Dr. Pramudjo Abdulgani, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

1. Secondary Prevention After ACS
Role of Beta Blockers
Pramudjo Abdulgani
Pekanbaru

2. Power of Prevention
“An ounce of prevention is worth a pound of cure”
Benjamin Franklin, 1736

3. 3
Burden of Atherosclerotic Vascular
Disease: CAD, CVD, PVD
• Prevalence– 25 million in United States
• Annual rates
Myocardial infarction–1.2 million
Strokes-795,000
CVD Mortality–814,000 (every 30 seconds a death)
Cardiac catheterization–1.1 million
Percutaneous revascularization–622,00
Surgical revascularization–232,000
• Annual direct cost–>$280 billion
American Heart Association. 2011 Heart and Stroke Statistical Update. At: http://www.americanheart.org.

4. 4
Centers for Disease Control and Prevention. Available at:
http://www.cdc.gov/nchs/ppt/hus/HUS2004Chartbk.ppt#280,25,Slide25. Accessed July 11, 2005.
Stroke
Cancer
Heart disease
Unintentional injuries
Chronic lower
respiratory disease
1000
100
10
1950 1960 1970 1980 1985 1990 1995 2002
Death Rates for Leading Causes of Death for All Ages (US, 1950-2002)
Year
Deathsper100,000Population(logscale)
Cardiovascular Disease Remains the
Leading Killer of Men and Women

5. 2 Phases of ACS Treatment
Libby P. Circ 2001;104:365,
Acute Long-termAcute Long-term
(<24hrs) (Discharge)
1. ASA
2. Clopidogrel
3. Heparin/LMWH
4. GP IIb/IIIa inhibitors
5. Beta-blockers
6. Nitrates
7. ACE inhibitors
1. ASA
2. Clopidogrel
3. Beta-blockers
4. ACE Inhibitors
5. Statins
6. Risk factor + Lifestyle ∆’s

6. 6
Nitrates
Calcium Channel Blockers
Beta Blockers
Diet
Exercise
Vitamin E
Vitamin C
Beta Carotene
Iron Chelation
Calcium Chelation
Alcohol
Red Wine
Folate
Vitamin B12
Biofeedback
Meditation
Blood Pressure Control
Glucose Control
Estrogen
Oat Bran
Walnuts
Garlic
ACE Inhibitors
Aspirin Coumadin
Gene Therapy
Olive Oil
Weight Loss
Fish Oils
Vegetables
L-Arginine
Stents
Niacin
Statins
Fibrates
Resins
Anti-Oxidants
Lasers
Acupuncture
Platelet antagonists
Phlebotomy
Fiber
Thyroid Hormones
Soy Beans
?
Potential Therapies for Atherosclerosis

7. 7
Secondary Prevention Guidelines
• Since the 2006 update of the AHA/ACC consensus
statement on secondary prevention, important evidence
from clinical trials has emerged that further supports and
broadens the merits of aggressive risk reduction therapies
• This growing body of evidence confirms that aggressive
comprehensive risk factor management improves survival,
reduces recurrent events and the need for interventional
procedures, and improves the quality of life
• The secondary prevention patient population includes
those with established coronary and other atherosclerotic
vascular disease, including peripheral arterial disease,
atherosclerotic aortic disease and carotid artery disease.

8. 8
Secondary Prevention Definition
• Therapy to reduce recurrent cardiovascular events and
decrease cardiovascular mortality in patients with
established atherosclerotic vascular disease
• Patients covered include those with established
coronary and other atherosclerotic vascular disease,
including peripheral arterial disease, atherosclerotic aortic
disease and carotid artery disease
• Individuals with sub-clinical atherosclerosis and patients
whose only manifestation is diabetes are covered in other
guidelines

