Beta BlockersBeta BlockersTreatment For Cardiovascular DiseaseTreatment For Cardiovascular Disease

Where Do They Fit? Where Do They Fit?

Joseph Brent Muhlestein, MD, FACCCo-Director of Cardiology Research, Intermountain Medical Center, Professor of Medicine, University of Utah

Nothing to Disclose

Introduction• Cardiovascular Disease is the major killer of the Western

World• Recently, significant successes have been made in

developing effective primary and secondary preventative therapies

• Surgery• Medicines• Life style changes• Some of these therapies have actually been shown to

save lives

Time (years)

No Symptoms ± Symptoms Symptoms

• Ischemic HeartDisease

• CerebrovascularDisease

• PeripheralVascularDisease

Schematic Timecourseof Human Atherogenesis

Pathogenesis of ACS

White HD. Am J Cardiol. 1997; 80(4A):2B-10B.

The matrix skeleton of an unstablecoronary artery plaque

fissures inthe fibrous cap

Plaque rupture with thrombosisPlaque rupture with thrombosis

1 mm FJ Schoen, BWH

Thrombus Fibrous cap

Lipid coreLipid core

Plaque rupture

site

fatal thrombus

collagenous fibrous cap

thrombogenic lipid core

Characteristics of Unstable and Stable Plaques

Thin Thin Fibrous CapFibrous Cap

Inflammatory Inflammatory CellsCells

FewFewSMCsSMCs

UnstableUnstable

ErodedErodedEndotheliumEndotheliumActivatedActivated

MacrophagesMacrophages

ThickThickFibrous CapFibrous Cap

Lack ofLack ofInflammatory Inflammatory CellsCells

Foam CellsFoam Cells

IntactIntactEndothelium Endothelium

MoreMoreSMCsSMCs

StableStable

Libby et al. Circulation 1995; 91:2844-50

MMPMMP

Beta Blockers: Where do they fit?

Physiology of the Sympathetic Nervous

System• Epinephrine / Norepinephrine• Hypertension• Hypercoagulability• Vasoreacivity• Fibrosis• Upregulated in many situations• Emotional excitement• Heart Failure• General anesthesia

Beta Blockers: Indications• Post MI

• CAD• Heart Failure• Hypertension• Non-cardiac surgery• Rate Control

- Atrial fibrillation- Inappropriate sinus tachycardia

• Arrhythmias

Beta Blockers Post-MI• Rationale

- Antiplatelet effect- Antiarrhthmic effect- General blood pressure effect

Evidence of Beta Blockers post MI• Norwegian multicenter study group (1981)

- 17 month follow-up- Patients presenting with Q-wave MI- Timolol versus placebo- 44.6% reduction in sudden death- 39.3% reduction in total death

• Beta-blocker heart attack trial (1982)- 3 years follow-up- Patients presenting with Q-wave MI- Propranolol versus placebo- 26% reduction in total mortality

Beta Blockers post MI (cont.)• Metoprolol study (1981)

- 90 day follow-up- metoprolol versus placebo- 36% reduction in over-all mortality

• BBPP (1986, 9 trials pooled)- 13,679 patients, a variety of beta blocker drugs- 1 year follow-up- 24% reduction in death

• ISIS I (1986)- 16,027 patients, atenolol versus placebo- 20 months follow-up- 15% reduction in death

Effect on sudden death of beta blockade following MI. Pooled data

from 5 trials

Effect of Beta-Blackade on Mortality among High-Risk and

Low-risk Patients after MI• HCFA cooperative cardiovascular project• 201,752 patients post-MI abstracted• Mortality determined at 2 years post MI• 34% of all patients received beta blockers

HCFA cooperative cardiovascular project:

Results2 Year Mortality Based on Initial EF

0%5%

10%15%20%25%30%35%40%

>50% 20-49% <20%

Mor

talit

y

Beta blocker No beta blocker

NEJM, 1998;339:489-97

HCFA cooperative cardiovascular project:

Results2 Year Mortality Based on Type of MI

0%2%4%6%8%

10%12%14%

Q-wave Non Q-wave

Mor

talit

y

Beta blocker No beta blocker

NEJM, 1998;339:489-97

LDS Hospital Data975 Patients with Angiographically Documented CAD Followed for >3 years

Mortality by whether post-MI patients (n=242) were placed on a beta blocker

6%

12%

0%2%4%6%8%

10%12%14%

Beta blocker No beta blocker

(P=0.19)

Beta Blockers in Heart Failure

Vicious Cycle of Heart Failure

The Beginning of the Beta Blocker Story• 1985, LDS Hospital, Jeffrey Anderson, et al

