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
• 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

• Peripheral
Vascular
Disease
Time (years)
No Symptoms ± Symptoms 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 Fibrous cap

1 mm FJ Schoen, BWH Lipid core

 fatal
Plaque thrombus
rupture
site collagenous fibrous cap

thrombogenic lipid core

 Characteristics of Unstable and Stable Plaques
Lack of
Inflammatory Inflammatory
Thin Cells Thick Cells
Few Fibrous Cap More Fibrous Cap
SMCs SMCs

Intact
Eroded Endothelium
Endothelium
Activated
Macrophages MMP Foam Cells

Unstable Stable

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

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: Results
2 Year Mortality Based on Initial EF

40%
35%
30%
Mortality

25%
20%
15%
10%
5%
0%
>50% 20-49% <20%

Beta blocker No beta blocker

NEJM, 1998;339:489-97
 HCFA cooperative
cardiovascular project: Results
2 Year Mortality Based on Type of MI

14%
12%
10%
Mortality

8%
6%
4%
2%
0%
Q-wave Non Q-wave

Beta blocker No beta blocker

NEJM, 1998;339:489-97
 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% (P=0.19) 12%

12%
10%
8%
6%
6%
4%
2%
0%
Beta blocker No beta blocker
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: EF
Lancet, 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 hospitalization
in 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
Titrated from
12.5 mg/25 mg Metoprolol
to 200 mg n=1990
once daily* XL

Placebo
Run-in
Placebo n=2001
2 0 2468 12 6 9 12 15 18 21
Months
Weeks
Single-
Double-blind
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

200 179 mg
159 mg
Mean dose (mg)

160

120

80

40

0
Placebo Metoprolol XL
Combination Beta and
Alpha Antagonists

Carvedilol
 Mortality in US Carvedilol
Heart Failure Program
Survival Patients
(%)
3.8†
1.0 4

 P=.001
0.9 3.3
3 †
P<.05
0.8 Placebo
(n=398) 2
0.7 Carvedilol 1.7
Risk
(n=696)
0.6 reduction=65% 1
0.7
P<.001
0 0
0 100 200 300 400 Progressive Sudden cardiac
Days HF death

Adapted from Packer et al, NEJM, 1996.

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
 COPERNICUS: All-Cause Mortality
100

90

80
% Survival

Carvedilol
70
Placebo

60
P = 0.00013

0
0 3 6 9 12 15 18 21
Months
COPERNICUS: Effect During First 8 Weeks
Death, Hospitalization and Permanent Withdrawal
20
% Patients with event

15
Placebo

10

5 Carvedilol

0
0 2 4 6 8
Weeks After Randomization

Krum H et al. JACC 2002

COPERNICUS: Effect During First 8 Weeks
Death, Hospitalization and Withdrawal in
Highest Risk Patients
30
% Patients with event

20 Placebo

10 Carvedilol

0
0 2 4 6 8
Weeks After Randomization
 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
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
 Univariate Effect of Beta-Blockade
on Death, MI, and Death/MI
20
Percent

15

10

0
Death MI Death/MI

No Beta-blocker Beta-blocker
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 other
Antihypertensive 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.