1 blood pressure, blood pressure agents and blood pressure guidelines ty j. gluckman, andrew p....

1

Blood Pressure, Blood Pressure Agents Blood Pressure, Blood Pressure Agents and Blood Pressure Guidelinesand Blood Pressure Guidelines

Ty J. Gluckman, Andrew P. DeFilippis, James Mudd, Catherine Campbell, Gregg Fonarow,

& Roger S. Blumenthal

2

Provides information on response to Rx. May help improve adherence to Rx 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 riskAmbulatory BP monitoring

Two readings, 5 minutes apart, sitting in chair

Confirm elevated reading in contralateral arm

In-office

Brief Description Method

JNC VII Guidelines for Measurement of BPJNC VII Guidelines for Measurement of BP

BP=Blood pressure, CVD=Cardiovascular disease, HTN=Hypertension, Rx=Treatment

Chobanian AV et al. JAMA 2003;289:2560-2572

3

JNC VII Causes of Secondary HypertensionJNC VII Causes of Secondary Hypertension

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


NSAIDS=Non-steroidal anti-inflammatory drugs

4Fields LE et al. Hypertension 2004;44:398-404

All

0

Pre

vale

nce

of H

yper

tens

ion

45

30

20

15

10

25

40

5

35

Mexican-American

Non-Hispanic White

Non-Hispanic Black

FM FM FM

National Health and Nutrition Examination Survey (NHANES)

Blood Pressure: Risk in U.S. AdultsBlood Pressure: Risk in U.S. Adults

1999-20001988-1994

F=Female, M=Male

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

5

0

20

40

60

80

Hyp

erte

nsio

n P

reva

len

ce (

%)

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%

JNC-VI. Arch Intern Med 1997;157:2413-2446

Blood Pressure: Risk Increases with AgeBlood Pressure: Risk Increases with Age

51%

66%72%

38%

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

6

Prospective Studies Collaboration. Lancet 2002;360:1903-1913

Usual Diastolic BP (mm Hg)Usual Systolic BP (mm Hg)

Isch

emic

Hea

rt D

isea

se M

orta

lity

(Flo

atin

g ab

solu

te r

isk)

50-59

60-69

70-79

80-89Age 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

Blood Pressure: Lower is BetterBlood Pressure: Lower is Better

Isch

emic

Hea

rt D

isea

se M

orta

lity

(Flo

atin

g ab

solu

te r

isk)

Ischemic Heart Disease Mortality and Blood Pressure

BP=Blood pressure

7

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

Total

0 0.5 1.0 1.5 2.0

0.79 (0.69 to 0.90)

He J et al. Am Heart J 1999;138:211-219

Better than placebo Worse than placebo

Blood Pressure: Risk of CHD with Active TreatmentBlood Pressure: Risk of CHD with Active Treatment

CHD=Coronary heart disease

8Abbott 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

UKPDS=UK Prospective Diabetes Study; ABCD=Appropriate Blood Pressure Control in Diabetes; MDRD=Modification of Dietary Protein in Renal Disease; HOT=Hypertension Optimal Treatment; AASK=African American Study of Kidney Disease and Hypertension

Blood Pressure: Number of Medications NeededBlood Pressure: Number of Medications Needed

9

Blood Pressure Evidence: Primary PreventionBlood Pressure Evidence: Primary Prevention

0 1 2 3 4 5 6 70

.04

.08

.12

.16

.20

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

Rat

e of

MI

or

fata

l CH

DAntihypertensive and Lipid-Lowering Treatment to Prevent

Heart Attack Trial (ALLHAT)

ALLHAT Investigators. JAMA 2002;288:2981-97

Years to CHD Event

BP=Blood pressure, CHD=Coronary heart disease, HTN=Hypertension, MI=Myocardial infarction

Chlorthalidone

Amlodipine

Lisinopril

33,357 patients with HTN and >1 CHD risk factor randomized to chlorthalidone, amlodipine, or lisinopril for 5 years

There is similar efficacy among BP lowering agents

10

0 6 12 18 24 30 36 42 48 54 60 66

Study Month

4

8

12

16

0Pro

port

ion

with

CV

de

ath,

MI,

or s

trok

e (%

)


Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study

Dahlöf B et al. Lancet 2002;359:995-1003

AtenololLosartan

13% RRR, P=0.021

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

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

11

Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA)


Non

fata

l MI a

nd

fata

l CH

D (

%) 6

2

4

01 2 3 4 5 60

Time since randomization (years)

RRR = 10%, P = 0.1052

Atenolol-based regimen

Amlodipine-based regimen

Dahlöf B et al. Lancet 2005;366:895-906

BP=Blood pressure, CV=Cardiovascular, CHD=Coronary heart disease, MI=Myocardial infarction

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

There is similar efficacy with both BP lowering regimens

12

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

There is comparable efficacy with a CAS or NCAS

0

5

10

15

20

25

0 6 12 18 24 36 48 5442 6030

Blood Pressure Evidence: Secondary PreventionBlood Pressure Evidence: Secondary Prevention

International Verapamil-Trandolapril Study (INVEST)

Months

RR=0.98, P=0.57

Calcium antagonist strategy (CAS)*Non-calcium antagonist strategy (NCAS)*

Pepine CJ et al. JAMA 2003;290:2805-2816

*Trandolapril (up to 4 mg) was added in those with DM, chronic kidney disease, or heart failure.

Inci

denc

e of

dea

th, M

I, or

str

oke

BP=Blood pressure, DM=Diabetes mellitus, HTN=Hypertension, MI=Myocardial infarction

13

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

Julius S et al. Lancet 2004;363:2022-2031

ARBS=Angiotensin receptor blocker, CCB=Calcium channel blocker, CV=Cardiovascular

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

There is similar efficacy with an ARB and CCB

14Nissen S et al. JAMA 2004;292:2217-26


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 BP

1,991 patients with CAD and a DBP <100 mmHg randomized to amlodipine (10 mg), enalapril (20 mg), or placebo for 2 years

A BP <130/80 mmHg is associated with fewer CV events*

15

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

modificationDBP* mmHg

SBP* mmHg

BP classification

JNC VII Guidelines for Management and TreatmentJNC VII Guidelines for Management and Treatment

and

or

or

or


ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=-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

16

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

JNC VII Lifestyle Modifications for BP ControlJNC VII Lifestyle Modifications for BP Control


BMI=Body mass index, SBP=Systolic blood pressure

17

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

JNC VII Compelling Indications for Drug ClassesJNC VII Compelling Indications for Drug Classes

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


ACE-I=Angiotensin converting enzyme inhibitor, Aldo ANT=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial infarction

18

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.

JNC VII Blood Pressure Treatment AlgorithmJNC VII Blood Pressure Treatment Algorithm


BP=Blood pressure, DBP=Diastolic blood pressure, SBP=Systolic blood pressure

19

Blood Pressure RecommendationsBlood Pressure Recommendations

Initiation or maintenance of lifestyle modification in those with BP >120/80 mmHg.

A target BP of <130/80mmHg for individuals with any of the following: DM, chronic renal disease, CAD or CAD risk equivalents, carotid artery disease, peripheral artery disease, abdominal aortic aneurysm, those with a Framingham risk score >10% and a goal of <140/90mmHg for individuals with none of the above.

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

*A BP >130/80 mmHg should be used for individuals with CKD or DM


20

Blood Pressure RecommendationsBlood Pressure Recommendations

ACE-I, ARB, CCB or thiazide diuretic as first line therapy, supplement with a second agent if BP goal is not achieved with monotherapy. A beta blocker is a more appropriate choice for post-MI or angina pectoris patients.