• 50 patients with IDC (EF<30%)• Randomized to metoprolol (12.5-50 mg bid)

versus placebo• Followed for 18 months• Results

- Low dose beta blockade tolerated by 80% of patients

- Death: metoprolol = 3, placebo = 8- Significant improvement in functional class

Metoprolol in Idiopathic Dilated Cardiomyopathy

(MDC) Study• 383 patients with IDC (LVEF<40%)• 90% were NYHA class II-III• Randomized to metoprolol or Placebo• (target doses: 50-75 mg po bid)• Follow-up: One year• Primary endpoint: Death or need for

transplant• Secondary endpoint: EFLancet, 1993, 342(8885):1441-1446

Death or Transplant

Change In Ejection Fraction

Change in Functional Status

Study Results

Primary Objectives• To determine whether metoprolol XL

reduces:- Total mortality- The combined end point of all-cause

mortality and all-cause hospitalizationin patients with HF (NYHA Class II–IV)

Inclusion Criteria• Age 40–80 years• NYHA Class II–IV• Standard treatment for HF for at least 2 weeks

before randomization• EF 35%, or 36% to 40% with a 6-minute

walk test 450 meters

• Resting heart rate 68 bpm• Supine systolic BP 100 mm Hg

Study Design

*The recommended starting dose was 12.5 mg of blind medicine in patients with NYHA Class III–IV heart failure and 25 mg in Class II heart failure.

Single-blind Double-blind

Months

n=2001

n=1990

Titrated from12.5 mg/25 mg

to 200 mgonce daily*

Placebo

MetoprololXL

211812 159612246802

PlaceboRun-in

Weeks

Mean Dose at Study Closure

0

40

80

120

160

200

Mea

n do

se (m

g)179 mg

159 mg

Placebo Metoprolol XL

Combination Beta and Alpha

AntagonistsCarvedilol

Adapted from Packer et al, NEJM, 1996.

Placebo (n=398)Carvedilol (n=696)

Days

Risk reduction=65% P<.001

Survival1.0

0.9

0.8

0.7

0.6

00 100 200 300 400 Progressive

HFSudden cardiac

death

Patients(%)

3.8†

3.3

0.7

1.7

4

3

2

1

0

P=.001†P<.05

Mortality in US Carvedilol Heart Failure Program

COPERNICUS: Major questions• Can the sickest (class IV) CHF

patients be safely and effectively treated with carvedilol?

• Can carvedilol therapy be initiated during the hospitalization for CHF?

COPERNICUS: Study design• 2289 patients enrolled

• Incusion criteria- Ischemic or non-ischemic cardiomyopathy- Severe (Class III-IV) CHF- LVEF <25%

• Exclusion- Allergic to carvedilol- Already on beta blocker therapy- Fluid over-load- On IV inotropes

COPERNICUS: High-Risk Subgroup

• Hospitalised at time of randomisation

• Hospitalised 3 times or more for CHF within last year

• LV ejection fraction < 15%

• Fluid retention (ascites, rales or oedema)

• Required IV positive inotropic agent or vasodilator within last 2 weeks

Packer M et al. N Engl J Med 2001

COPERNICUS: Study course• Patients stabilized with diuretics and ACE

inhibitor therapy• Patients may be given digoxin and

amiodarone but not required• Patients slowly titrated with carvedilol

therapy as tolerated- Start with 3.125 mg po bid- Initial titration often performed while in the

hospital- Up-titrate dose about every two weeks- Patients followed for 2 years

% S

urvi

val

% S

urvi

val

0000

33 66 99 1212 1515 1818 2121MonthsMonths

100100

9090

8080

6060

7070

P = 0.00013P = 0.00013

CarvedilolCarvedilol

PlaceboPlacebo

COPERNICUS: All-Cause Mortality

COPERNICUS: Effect During First 8 Weeks

Krum H et al. JACC 2002Krum H et al. JACC 2002

Death, Hospitalization and Permanent WithdrawalDeath, Hospitalization and Permanent Withdrawal

CarvedilolCarvedilol

0000 22 44 66 88

% P

atie

nts

with

eve

nt%

Pat

ient

s w

ith e

vent

2020

1010

55

1515PlaceboPlacebo

Weeks After RandomizationWeeks After Randomization

COPERNICUS: Effect During First 8 Weeks

PlaceboPlacebo

CarvedilolCarvedilol

3030

2020

1010

0000 22 44 66 88

% P

atie

nts

with

eve

nt%

Pat

ient

s w

ith e

vent

Death, Hospitalization and Withdrawal inDeath, Hospitalization and Withdrawal inHighest Risk PatientsHighest Risk Patients

