 6 months of treatment
Resistant Hypertension (Continued)Resistant Hypertension (Continued)
Source: Calhoun DA et al. Circulation 2008;117:e510-526
CrCl=Creatinine clearance
Source: Prospective Studies Collaboration. Lancet 2002;360:1903-1913
Usual Diastolic BP (mm Hg)Usual Systolic BP (mm Hg)
Isch
em
ic H
eart
Dis
ease
M
ort
alit
y(F
loati
ng a
bso
lute
ris
k)
50-59
60-69
70-79
80-89
Age at Risk (Y)
40-49
256
128
64
32
16
8
4
2
1
0120 140 160 180
50-59
60-69
70-79
80-89
Age at Risk (Y)
40-49
256
128
64
32
16
8
4
2
1
080 90 100 11070
Isch
em
ic H
eart
Dis
ease
M
ort
alit
y(F
loati
ng a
bso
lute
ris
k)
Ischemic heart disease mortality and blood pressure
BP=Blood pressure
High Blood Pressure Evidence: High Blood Pressure Evidence: Increased Risk with Increased Risk with Increased LevelsIncreased Levels
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
Total0 0.5 1.0 1.5 2.0
0.79 (0.69 to 0.90)
Source: He J et al. Am Heart J 1999;138:211-219
Better than placebo Worse than placebo
CHD=Coronary heart disease
High Blood Pressure Evidence: High Blood Pressure Evidence: Risk of CHD with Risk of CHD with TreatmentTreatment
Source: Abbott K et al. J Clin Pharmacology 2004;44:431-438
Trial (SBP Achieved)
1 1.5 2 2.5 3 3.5 4
AASK (127 mm Hg)
HOT (138 mm Hg)
MDRD (132 mm Hg)
ABCD (127 mm Hg)
UKPDS (144 mm Hg)
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
High Blood Pressure Evidence: High Blood Pressure Evidence: Number of Number of Medications NeededMedications Needed
33,357 patients with HTN and >1 CHD risk factor randomized to chlorthalidone, amlodipine, or lisinopril for 5 years
All three BP lowering agents provide similar efficacy
0 1 2 3 4 5 6 70
.04
.08
.12
.16
.20
Rate
of
MI
or
fata
l C
HD
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Source: ALLHAT Investigators. JAMA 2002;288:2981-2997
Years to CHD Event
BP=Blood pressure, CHD=Coronary heart disease, HTN=Hypertension, MI=Myocardial infarction
ChlorthalidoneAmlodipineLisinopril
RR (95% CI) P-value
A/C 0.98
(0.90-1.07)
0.65
L/C 0.99
(0.91-1.08)
0.81
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study
Source: Dahlöf B et al. Lancet 2002;359:995-1003
ARB=Angiotensin receptor blocker, CV=Cardiovascular, DBP=Diastolic blood pressure, LVH=Left ventricular hypertrophy,
MI=Myocardial infarction, SBP=Systolic blood pressure
*Defined by SBP=160-200 mmHg or DBP=95-115 mmHg
0 6 12 18 24 30 36 42 48 54 60 66
Study Month
4
8
12
16
0Pro
port
ion w
ith C
V
death
, M
I, o
r st
roke
(%
) Atenolol
13% RRR, P=0.021
LosartanLosartan
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
9,193 high-risk hypertensive* patients with LVH randomized to losartan (100 mg) or atenolol (100 mg) for 5 years
An ARB provides greater efficacy in patients with LVH
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
Both BP lowering regimens provide similar efficacy
Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA)
Nonfa
tal M
I and f
ata
l C
HD
(%
)
6
2
4
01 2 3 4 5 60
Time since randomization (years)
RRR=10%, P=0.1052
Atenolol-based regimen
Amlodipine-based regimen
Source: Dahlöf B et al. Lancet 2005;366:895-906
BP=Blood pressure, CV=Cardiovascular, CHD=Coronary heart disease, MI=Myocardial infarction
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA)
Secondary endpointsNonfatal MI + fatal CHD 7.4 8.5Total coronary endpoint 14.6 16.8Total CV events/procedures 27.4 32.8 All-cause mortality 13.9 15.5 CV mortality 4.9 6.5 Fatal/nonfatal stroke 6.2 8.1 Fatal/nonfatal HF 2.5 3.0