9. 9
• Aspirin
• Clopidogrel
• β-blockers
• ACE inhibitors/ARBs
• Aldosterone blockade (Low EF)
• Lipids
- Fasting lipid panel within 24 h
of hospitalization
– Statins before discharge
– Goal LDL-C <100 mg/dL
– LDL <70 mg/dL is reasonable
• BP <140/90 mm Hg (<130/80
mm Hg with diabetes or CKD)
• Smoking cessation/no
environmental smoke
exposure
• Physical activity (30 min,
7 d/wk; min 5 d/wk)
• Weight management
• Diabetes management: HbA1c
<7%
• Annual influenza
immunization
Medications Goals
King SB 3rd, et al. J Am Coll Cardiol. 2008;51:172-209.
Anderson JL, et al. J Am Coll Cardiol. 2007;50:652-726.
Secondary Prevention:

10. 10
Class I
Benefit >>> Risk
Procedure or
treatment SHOULD
be performed or
administered
Class IIa
Benefit >> Risk
Additional studies with
focused objectives
needed
IT IS REASONABLE to
perform procedure or
administer treatment
Class IIb
Benefit ≥ Risk
Additional studies with
broad objectives
needed; Additional
registry data would be
helpful
Procedure or treatment
MAY BE CONSIDERED
Class III
Risk ≥ Benefit
No additional studies
needed
Procedure or treatment
should NOT be
performed or
administered SINCE IT
IS NOT HELPFUL AND
MAY BE HARMFUL
Applying Classification of Recommendations
and Level of Evidence
A: Multiple randomized controlled trials
B: Single trial, non-randomized studies
C: Expert opinion
Level of
Evidence

11. 11
ββββ-blocker Recommendations

12. 12
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Beta-blocker therapy should be used in all patients with
left ventricular systolic dysfunction (ejection fraction
40%) with heart failure or prior myocardial infarction,
unless contraindicated. (Use should be limited to
carvedilol, metoprolol succinate, or bisoprolol, which
have been shown to reduce mortality.)
Beta-blocker therapy should be started and continued for
3 years in all patients with normal left ventricular
function who have had myocardial infarction or ACS
Consider chronic therapy for all other patients with
coronary or other vascular disease or diabetes unless
contraindicated.
MI=Myocardial infarction, HF=Heart Failure
ββββ-blocker Recommendations
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

13. 13
Phase of
Treatment
Acute
treatment
Secondary
prevention
Overall
Total #
Patients
28,970
24,298
53,268
0.5 1.0 2.0
RR of death
β-blocker
better
RR (95% CI)
Placebo
better
0.87 (0.77-0.98)
0.77 (0.70-0.84)
0.81 (0.75-0.87)
ββββ-blocker Evidence
Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart
Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
Summary of Secondary Prevention Trials of β-blocker Therapy
CI=Confidence interval, RR=Relative risk

14. 14
6,644 patients with LVEF <0.40 after a MI with or without HF randomized to
carvedilol or placebo for 24 months
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
RR 0.77 P=.03
0.7
0.75
0.8
0.85
0.9
0.95
1
0 0.5 1 1.5 2 2.5
Carvedilol
Placebo
Years
ProportionEvent-free
n=975
n=984
ββββ-blocker Evidence: Post MI with
Left Ventricular Dysfunction
Carvedilol Post-Infarct Survival Control in LV Dysfunction
(CAPRICORN)

15. 15
Months
Survival
US Carvedilol Study*1
Carvedilol
(n=696)
Placebo
(n=398)
Risk Reduction=65%
P<.001
0 3 6 9 12
Months of Follow-up
Survival
MERIT-HF3
0 3 6 9 12 15 18 21
Placebo
(n=2001)
Metoprolol CR/XL
(n=1990)
P=.0062
Risk Reduction=34%
Time After Inclusion (months)
Survival
CIBIS II2
1Packer M et al. N Engl J Med. 1996;334:1349-1355. 2CIBIS II Investigators and Committees. Lancet. 1999;353:9-13.
3MERIT-HF Study Group. Lancet. 1999;353:2001-2007.
0
Bisoprolol
(n=1327)
Placebo
(n=1320)
P<.0001
Risk Reduction=34%
1.0
0.8
0.6
0
6 2112 24
1.0
0.8
0.6
0
1.0
0.8
0.6
0
3 9 15 18
Months
P=.0014
Survival
Carvedilol
(n=1156)
Placebo
(n=1133)
0 3 6 9 12 15 18 21
0
Risk Reduction=35%
1.0
0.8
0.6
COPERNICUS4
ββββ-blocker Evidence: Benefit in HF and LVSD