Weeks After RandomizationWeeks After Randomization

Reasons Given for Not Using -Blockers

in Patients With Severe Heart Failure:

All proven wrong by COPERNICUS

• Lack of appreciation for disease process- My patient has terminal disease. There is nothing I can do to help

him / her

• Misunderstanding about efficacy - I can accomplish what I need to do with other CHF drugs without

having to use a -blocker

• Excessive concern about safety - My patient is too unstable for a -blocker. It would be best to delay

treatment for a while until he / she is more stable

COPERNICUS: Conclusions• This study demonstrates that, even in

the most sick CHF patients, carvedilol therapy results in significant clinical benefit.

• Also, this life-saving therapy can be initiated very early after volume stabilization, often-times even during initial hospitalization.

Carvedilol or Metoprolol in Heart Failure: Which is Best?

Beta Blockers in CAD• Beta blockers are good for post-MI

• Beta blockers are good for CHF• What about run-of-mill CAD?

- Beta blockers are good anti-anginal agents• But do they save lives?

- No randomized trials- Without data, national guidelines recommend it for

USA

LDS Hospital Study• 4,304 patients with angiographically-confirmed coronary

artery disease- No history of CHF- No history of MI

• Data recorded included baseline demographics, socioeconomic status, cardiac risk factors, clinical presentation, therapeutic procedures.

• Certain cardiac medications including beta-blockers which were prescribed at discharge were recorded

• Patients were followed for an average of 3±1.9 years for outcomes of all-cause death and myocardial infarction.

AHA, 2002

0

5

10

15

20

Death MI Death/MI

No Beta-blocker Beta-blocker

Perc

ent

Univariate Effect of Beta-Blockade on Death, MI, and Death/MI

LDS Hospital Study: Conclusions• Prescription of beta-blockers at hospital

discharge seems protective against all-cause death for patients with coronary artery disease even if they do not have history of heart failure or myocardial infarction.

• Prescription of beta-blockers in these patients does not appear protective against future myocardial infarction.

Beta Blockers in Hypertension

Atenolol Versus Placebo Meta-analysis

Atenolol versus otherAntihypertensive agents:

Meta-analysis

Recent Guidelines Changes Regarding Beta Blockers and

Hypertension• In early versions of JNC, beta-blockers were

considered first-line therapy.• But in JNC 7, beta-blockers were considered only

either as add-on therapy to thiazide-type diuretics, or as initial therapy in patients with compelling other indications.

• Recent European hypertension guidelines have relegated beta-blockers to fourth-line agents, after diuretics, RAAS blockers, and CCBs in patients with uncomplicated hypertension.

Beta Blockers in Non-Cardiac Surgery• General anesthesia produces

significant sympathetic responses.• Peri-operative MI is significant in older

patients undergoing non-cardiac surgery

• Beta blockade may be helpful

Peri-operative Beta Blockers in Non-

cardiac Surgery Study • 200 elderly patients undergoing non-cardiac surgery

• Randomized to atenolol versus placebo• Followed for up to two years• Death• Peri-operative MI

NEJM 1996

Peri-operative Beta Blockers

Peri-operative Beta Blockers

Peri-operative Beta Blockers

2007 National Guidelines

Revised Meta-analysis

• Conclusions: - Guideline bodies should retract their recommendations based on fictitious

data without further delay. - The well-conducted trials indicate a statistically significant 27% increase in

mortality from the initiation of perioperative β-blockade that guidelines currently recommend.

Perioperative Beta Blocker Therapy:

Brent’s Opinion• If patients are already on beta blocker therapy, leave them on it through the entire perioperative period.

• If they are not, then probably leave them that way.

• We hoped beta blockers would help, and indeed they do prevent heart attacks, but unfortunately they also increase the risk of strokes and death.

Miscellaneous Other Uses of Beta Blockers for

Cardiovascular Patients• Rate control for atrial fibrillation• Prevention of supraventricular tachycardia• Treatment of inappropriate sinus

tachycardia• Treatment and prevention of non-

sustained ventricular tachycardia• Treatment of thyroid storm associated

hypertension and tachycardia

Conclusions• Beta blocker therapy continues to be a

very important strategy in the management of a wide variety of cardiovascular patients

• It remains one of a very few agents that has actually been shown to save lives.

• The major change from the past is that beta blockers are now lower priority for the primary treatment of hypertension.