Amlodipine-based
rate/1000patient years
<0.05<0.01
<0.0001
<0.05 0.001
<0.001 NS
P
Amlodipine-based better
Atenolol-based better
0.50 0.70 1.00 1.45 2.00
Atenolol-based
rate/1000patient years
Source: Dahlöf B et al. Lancet 2005;366:895-906
CHD=Coronary heart disease, CV=Cardiovascular, HF=Heart failure, MI=Myocardial infarction
An amlodopine-based regimen appears to reduce the rate of other CV events
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
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*
An amlodipine-based regimen provides greater benefit
Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension
(ACCOMPLISH)
Benazepril/HCTZ
Benazepril/Amlodipine
Com
posi
te o
f C
V d
eath
, M
I, s
troke
, hosp
italiz
ati
on f
or
angin
a, su
dden c
ard
iac
arr
est
, and c
oro
nary
re
vasc
ula
riza
tion (
%)
20% RRR, HR=0.80, P=0.0002
Source: Jamerson K et al. NEJM 2008;359:2417-2428
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.000 200 400 600 800 1000 1200 1400
*The study was prematurely stopped
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
CV=Cardiovascular, MI=Myocardial infarction
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
Blood pressure control in patients >80 years of age provides benefit
Hypertension in the Very Elderly (HYVET) Trial
Source: Beckett NS et al. NEJM 2008;358:1887-1898
CV=Cardiovascular, CVA=Cerebrovascular accident
Rate
/100
0 pa
tient
yea
rs (%
)
P=0.06 P=0.05
P=0.02
P<0.001
P<0.001
(Primary end point)
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Primary Evidence: Primary PreventionPrevention
Indapamide + perindopril
Placebo
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
Both a CAS and NCAS provide similar efficacy
0 6 12 18 24 36 48 5442 6030
International Verapamil-Trandolapril Study (INVEST)
Months
RR=0.98, P=0.57
Calcium antagonist strategy (CAS)*Non-calcium antagonist strategy (NCAS)*
Source: Pepine CJ et al. JAMA 2003;290:2805-2816
*Trandolapril (up to 4 mg) was added in those with diabetes mellitus, chronic kidney disease, or heart failure
Inci
dence
of a
ll ca
use
deat
h, n
onfa
tal M
I, or
no
nfat
al s
trok
e
BP=Blood pressure, CAS=Calcium antagonist strategy, HTN=Hypertension, MI=Myocardial infarction, NCAS=Non-calcium antagonist strategy
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Secondary Evidence: Secondary PreventionPrevention
0
20
10
15
5
Favors valsartan Favors amlodipine
Primary cardiac composite endpointCardiac mortalityCardiac morbidity
All myocardial infarctionAll congestive heart failureAll strokeAll-cause deathNew-onset diabetes
0.5 1 2
Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial
Source: Julius S et al. Lancet 2004;363:2022-2031
BP=Blood pressure, CV=Cardiovascular, HTN=Hypertension
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
Both blood pressure lowering regimens provide similar efficacy
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Secondary Evidence: Secondary PreventionPrevention
Source: Nissen S et al. JAMA 2004;292:2217-2226
Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) Trial
*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
CV
eve
nt r
ate*
0
0.25
0.20
0.10
0.05
6 12 18 24
0.15
0
Placebo
AmlodipineEnalapril
Months
Follow-up BP (mmHg)
125/77124/77130/78
BP=Blood pressure, CAD=Coronary artery disease, CV=Cardiovascular, DBP=Diastolic blood pressure
