Transcript Slide 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
Introduction
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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
Schematic Timecourse
of Human Atherogenesis
• Ischemic Heart
Disease
• Cerebrovascular
Disease
Time (years)
No Symptoms
± Symptoms
• Peripheral
Vascular
Disease
Symptoms
Pathogenesis of ACS
White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
The matrix skeleton of an unstable
coronary artery plaque
fissures in
the fibrous cap
Plaque rupture with thrombosis
Thrombus
1 mm
FJ Schoen, BWH
Fibrous cap
Lipid core
Plaque
rupture
site
fatal
thrombus
collagenous fibrous cap
thrombogenic lipid core
Characteristics of Unstable and Stable Plaques
Thin
Few Fibrous Cap
SMCs
Inflammatory
Cells
Eroded
Endothelium
Activated
Macrophages
More
SMCs
Thick
Fibrous Cap
Lack of
Inflammatory
Cells
Intact
Endothelium
MMP
Unstable
Libby et al. Circulation 1995; 91:2844-50
Foam Cells
Stable
Beta Blockers: Where do they fit?
Physiology of the
Sympathetic Nervous System
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Epinephrine / Norepinephrine
Hypertension
Hypercoagulability
Vasoreacivity
Fibrosis
Upregulated in many situations
Emotional excitement
Heart Failure
General anesthesia
Beta Blockers: Indications
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Post MI
CAD
Heart Failure
Hypertension
Non-cardiac surgery
Rate Control
- Atrial fibrillation
- Inappropriate sinus tachycardia
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Arrhythmias
Beta Blockers Post-MI
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Rationale
- Antiplatelet effect
- Antiarrhthmic effect
- General blood pressure effect
Evidence of Beta Blockers post MI
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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
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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.)
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Metoprolol study (1981)
- 90 day follow-up
- metoprolol versus placebo
- 36% reduction in over-all mortality
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BBPP (1986, 9 trials pooled)
- 13,679 patients, a variety of beta blocker drugs
- 1 year follow-up
- 24% reduction in death
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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
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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: Results
Mortality
2 Year Mortality Based on Initial EF
40%
35%
30%
25%
20%
15%
10%
5%
0%
>50%
20-49%
Beta blocker
NEJM, 1998;339:489-97
<20%
No beta blocker
HCFA cooperative
cardiovascular project: Results
2 Year Mortality Based on Type of MI
14%
Mortality
12%
10%
8%
6%
4%
2%
0%
Q-wave
Beta blocker
NEJM, 1998;339:489-97
Non Q-wave
No beta blocker
LDS Hospital Data
975 Patients with Angiographically Documented CAD Followed for >3 years
Mortality by whether post-MI patients
(n=242) were placed on a beta blocker
14%
12%
10%
8%
6%
4%
2%
0%
(P=0.19)
12%
6%
Beta blocker
No beta blocker
Beta Blockers in Heart Failure
Vicious Cycle of Heart Failure
The Beginning of the Beta Blocker Story
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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
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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: EF
Lancet, 1993, 342(8885):1441-1446
Death or Transplant
Change In Ejection Fraction
Change in Functional Status
Study Results
Primary Objectives
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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 II–IV)
Inclusion Criteria
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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
Titrated from
12.5 mg/25 mg
to 200 mg
once daily*
Metoprolol
XL
n=1990
Placebo
n=2001
Placebo
Run-in
2
0 2468 12
Weeks
Singleblind
6
9 12 15 18 21
Months
Double-blind
*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.
Mean Dose at Study Closure
Mean dose (mg)
200
179 mg
159 mg
160
120
80
40
0
Placebo
Metoprolol XL
Combination Beta and
Alpha Antagonists
Carvedilol
Mortality in US Carvedilol
Heart Failure Program
Survival
Patients
(%)
1.0
3.8†
4
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P=.001
3.3
0.9
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3
0.8
Placebo
(n=398)
Carvedilol
(n=696)
0.7
2
1.7
Risk
reduction=65%
P<.001
0.6
1
0
0
100
200
300
P<.05
400
Days
Adapted from Packer et al, NEJM, 1996.
0.7
0
Progressive Sudden cardiac
death
HF
COPERNICUS: Major questions
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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
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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
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Hospitalised at time of randomisation
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Hospitalised 3 times or more for CHF within
last year
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LV ejection fraction < 15%
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Fluid retention (ascites, rales or oedema)
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Required IV positive inotropic agent or
vasodilator within last 2 weeks
Packer M et al. N Engl J Med 2001
COPERNICUS: Study course
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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
COPERNICUS: All-Cause Mortality
100
% Survival
90
80
Carvedilol
70
Placebo
60
P = 0.00013
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0
3
6
9
12
Months
15
18
21
COPERNICUS: Effect During First 8 Weeks
Death, Hospitalization and Permanent Withdrawal
% Patients with event
20
15
Placebo
10
Carvedilol
5
0
0
2
4
6
Weeks After Randomization
Krum H et al. JACC 2002
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COPERNICUS: Effect During First 8 Weeks
Death, Hospitalization and Withdrawal in
Highest Risk Patients
% Patients with event
30
Placebo
20
10
Carvedilol
0
0
2
4
6
Weeks After Randomization
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Reasons Given for Not Using b-Blockers
in Patients With Severe Heart Failure:
All proven wrong by COPERNICUS
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Lack of appreciation for disease process
- My patient has terminal disease. There is nothing I can do to help
him / her
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Misunderstanding about efficacy
- I can accomplish what I need to do with other CHF drugs without
having to use a b-blocker
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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
COPERNICUS: Conclusions
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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
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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
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But do they save lives?
- No randomized trials
- Without data, national guidelines recommend it for
USA
LDS Hospital Study
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4,304 patients with angiographically-confirmed
coronary artery disease
- No history of CHF
- No history of MI
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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
Univariate Effect of Beta-Blockade
on Death, MI, and Death/MI
Percent
20
15
10
5
0
Death
MI
No Beta-blocker
Death/MI
Beta-blocker
LDS Hospital Study: Conclusions
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Prescription of beta-blockers at hospital
discharge seems protective against allcause 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 other
Antihypertensive agents:
Meta-analysis
Recent Guidelines Changes Regarding
Beta Blockers and Hypertension
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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 NonCardiac Surgery
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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
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200 elderly patients undergoing noncardiac 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
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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
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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
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Rate control for atrial fibrillation
Prevention of supraventricular tachycardia
Treatment of inappropriate sinus
tachycardia
Treatment and prevention of nonsustained ventricular tachycardia
Treatment of thyroid storm associated
hypertension and tachycardia
Conclusions
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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.