16. 16
Study Drug
HF
Severity
Patients
(n)
Follow-up
(years)
Mean
Dosage
Effects on Outcomes
CIBIS Bisoprolol* Moderate-
Severe
641 1.9 3.8
mg/day
All cause mortality
↓↓↓↓22% (p=NS)
CIBIS-II Bisoprolol* Moderate-
Severe
2,647 1.3 7.5
mg/day
All cause mortality
↓↓↓↓34% (P<0.0001)
BEST Bucindolol* Moderate-
Severe
2,708 2.0 152
mg/day
All cause mortality
↓↓↓↓10% (p=NS)
MERIT-HF Metoprolol
succinate#
Mild-
Moderate
3,991 1.0 159
mg/day
All cause mortality
↓↓↓↓34% (P=0.0062)
MDC Metprolol
tartrate*
Mild-
Moderate
383 1.0 108
mg/day
Death or Need for Tx
↓↓↓↓30% (P=NS)
CAPRICORN Carvedilol Mild 1,989 1.3 40
mg/day
All cause mortality
↓↓↓↓23% (P =0.03)
US Carvedilol Carvedilol Mild-
Moderate
1,094 0.5 45
mg/day
All-cause mortality†
↓↓↓↓65% (P=.0001)
COPERNICUS Carvedilol Severe 2,289 0.9 37
mg/day
All-cause mortality
↓↓↓↓35% (P =0.0014)
ββββ-blocker Evidence: Benefit in HF and LVSD
*Not an approved indication
†Not a planned end point.
#Not approved for severe HF or mortality reduction alone

17. Which beta-blocker?
No good evidence that one beta-blocker is more
effective in than another in managing stable angina.9
Select according to contraindications, co-morbidities,
patient preference and cost.8
Avoid beta-blockers if history of asthma or
bronchospasm. Contraindicated in decompensated
heart failure or critical peripheral vascular disease.9
Do not combine a beta blocker with verapamil and use
caution with diltiazem.9
Sudden withdrawal may cause exacerbation of
angina9
17

18. History of beta-blockers and IHD
• 1956-58 James Black (later to receive the Nobel Prize for
Medicine and a knighthood) proposed that inhibition of the
stress hormones adrenaline and noradrenaline would prevent
angina and heart attacks
• First beta-blocker, propranolol, came to market in 1964
• Propranolol, and other BBs, benefitted angina cases
• Oral propranolol, decreased death rate in post MI cases
• IV/oral BBs (atenolol and metoprolol) reduced death rate in
acute MI cases
• Atenolol and bisoprolol reduced ischaemia and hard end-points
in patients with chronic angina
• All the above benefits stem from beta-1 blockade and are
diminished by ISA
• 1964 – Propranolol was noted to reduce blood pressure (B.
Prichard)

19. Beta Receptors
Beta 1 - on cardiac scarcolemma
- coupled by G protein system
- cAMP activation
- opening of calcium channels
Positive - inotropic, chronotropic, lusitropic
effect, dromotropic effect

20. Beta 2 – on bronchial and vascular smooth
muscle - relaxation
Increased in heart failure
Beta 3 – mediate vasodilatation by release of
nitric oxide

21. Distribution of Beta-Receptors
Beta - 1 Beta - 2
Myocardium (B-1 > B-2)
Kidney (renin release)
Smooth Muscle
- blood vessels
- bronchi
- genitourinary system
Skeletal Muscle
- metabolism
- glycogenolysis
- contraction
Fat Tissue
- lipolysis
- lipoprotein lipase
Liver
- glycogenolysis
- gluconeogenesis
Pancreas
- insulin release
Sympathetic nerve terminals
Eye