1,991 patients with CAD and a DBP <100 mmHg randomized to amlodipine (10 mg), enalapril (20 mg), or placebo for 2 years
Treatment with amlodipine results in reduced CV events
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Secondary Evidence: Secondary PreventionPrevention
Source: Hansson L et al. Lancet 1998;351:1755-1762
Hypertension Optimal Treatment (HOT) Study
Diastolic BP goal
Patients without Diabetes
Majo
r C
V e
vents
per
100
0 p
ati
ent-
years
Patients with Diabetes
Diastolic BP goal
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
More intensive blood pressure control provides greater benefit in diabetics
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Effect of Intensive Evidence: Effect of Intensive Blood Pressure ControlBlood Pressure Control
BP=Blood pressure, CV=Cardiovascular
Source: Verdecchia P et al. Lancet 2009;374:525-533 Source: Verdecchia P et al. Lancet 2009;374:525-533
Cardio-SIS Trial
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
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
Inci
dence
of
LVH
(%
)
Usual Control
17.0
Tight Control
21
14
7
0
11.4
P=0.013
Com
posi
te o
f C
V
events
* (%
)Usual Control
9.4
Tight Control
15
10
5
0
4.8
P=0.003
*Composite of death, MI, CVA, TIA, CHF, angina, new AF, revascularization, aortic dissection, PAD, and ESRD
*Composite of death, MI, CVA, TIA, CHF, angina, new AF, revascularization, aortic dissection, PAD, and ESRD
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)
More intensive blood pressure control provides greater benefit
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Effect of Intensive Evidence: Effect of Intensive Blood Pressure ControlBlood Pressure Control
HR=1.15, p=0.036
International Verapamil-Trandolapril Study (INVEST)—DM Substudy
BP=Blood pressure, CV=Cardiovascular
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Effect of Intensive Evidence: Effect of Intensive Blood Pressure ControlBlood Pressure Control
Source: Cooper-DeHoff RM et al. JAMA 2010;304:61-68
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
Tight BP control is not associated with reduced adverse CV events
Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial
Pat
ien
ts w
ith
Eve
nts
(%
)
0
5
10
15
20
Years Post-Randomization0 1 2 3 4 5 6 7 8
Pat
ien
ts w
ith
Eve
nts
(%
)
0
5
10
15
20
Years Post-Randomization0 1 2 3 4 5 6 7 8
Tota
l st
roke
HR=0.8895% CI (0.73-1.06)
HR=0.5995% CI (0.39-0.89)
Nonfa
tal M
I, n
onfa
tal
stro
ke, or
CV
death
BP=Blood pressure, DM=Diabetes mellitus, HR=Hazard ratio, SBP=Systolic blood pressure
ACCORD study group. NEJM 2010;362:1575-1585
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
Intensive BP control in DM does not reduce a composite of adverse CV events, but does reduce the rate of stroke
Blood Pressure Lowering Therapy Blood Pressure Lowering Therapy Evidence: Effect of Intensive Evidence: Effect of Intensive Blood Pressure ControlBlood Pressure Control
2-drug combination for most† (usually thiazide-type diuretic and ACE-I or ARB or BB or CCB).
Yes >100 >160 Stage 2 Hypertension
Drug(s) for compelling indications.‡
Other antihypertensive drugs (as needed).
Thiazide-type diuretics for most. May consider ACE-I, ARB, BB, CCB, or combination of these.
Yes 90–99 140–159
Stage 1 Hypertension
Drug(s) for compelling indications.‡
No antihypertensive drug indicated.
