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Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit?
Beta Blockers Treatment For Cardiovascular Disease Where Do They Fit?
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
Intact
Eroded Endothelium
Endothelium
Activated
Macrophages MMP Foam Cells
Unstable Stable
40%
35%
30%
25%
Mortality
20%
15%
10%
5%
0%
>50% 20-49% <20%
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
NEJM, 1998;339:489-97
LDS Hospital Data
975 Patients with Angiographically Documented CAD Followed for >3 years
14% 12%
(P=0.19)
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
XL n=1990
once daily*
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
1.0 (%) †
4 3.8
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
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
15
% Patients with event
Placebo
10
5 Carvedilol
0
0 2 4 6 8
Weeks After Randomization
20 Placebo
10 Carvedilol
0
0 2 4 6 8
Weeks 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
Univariate Effect of Beta-Blockade
on Death, MI, and Death/MI
20
15
Percent
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.