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


21

Angiotensin Converting Enzyme Inhibitor Angiotensin Converting Enzyme Inhibitor Evidence and GuidelinesEvidence and Guidelines

22

ACE Inhibitor: Mechanism of ActionACE Inhibitor: Mechanism of Action

Angiotensin II

Kininase II

Angiotensin I

Angiotensinogen

InhibitorACE

ReninBradykinin

Inactive Fragments

SympatheticVasopressin

AldosteroneVasoconstriction

ACE=Angiotensin converting enzyme

Kininogen

Kallikrein

VasodilationProstaglandins

tPA

23

Days of Follow-Up

CV

dea

th, M

I, or

st

roke

(%

)

22% RRR, P<0.0010.00

0.05

0.10

0.15

0.20

0 500 1000 1500

ACE Inhibitor Evidence: Secondary PreventionACE Inhibitor Evidence: Secondary Prevention

Placebo

Ramipril

HOPE Investigators. NEJM 2000;342:145-153

Heart Outcomes Prevention and Evaluation (HOPE) Study

ACE-I=Angiotensin converting enzyme inhibitors, 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

ACE-I reduce CV events in high-risk individuals

24

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

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

ACE-I reduce CV events in intermediate-risk individualsACE-I=Angiotensin converting enzyme inhibitors, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction

25


Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial

Prim

ary

End

Poi

nt (

%)*

30

25

20

15

10

5

00 1 2 3 4 5 6

Years After Randomization

PlaceboTrandolapril

The PEACE Trial Investigators. NEJM 2004;351:2058-68

*Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization

8,290 patients with stable CAD and normal LV function randomized to trandolapril (4 mg) or placebo for 5 years

ACE-I do not reduce CV events in lower-risk individuals

26

0

5

10

15

20

0 1 2 3 4 5

HOPE, placebo

HOPE, active drug (ramipril)

PEACE, placebo


Comparison between the HOPE and PEACE trials

Patients enrolled in the PEACE trial were at lower risk*

MI,

Car

diac

dea

th,

or S

trok

e (%

)

The PEACE Trial Investigators. NEJM 2004;351:2058-68

CHD=Coronary heart disease, MI=Myocardial infarction

*Reflects better blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet therapy, -blocker, lipid-lowering medication)

Years

27

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

Danchin N et al. Arch Intern Med 2006;166:787-796

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 CVD HR=0.81, MI HR=0.82, and stroke HR=0.77

ACE-I=Angiotensin converting enzyme inhihbitors, CVD=Cardiovascular disease, MI=Myocardial infarction

28

Years

Pro

babi

lity

of E

vent

0

0.05

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)0.1

Flather MD et al. Lancet 2000;355:1575–1581

SAVERadionuclid

eEF <40%

AIREClinical and/or radiographic signs of HF

TRACEEchocardiogram

EF <35%


ACE-I=Angiotensin converting enzyme inhibitors, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio

ACE-I provide substantial benefit in post-MI LVSD

29

ACE Inhibitor RecommendationsACE Inhibitor Recommendations

An ACE inhibitor in those following a MI, regardless of EF or in those with CAD* along with hypertension (SBP >120 mmHg), LVSD (EF <0.40), heart failure, DM, or CKD

Optional use of an ACE inhibitor in those with low risk CAD*, well controlled risk factors, normal EF, and successful revascularization

Secondary Prevention

*Defined by previous MI or angiographically significant CAD



ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, CKD=Chronic kidney disease, CV=Cardiovascular, DM=Diabetes mellitus, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, SBP=Systolic blood pressure

30

Angiotensin Receptor Blocker Evidence Angiotensin Receptor Blocker Evidence and Guidelinesand Guidelines

31

Receptors

Angiotensin Receptor Blocker: Mechanism of ActionAngiotensin Receptor Blocker: Mechanism of Action

AT II Receptor Blocker

Antiproliferative Action

VasodilationProliferative Action

Vasoconstriction

ATIIATI

Angiotensinogen

Other Pathways

Renin

AT I Receptor

Blocker

Angiotensin I

Angiotensin IIACE

32

2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE-I randomized to candesartan (32 mg) or placebo for 34 months

ARB reduce CV events in those intolerant of ACE-I

0 1 2 3Years

50

HR 0.77 p=0.00040

40

30

20

10

Candesartan

Placebo

ARB Evidence: Secondary PreventionARB Evidence: Secondary Prevention

Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial

Granger CB et al. Lancet 2003;362:772-777

ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction

CV

Dea

th o

r H

ospi

taliz

atio

n fo

r H

F

33


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

Cau

se M

orta

lity

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction

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

ARB provide similar efficacy to ACE-I in Post-MI LVSD

34

0 1 2 3

0

10

20

30

40

50


HR 0.85, p=0.011

Candesartan

Placebo

CV

Dea

th o

r H

ospi

taliz

atio

n fo

r H

F

Years

Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Added Trial

ACE-I=Angiotensin converting enzyme inhibitors, ARB=Angiotensin receptor blockers, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, RAS=Renin angiotensin system