Yes 80–89 120–139
Prehypertension
Encourage <80 <120 Normal
With compelling indications
Without compelling indications
Initial drug therapy Lifestyle
modification
DBP* mmHg
SBP* mmHg
BP classification
and
or
or
or
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
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
*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
JNC VII Guidelines: JNC VII Guidelines: Management and TreatmentManagement and Treatment
Modification Recommendation Approximate SBP Reduction Range
Weight reduction Maintain normal body weight (BMI=18.5-25)
5-20 mmHg/10 kg weight lost
DASH eating plan
Diet rich in fruits, vegetables, low fat dairy and reduced in fat
8-14 mmHg
Restrict sodium intake
<2.4 grams of sodium per day 2-8 mmHg
Physical activity Regular aerobic exercise for at least 30 minutes most days of the week
4-10 mmHg
Moderate alcohol <2 drinks/day for men and <1 drink/day for women
2-4 mmHg
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
BMI=Body mass index, BP=Blood pressure, SBP=Systolic blood pressure
JNC VII Guidelines: JNC VII Guidelines: Lifestyle Modifications for BP Lifestyle Modifications for BP ControlControl
Clinical-Trial BasisCompelling Indication
ALLHAT, HOPE, ANBP2,LIFE, CONVINCE
High CAD Risk
ACC/AHA Post-MI Guidelines, BHAT, SAVE, Capricorn,
EPHESUS
Post-MI
MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT,
RALES
Initial Therapy Options
Diuretic, BB, ACE-I, CCB
BB, ACE-I, Aldo ANT
Diuretic, BB, ACE-I,ARB, Aldo ANT
Heart Failure
Recurrent Stroke Prevention
PROGRESSDiuretic, ACE-I
NKF-ADA Guideline,UKPDS, ALLHAT
NKF Guidelines, Captopril Trial, RENAAL, IDNT, REIN,
AASK
Diuretic, BB, ACE-I,ARB, CCB
ACE-I, ARB
Diabetes Mellitus
Chronic Kidney Disease
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
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: JNC VII Guidelines: Compelling Indications for Drug Compelling Indications for Drug ClassesClasses
Optimize dosages or add additional drugs until goal BP is achieved.Consider consultation with hypertension specialist.
Lifestyle modifications
Initial drug choices
Not at goal BP
Not at goal BP (<140/90 mm Hg)(<130/80 mm Hg for those with diabetes mellitus
or chronic kidney disease)
WITH compelling indicationsWITHOUT compelling indications
Stage 1 hypertension(SBP 140–159 mm Hg or DBP 90–99 mm Hg):
Thiazide-type diuretic for most.May consider ACEI, ARB, BB, CCB, or combo.
Stage 2 hypertension(SBP 160 or DBP 100 mm Hg):
Two-drug combination for most (usually thiazide-type diuretic and
ACEI or ARB or BB or CCB).
Drugs for compelling indications:
Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB)
as needed.
Source: Chobanian AV et al. JAMA 2003;289:2560-2572
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
JNC VII Guidelines:JNC VII Guidelines:Blood Pressure Treatment Blood Pressure Treatment AlgorithmAlgorithm
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
I IIa IIb III
Blood Pressure RecommendationsBlood Pressure Recommendations
Primary and Secondary Prevention
Source: Buse JB et al. Circulation 2007;115:114-126
• 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
AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMBlood Pressure RecommendationsBlood Pressure RecommendationsPrimary Prevention
Source: Buse JB et al. Circulation 2007;115:114-126
• 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
AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMBlood Pressure Recommendations Blood Pressure Recommendations (Continued)(Continued)
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.
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ADA=American Diabetes Association, BP=Blood pressure, DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure
ADA Blood Pressure RecommendationsADA Blood Pressure Recommendationsfor Patients with Diabetes Mellitusfor Patients with Diabetes Mellitus
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.
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
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
ADA Blood Pressure RecommendationsADA Blood Pressure Recommendationsfor Patients with Diabetes Mellitus for Patients with Diabetes Mellitus (Continued)(Continued) 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.
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure,
DM=Diabetes mellitus, GFR=Glomerular filtrate rate
ADA Blood Pressure RecommendationsADA Blood Pressure Recommendationsfor Patients with Diabetes Mellitus for Patients with Diabetes Mellitus (Continued)(Continued) Primary Prevention
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.