22. Anti-ischaemic Effects of
betablockade
Negative inotropic, chronotropic and
dromotropic effect
Decreases myocardial oxygen demand
Decrease in heart rate – long diastolic
myocardial perfusion

23. PROPERTIES OF ββββ-BLOCKERS
Name ββββ-1
Selective
αααα-
blockade
Lipophilic Increases
ISA
Other ancillary
properties
Atenolol Yes No No No No
Acebutolol Disputed No No yes No
Bisoprolol Yes No Weak No No
Bucindolol No No Yes Disputed Vasodilator action
Carvedilol No Yes Yes No Antioxidant, effects
on endothelial
function
Celiprolol Yes No No ββββ-2 only No
Metoprolol Yes No Yes No No
Nebivolol Yes No ? No Vasodilation through
nitric oxide
Propranolol No No Yes No Membrane stabilizing
Effect
Timolol No No Weak No Anti-platelet effects

24. Different Pharmacological Profiles
of Beta-Blockers Studied in
Heart Failure
*Antioxidant and antiproliferative.
ββββ1111−−−−
blockade
ββββ2222−−−−
blockade
αααα1111−−−−
blockade ISA
Ancillary
properties
Propranolol +++ +++ 0 0 0
Metoprolol +++ 0 0 0 0
Bisoprolol +++ 0 0 0 0
Bucindolol +++ +++ +(0) +(0) 0
Carvedilol +++ +++ +++ 0 +++(*)

25. Βeta-2 blockade
Alpha-
blockade
Βeta-2 ISA
High beta-1
selectivity
(absence of
beta-2
blokade
Strong Weak
Propanolol Atenolol Labetolol
Pindolol,
Bopindolol,
Celiprolol,
Nebivolol
Bisoprolol
Cruickshank JM. Int J Cardiol 2007;120:10–27

26. Trial Evidence
CIBIS I - Bisoprolol improves LV function
CIBIS II -1999
MERIT - HF, 1999 - Metoprolol – reduce
morbidity & mortality; reduce healthcare costs in
mild - mod heart failure.
COPERNICUS study, 2001 - use of Carvedilol in
severe HF. 35% survival benefit
COMET study, 2003 - suggests Carvedilol vs
Metoprolol increases mortality.
SENIORS, 2005 - Placebo vs Nebivolol

27. Bisoprolol still WONDER us !!!

28. Conclusions
• ACS is a manifestation of diffuse
atherothrombosis
– Multiple plaques, inflammation +
thrombosis
• Long-term medical Rx to prevent events: 5
drugs
“Athero + thrombosis”
Statins (high-dose) ASA (low-dose)
ACE Inhibitor Clopidogrel
Beta-blocker

29. Secondary Prevention
Class I Indications
Aspirin
Beta-blockers: (all pts, slow titration with moderate to
severe failure
ACE-Inhibitors: CHF, EF<40%, HTN, DM
(All pts-Class IIa) ARB when intolerant to ACE.
(Class IIa as alternative to ACEI)
Aldosterone blockade: An ACEI, CHF with either
EF<40% or DM and if CrCl>30 ml/min and K<5.0
mEq/L
Statins
Standard Risk Factor Management

30. 30
Conclusions
• Comprehensive application of secondary
prevention therapies is highly effective in
reducing the risk of cardiovascular events
• Despite the clinical trial evidence and national
guidelines, large number of eligible patients are
not receiving one or more of these
recommended therapies
• As such, large number of patients are having CV
events that could be avoided if there was better
implementation
• Every effort should be made to bridge the
cardiovascular risk reduction gap

31. THANK YOUTHANK YOUTHANK YOUTHANK YOU
.....to a man with a hammer,
everything looks like a nail....