McMurray JJ et al. Lancet 2003;362:767-71

2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition to an ACE-I for 34 months

Chronic dual RAS blockade provides additional benefit

35

Angiotensin Receptor Blocker RecommendationsAngiotensin Receptor Blocker Recommendations


An ARB in those with asymptomatic LVSD (EF <0.40) or DM following a MI who can (Class IIa, Level B) or cannot (Class I, Level B) tolerate an ACE-I

An ARB in those with symptomatic LVSD (EF <0.40) and intolerance of an ACE-I

Addition of an ARB to an ACE-I in those with symptomatic HF or LVSD (EF <0.40)




ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction


36

-blocker Evidence and Guidelines-blocker Evidence and Guidelines

37

Parasympathetic Nerve Terminal

Sympathetic Cholinergic Nerve Terminal

1

M2

M2

M2

1 2

2

2

1 2

2 2

NE

ACh

-blocker: Targets and Receptor Selectivity-blocker: Targets and Receptor Selectivity

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

=Alpha receptor, Ach=Acetylcholine, =Beta receptor, M=Muscarinic receptor, NE=Norepinephrine

Klabunde, RE (ed) Cardiovascular Physiology Concepts LWW 2001

38

-blocker Evidence: Secondary Prevention-blocker Evidence: Secondary Prevention

Placebo-Controlled Post-MI Trials* Using Oral -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 InterventionTrial

2,395Metoprolol

tartrate12 months PNS NA

-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

39

Study DrugHF

SeverityPatients

(n)Follow-up

(years)Mean

Dosage Effects on Outcomes

CIBIS Bisoprolol* Moderate-Severe

641 1.9 3.8 mg/day

All cause mortality (p=NS)

CIBIS-II Bisoprolol* Moderate-Severe

2,647 1.3 7.5mg/day

All cause mortality34% (P<0.0001)

BEST Bucindolol* Moderate-Severe

2,708 2.0 152mg/day

All cause mortality (p=NS)

MERIT-HF Metoprolol succinate#

Mild-Moderate

3,991 1.0 159mg/day

All cause mortality34% (P=0.0062)

MDC Metoprolol tartrate*

Mild-Moderate

383 1.0 108mg/day

Death or Need for TX (P=NS)

CAPRICORN Carvedilol Mild 1,989 1.3 40mg/day

All cause mortality 23% (P =0.03)

US Carvedilol Carvedilol Mild-Moderate

1,094 0.5 45mg/day

All-cause mortality†65% (P=.0001)

COPERNICUS Carvedilol Severe 2,289 0.9 37mg/day

All-cause mortality35% (P =0.0014)

-blocker Evidence: Benefit in HF and/or LVSD-blocker Evidence: Benefit in HF and/or LVSD

*Not an approved indication†Not a planned end point. #Not approved for severe HF or mortality reduction alone

HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NS=Not significant, TX=Transplant

40

Phase of Treatment

Acute treatment

Secondaryprevention

Overall

Total #Patients

28,970

24,298

53,268

0.5 1.0 2.0RR of death

-blockerbetter

RR (95% CI)

Placebobetter

0.87 (0.77-0.98)

0.77 (0.70-0.84)

0.81 (0.75-0.87)

-blocker Evidence: Secondary Prevention-blocker Evidence: Secondary Prevention

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 -blocker Therapy

CI=Confidence interval, RR=Relative risk

41

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII -blocker in all patients following MI or ACS

-blocker in all patients with LVSD

-blocker in those with other forms of CV disease or DM, unless contraindicated

*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, CV=Cardiovascular, DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction

-blocker Recommendations*-blocker Recommendations*



1 blood pressure, blood pressure agents and blood pressure guidelines ty j. gluckman, andrew p....

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