ACE=Angiotensin converting enzyme, BP=Blood pressure, CKD=Chronic kidney disease, DM=Diabetes mellitus
*A BP >130/80 mmHg should be used for individuals with CKD or DM
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
I IIa IIb III
Blood Pressure RecommendationsBlood Pressure Recommendations
Secondary Prevention
Angiotensin Converting Angiotensin Converting Enzyme Inhibitor Evidence Enzyme Inhibitor Evidence
and Guidelinesand Guidelines
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Angiotensin II
Kininase II
Angiotensin I
Angiotensinogen
ACE
ReninBradykinin
Inactive Fragments
Sympathetic
VasopressinAldosterone
Vasoconstriction
ACE=Angiotensin converting enzyme
Kininogen
KallikreinVasodilatio
nProstaglandins
tPA
Inhibitor
ACE Inhibitor: ACE Inhibitor: Mechanism of ActionMechanism of Action
Days of Follow-Up
CV
death
, M
I,
or
stro
ke (
%)
22% RRR, P<0.0010.00
0.05
0.10
0.15
0.20
0 500 1000 1500
Placebo
Ramipril
Source: HOPE Investigators. NEJM 2000;342:145-153
Heart Outcomes Prevention and Evaluation (HOPE) Study
ACE=Angiotensin converting enzyme, DM=Diabetes mellitus, CV=Cardiovascular, HF=Heart failure, LVSD=Left
ventricular systolic dysfunction, MI=Myocardial infarction
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
An ACE inhibitor provides benefit in high-risk individuals
ACE Inhibitor ACE Inhibitor Evidence: Secondary Evidence: Secondary PreventionPrevention
0 0.5 1 1.5 2
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)
European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease
(EUROPA)
Favors Perindopril Favors Placebo
Source: EUROPA Investigators. Lancet 2003;362:782-788
12,218 patients with CAD and presumed normal LV function randomized to perindopril (8 mg) or placebo for 4 years
An ACE inhibitor provides benefit in intermediate-risk individuals
ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction
ACE Inhibitor ACE Inhibitor Evidence: Evidence: Secondary Secondary PreventionPrevention
Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial
Pri
mary
End P
oin
t (%
)* 30
25
20
15
10
5
00 1 2 3 4 5 6
Years After Randomization
Placebo
Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
*Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization
Trandolapril
8,290 patients with stable CAD and normal LV function randomized to trandolapril (4 mg) or placebo for 5 years
An ACE inhibitor does not provide benefit in lower-risk individuals
ACE Inhibitor ACE Inhibitor Evidence: Secondary Evidence: Secondary PreventionPrevention
ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, LV=Left ventricular
Comparison between the HOPE and PEACE trials
Patients enrolled in the PEACE trial were lower risk*
MI, C
ard
iac
death
, or
Str
oke
(%
)
Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
CHD=Coronary heart disease, MI=Myocardial infarction
*Reflects better blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet
therapy, beta-blocker, lipid-lowering medication)
Years
HOPE, placebo
HOPE, active drug (ramipril)
PEACE, placebo
ACE Inhibitor ACE Inhibitor Evidence: Secondary Evidence: Secondary PreventionPrevention
Clinical Trial
HOPE 9,297 1051
0.4 0.6 0.8 1.0 1.2 1.4 1.6
N
ACE-I Better Placebo Better
EUROPA 12,218 795
PEACE 8,290 633 HR=0.89 P=0.13
HR=0.89 P=0.10
HR=0.84 P=0.005
Deaths
All Trials 33,960 >3000 HR=0.86 P<0.001
Sources:Danchin N et al. Arch Intern Med 2006;166:787-796
The HOPE Trial Investigators. NEJM 2000;342:145-153The EUROPA Study. Lancet 2003; 362: 782-788
The PEACE Trial Investigators. NEJM 2004;351:2058-2068
