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Beta Blockers

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Title: Beta Blockers


1
  • Beta Blockers
  • Treatment For Cardiovascular Disease
  • Where Do They Fit?
  • Joseph Brent Muhlestein, MD, FACC
  • Co-Director of Cardiology Research,
  • Intermountain Medical Center,
  • Professor of Medicine, University of Utah

Nothing to Disclose
2
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

3
Schematic Timecourse of Human Atherogenesis
Ischemic Heart Disease
Cerebrovascular Disease
Peripheral Vascular Disease
Time (years)
No Symptoms Symptoms
Symptoms
4
Pathogenesis of ACS
White HD. Am J Cardiol. 1997 80(4A)2B-10B.
5
The matrix skeleton of an unstable coronary
artery plaque
fissures in the fibrous cap
6
Plaque rupture with thrombosis
Fibrous cap
Thrombus
Lipid core
FJ Schoen, BWH
1 mm
7
fatal thrombus
Plaque rupture site
collagenous fibrous cap
thrombogenic lipid core
8
Characteristics of Unstable and Stable Plaques
Lack of Inflammatory Cells
Inflammatory Cells
Thick Fibrous Cap
Thin Fibrous Cap
Few SMCs
More SMCs
Intact Endothelium
Eroded Endothelium
Activated Macrophages
MMP
Foam Cells
Unstable
Stable
Libby et al. Circulation 1995 912844-50
9
Beta Blockers Where do they fit?
10
Physiology of the Sympathetic Nervous System
  • Epinephrine / Norepinephrine
  • Hypertension
  • Hypercoagulability
  • Vasoreacivity
  • Fibrosis
  • Upregulated in many situations
  • Emotional excitement
  • Heart Failure
  • General anesthesia

11
Beta Blockers Indications
  • Post MI
  • CAD
  • Heart Failure
  • Hypertension
  • Non-cardiac surgery
  • Rate Control
  • Atrial fibrillation
  • Inappropriate sinus tachycardia
  • Arrhythmias

12
Beta Blockers Post-MI
  • Rationale
  • Antiplatelet effect
  • Antiarrhthmic effect
  • General blood pressure effect

13
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

14
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

15
Effect on sudden death of beta blockade following
MI. Pooled data from 5 trials
16
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

17
HCFA cooperative cardiovascular project Results
NEJM, 1998339489-97
18
HCFA cooperative cardiovascular project Results
NEJM, 1998339489-97
19
LDS Hospital Data 975 Patients with
Angiographically Documented CAD Followed for gt3
years
(P0.19)
20
Beta Blockers in Heart Failure
21
Vicious Cycle of Heart Failure
22
The Beginning of the Beta Blocker Story
  • 1985, LDS Hospital, Jeffrey Anderson, et al
  • 50 patients with IDC (EFlt30)
  • 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

23
Metoprolol in Idiopathic Dilated Cardiomyopathy
(MDC) Study
  • 383 patients with IDC (LVEFlt40)
  • 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 EF

Lancet, 1993, 342(8885)1441-1446
24
Death or Transplant
25
Change In Ejection Fraction
26
Change in Functional Status
27
Study Results
28
Primary Objectives
  • To determine whether metoprolol XL reduces
  • Total mortality
  • The combined end point of all-cause mortality
    and all-cause hospitalization in patients with HF
    (NYHA Class IIIV)

29
Inclusion Criteria
  • Age 4080 years
  • NYHA Class IIIV
  • 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

30
Study Design
Titrated from 12.5 mg/25 mg to 200 mg once daily
Metoprolol XL
n1990
Placebo Run-in
n2001
Placebo
2
21
18
12
15
9
6
12
2
4
6
8
0
Months
Weeks
Single- blind
Double-blind
The recommended starting dose was 12.5 mg of
blind medicine in patients with NYHA Class IIIIV
heart failure and 25 mg in Class II heart failure.
31
Mean Dose at Study Closure
179 mg
2
0
0
159 mg
1
6
0
1
2
0
Mean dose (mg)
8
0
4
0
0
Placebo
Metoprolol XL
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Combination Beta and Alpha Antagonists
Carvedilol
37
Mortality in US Carvedilol Heart Failure Program
Survival
Patients ()
1.0
3.8
4
?P.001
3.3?
0.9
3
Plt.05
0.8
Placebo (n398)
2
1.7
0.7
Carvedilol (n696)
Risk reduction65 Plt.001
1
0.6
0.7
0
0
0
100
200
300
400
Progressive HF
Sudden cardiac death
Days
Adapted from Packer et al, NEJM, 1996.
38
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?

39
COPERNICUS Study design
  • 2289 patients enrolled
  • Incusion criteria
  • Ischemic or non-ischemic cardiomyopathy
  • Severe (Class III-IV) CHF
  • LVEF lt25
  • Exclusion
  • Allergic to carvedilol
  • Already on beta blocker therapy
  • Fluid over-load
  • On IV inotropes

40
COPERNICUS High-Risk Subgroup
  • Hospitalised at time of randomisation
  • Hospitalised 3 times or more for CHF within last
    year
  • LV ejection fraction lt 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
41
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

42
COPERNICUS All-Cause Mortality
100
90
80
Carvedilol
Survival
70
Placebo
60
P 0.00013
0
0
3
6
9
12
15
18
21
Months
43
COPERNICUS Effect During First 8 Weeks
Death, Hospitalization and Permanent Withdrawal
20
15
Placebo
10
Patients with event
Carvedilol
5
0
0
2
4
6
8
Weeks After Randomization
Krum H et al. JACC 2002
44
COPERNICUS Effect During First 8 Weeks
Death, Hospitalization and Withdrawal in Highest
Risk Patients
30
Placebo
20
Patients with event
Carvedilol
10
0
0
2
4
6
8
Weeks After Randomization
45
Reasons Given for Not Using b-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 b-blocker
  • Excessive concern about safety
  • My patient is too unstable for a b-blocker. It
    would be best to delay treatment for a while
    until he / she is more stable


46
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.

47
Carvedilol or Metoprolol in Heart Failure Which
is Best?
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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

59
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 31.9
    years for outcomes of all-cause death and
    myocardial infarction.

AHA, 2002
60
Univariate Effect of Beta-Blockade on Death, MI,
and Death/MI
Percent
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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.

63
Beta Blockers in Hypertension
64
Atenolol Versus Placebo Meta-analysis
65
Atenolol versus other Antihypertensive
agents Meta-analysis
66
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.

67
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

68
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
69
Peri-operative Beta Blockers
70
Peri-operative Beta Blockers
71
Peri-operative Beta Blockers
72
2007 National Guidelines
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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
    ß-blockade that guidelines currently recommend.

86
Perioperative Beta Blocker Therapy Brents
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.

87
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

88
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.
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