9/24/2013

1

Beta BlockersTreatment For Cardiovascular

DiseaseWhere 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

9/24/2013

2

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.

9/24/2013

3

The matrix skeleton of an unstablecoronary artery plaque

fissures inthe fibrous cap

Plaque rupture with thrombosis

1 mm FJ Schoen, BWH

ThrombusThrombus Fibrous cap

Lipid coreLipid core

9/24/2013

4

Plaque rupture

site

fatal thrombus

collagenous fibrous cap

thrombogenic lipid core

Characteristics of Unstable and Stable Plaques

Thin Fibrous Cap

Inflammatory Cells

FewSMCs

Unstable

ErodedEndotheliumActivated

Macrophages

ThickFibrous Cap

Lack ofInflammatory Cells

Foam Cells

IntactEndothelium

MoreSMCs

Stable

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

MMP

9/24/2013

5

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

9/24/2013

6

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

9/24/2013

7

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

9/24/2013

8

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

9/24/2013

9

HCFA cooperative cardiovascular project: Results

NEJM, 1998;339:489-97

HCFA cooperative cardiovascular project: Results

NEJM, 1998;339:489-97

9/24/2013

10

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

(P=0.19)

Beta Blockers in Heart Failure

9/24/2013

11

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

9/24/2013

12

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

9/24/2013

13

Change In Ejection Fraction

Change in Functional Status

9/24/2013

14

Study ResultsStudy 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)

9/24/2013

15

Inclusion Criteria• Age 40–80 years

• NYHA Class II–IV• Standard treatment for HF for at least 2

weeksbefore 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 DesignStudy 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

9/24/2013

16

Mean Dose at Study Closure

0

40

80

120

160

200M

ean

dose

(m

g)179 mg

159 mg

Placebo Metoprolol XL

9/24/2013

17

9/24/2013

18

Combination Beta and Alpha Antagonists

Carvedilol

9/24/2013

19

Adapted from Packer et al, NEJM, 1996.

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

Days

Risk reduction=65% P<.001

Survival

1.0

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?

9/24/2013

20

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

9/24/2013

21

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

00

3 6 9 12 15 18 21

Months

100

90

80

60

70

P = 0.00013

Carvedilol

Placebo

COPERNICUS: All-Cause Mortality

9/24/2013

22

COPERNICUS: Effect During First 8 Weeks

Krum H et al. JACC 2002

Death, Hospitalization and Permanent Withdrawal

Carvedilol

00 2 4 6 8

% P

atie

nts

with

eve

nt20

10

5

15Placebo

Weeks After Randomization

COPERNICUS: Effect During First 8 Weeks

Placebo

Carvedilol

30

20

10

00 2 4 6 8

% P

atie

nts

with

eve

nt

Death, Hospitalization and Withdrawal inHighest Risk Patients

Weeks After Randomization

9/24/2013

23

Reasons Given for Not Using -Blockersin 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.

9/24/2013

24

Carvedilol or Metoprolol in Heart Failure: Which is Best?

9/24/2013

25

9/24/2013

26

9/24/2013

27

9/24/2013

28

9/24/2013

29

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

9/24/2013

30

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

Per

cent

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

9/24/2013

31

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.

9/24/2013

32

Beta Blockers in Hypertension

Atenolol Versus Placebo Meta-analysis

9/24/2013

33

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.

9/24/2013

34

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 MINEJM 1996

9/24/2013

35

Peri-operative Beta Blockers

Peri-operative Beta Blockers

9/24/2013

36

Peri-operative Beta Blockers

2007 National Guidelines

9/24/2013

37

9/24/2013

38

9/24/2013

39

9/24/2013

40

9/24/2013

41

9/24/2013

42

9/24/2013

43

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.

9/24/2013

44

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.