Meta-Analysis of the HOPE, EUROPA, and PEACE Trials*
RR of Mortality
*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
ACE Inhibitor ACE Inhibitor Evidence: Secondary Evidence: Secondary PreventionPrevention
Years
Pro
babili
ty o
f Event
0
0.05
0.1
0.15
0.2
0.25
0.3
0 1 2 3
0.35
0.4
4
ACE-I
Placebo
OR 0.74 (0.66–0.83)OR 0.74 (0.66–0.83)
Source: Flather MD et al. Lancet 2000;355:1575–1581
SAVERadionucli
deEF <40%
AIREClinical and/or radiographic signs of HF
TRACEEchocardiogra
mEF <35%
ACE-I=Angiotensin converting enzyme inhibitor, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio
An ACE-I provides substantial benefit in post-MI LVSD
ACE Inhibitor ACE Inhibitor Evidence: Secondary Evidence: Secondary PreventionPrevention
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
An ACE inhibitor in all other patients
ACE=Angiotensin converting enzyme, CKD=Chronic kidney disease, DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
I IIa IIb III
ACE Inhibitor RecommendationsACE Inhibitor Recommendations
Secondary Prevention
I IIa IIb III
Source: Buse JB et al. Circulation 2007;115:114-126
• 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.
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
*Includes beta-blockers, thiazide diuretics, and calcium channel blockers
AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMBlood Pressure RecommendationsBlood Pressure RecommendationsPrimary 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.
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus
ADA Blood Pressure RecommendationsADA Blood Pressure Recommendationsfor Patients with Diabetes Mellitus for Patients with Diabetes Mellitus (Continued)(Continued) Primary Prevention
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence and GuidelinesEvidence and Guidelines
Evidence for Current Cardiovascular Evidence for Current Cardiovascular DiseaseDisease
Prevention GuidelinesPrevention Guidelines
Receptors
AT II Receptor Blocker
Antiproliferative Action
Vasodilation
Proliferative Action
Vasoconstriction
ATIIATI
Angiotensinogen
Other Pathways
Renin
AT I Recepto
r Blocker
Angiotensin I
Angiotensin II
ACE
Angiotensin Receptor Angiotensin Receptor Blocker: Mechanism of Blocker: Mechanism of ActionAction
2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE inhibitor randomized to candesartan (32 mg)
or placebo for 34 months
An ARB provides benefit in those intolerant of an ACE inhibitor
0 1 2 3Years
50
HR 0.77 p=0.00040
40
30
20
10
Candesartan
Placebo
Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial
Source: Granger CB et al. Lancet 2003;362:772-777
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, CV=Cardiovascular, EF=Ejection fraction,
HF=Heart failure, LVSD=Left ventricular systolic dysfunction
CV
Death
or
Hosp
italiz
ati
on
for
HF
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
Source: Pfeffer M et al. NEJM 2003;349:1893-1906
Valsartan in Acute Myocardial Infarction Trial (VALIANT)
0.0
0.1
0.2
0.3
0.4
0 6 12 18 24 30 36
Valsartan
Valsartan and Captopril
Captopril
All
Cause
Mort
alit
y
Months
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, EF=Ejection
fraction, LVSD=Left ventricular systolic dysfunction
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
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
An ARB provides similar efficacy to an ACE inhibitor in Post-MI LVSD
0 1 2 3
0
10
20
30
40
50
HR 0.85, p=0.011
Candesartan
Placebo
CV
Death
or
Hosp
italiz
ati
on
for
HF
Years
Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Added Trial
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, EF=Ejection fraction, HF=Heart failure,
LVSD=Left ventricular systolic dysfunction
Source: McMurray JJ et al. Lancet 2003;362:767-771
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
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
Addition of an ARB to an ACE inhibitor may provide benefit in those with LVSD
Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)
Source: ON TARGET Investigators. NEJM 2008;358:1547-1559
ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, CVD=Cardiovascular disease, DM=Diabetes mellitus, MI=Myocardial infarction
CV Death / MI / Stroke / Hospitalization for Heart
Failure
CV Death / MI / Stroke / Hospitalization for Heart
Failure
0.8 0.9 1.0 1.1 1.2
RR (95% CI)
Non
-infe
riorit
y M
argi
n
Primary Composite (p = 0.003)
CV Death / MI / Stroke (HOPE Composite)
(p = <0.001)
Telmisartan better Ramipril better
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
25,620 patients with CVD or DM randomized to ramipril (10 mg), telmisartan (80 mg), or a combination of both for 56 months
An ARB provides similar efficacy to an ACE-I in high risk patients
Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)
Source: ON TARGET Investigators. NEJM 2008;358-1547-1559
CVD=Cardiovascular disease, DM=Diabetes mellitus, MI=Myocardial infarction, RAS=Renin angiotensin system
CV
Death
, M
I,
Str
oke
, or
Hosp
italiz
ati
on f
or
Heart
Failu
re
0.20
0.15
0.10
0.05
0.000 1 2 3 4 5
Follow-up (years)
Telmisartan
Ramipril
Telmisartan plus ramipril*
*Dual RAS blockade leads to greater renal impairment HR=1.33
(p<0.001)
*Dual RAS blockade leads to greater renal impairment HR=1.33
(p<0.001)
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
25,620 patients with CVD or DM randomized to ramipril (10 mg), telmisartan (80 mg), or a combination of both for 56 months
Dual RAS blockade provides no additional benefit but leads to greater renal impairment
Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease
(TRANSCEND)
Perc
en
t of
pati
en
ts
P=0.216P=0.048
P=0.055
Source: TRANSCEND Investigators. Lancet. 2008;372:1174-83
*Primary endpoint is a composite of CV death, MI, stroke or heart failure hospitalization
Angiotensin Receptor Blocker Angiotensin Receptor Blocker Evidence: Secondary PreventionEvidence: Secondary Prevention
*
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, CV=Cardiovascular, MI=Myocardial infarction
5,926 high risk patients intolerant to ACE inhibitors randomized to telmisartan (80 mg) or placebo for 56
months
An ARB is well tolerated in those unable to take an ACE inhibitor
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
An ARB in other patients who are intolerant of an ACE inhibitor
Use of an ARB in combination with an ACE inhibitor is not well established in those with systolic heart failure
ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, HF=Heart failure, MI=Myocardial infarction
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
I IIa IIb III
Angiotensin Receptor Blocker Angiotensin Receptor Blocker RecommendationsRecommendationsSecondary Prevention
I IIa IIb III
I IIa IIb III
Source: Buse JB et al. Circulation 2007;115:114-126
• 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.
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
*Includes beta-blockers, thiazide diuretics, and calcium channel blockers
AHA Primary Prevention of CV Disease in AHA Primary Prevention of CV Disease in DMDMBlood Pressure RecommendationsBlood Pressure RecommendationsPrimary 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.
Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus
ADA Blood Pressure RecommendationsADA Blood Pressure Recommendationsfor Patients with Diabetes Mellitus for Patients with Diabetes Mellitus (Continued)(Continued) Primary Prevention
Beta-blockBeta-blocker Evidence and er Evidence and GuidelinesGuidelines
Evidence for Current Cardiovascular Evidence for Current Cardiovascular Disease Disease
Prevention GuidelinesPrevention Guidelines
Parasympathetic Nerve Terminal
Sympathetic Cholinergic Nerve Terminal
a1
M2
M2
M2
a1 b2
b2
b2
b1 a2
a2 a2
NE
ACh
Sympathetic Nerve Terminal
+++
_
NE NE_ +
_ _Heart Blood Vessel
Inotropy
Chronotropy
Dromotropy
Vasoconstriction
Vasoconstriction
Vasodilation
Vasodilation
1 selective blocker
non-selective blocker non-selective blocker with 1 blocking activity
a=Alpha receptor, Ach=Acetylcholine, b=Beta receptor, M=Muscarinic receptor, NE=Norepinephrine
Source: Klabunde, RE (ed) Cardiovascular Physiology Concepts LWW 2001
Beta-blocker:Beta-blocker:Targets and Receptor Targets and Receptor SelectivitySelectivity
Placebo-controlled post-MI trials* using oral beta-blockers
StudyPatients
(N)Treatment
GroupsDuration of Follow-Up
Effect on Mortality
Effect on Reinfarction
Göteborg Study† 1,395Metoprolol
tartrate3 months
36%(P.03)
PNS
Timolol Trial(Norwegian)
1,884 Timolol 17 months 39%
(P.003) 28%
(P.0005)
Lopressor Intervention
Trial2,395
Metoprolol tartrate
12 months PNS NA
Beta-blocker Heart Attack Trial
3,837 Propranolol 25 months 26%
(P.005)PNS
CAPRICORN Trial 1,959 Carvedilol 15 months 23%
(P=.03) 40%
(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
Beta-blocker Evidence:Beta-blocker Evidence:Secondary PreventionSecondary Prevention
Phase of Treatment
Acute treatment
Secondaryprevention
Overall
Total #Patients
28,970
24,298
53,268
0.5 1.0 2.0RR of death
Beta-blockerbetter
RR (95% CI)
Placebobetter
0.87 (0.77-0.98)
0.77 (0.70-0.84)
0.81 (0.75-0.87)
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.
Summary of secondary prevention trials of beta-blocker therapy
CI=Confidence interval, RR=Relative risk
Beta-blocker Evidence:Beta-blocker Evidence:Secondary PreventionSecondary Prevention
*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
Study Drug HF Severity
Patients (n)
Follow-up
Mean Dosage
Effects on Outcomes
CIBIS Bisoprolol* Moderate-Severe
641 1.9 Years 3.8 mg/day
All cause mortality (p=NS)
CIBIS-II Bisoprolol* Moderate-Severe
2,647 1.3 Years 7.5mg/day
All cause mortality34% (P<0.0001)
BEST Bucindolol* Moderate-Severe
2,708 2.0 Years 152mg/day
All cause mortality (p=NS)
MERIT-HF Metoprolol succinate#
Mild-Moderate
3,991 1.0 Years 159mg/day
All cause mortality34% (P=0.0062)
MDC Metoprolol tartrate*
Mild-Moderate
383 1.0 Years 108mg/day
Death or Need for TX (P=NS)
CAPRICORN Carvedilol Mild 1,989 1.3 Years 40mg/day
All cause mortality 23% (P =0.03)
US Carvedilol
Carvedilol Mild-Moderate
1,094 0.5 Years 45mg/day
All-cause mortality†65% (P=.0001)
COPERNICUS Carvedilol Severe 2,289 0.9 Years 37mg/day
All-cause mortality35% (P =0.0014)
SENIORS Nebivolol Moderate 2,128 3.0 Years 7.7 mg/day
All-cause mortality or CV hospitalization
14% (P =0.039)
Beta-blocker Evidence:Beta-blocker Evidence:Benefit in HF and/or LVSDBenefit in HF and/or LVSD
Beta-blocker should be used in all patients with LVSD (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.)
Beta-blocker for 3 years in all patients with normal left ventricular function who have had a MI or ACS
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
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
I IIa IIb III
Beta-Blocker RecommendationsBeta-Blocker Recommendations
Secondary Prevention
I IIa IIb III
I IIa IIb III
Beta-blocker in patients with LVSD (ejection fraction <40%) without HF or prior MI
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
Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
Beta-Blocker Recommendations Beta-Blocker Recommendations (Continued)(Continued) Secondary Prevention
I IIa IIb III
I IIa IIb III