Secondary Prevention After ACSRole of Beta Blockers

Pramudjo Abdulgani

Pekanbaru

Power of Prevention

“An ounce of prevention is worth a pound of cure” Benjamin Franklin, 1736

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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.

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Centers for Disease Control and Prevention. Availab le at: http://www.cdc.gov/nchs/ppt/hus/HUS2004Chartbk.ppt# 280,25,Slide25. Accessed July 11, 2005.

Stroke

Cancer

Heart disease

Unintentional injuries

Chronic lowerrespiratory disease

1000

100

10

1950 1960 1970 1980 1985 1990 1995 2002

Death Rates for Leading Causes of Death for All Age s (US, 1950-2002)

YearDea

ths

per

100,

000

Pop

ulat

ion

(log

scal

e)

Cardiovascular Disease Remains the Leading Killer of Men and Women

2 Phases of ACS Treatment

Libby P. Circ 2001;104:365,

Acute Long-termAcute Long-term(<24hrs) (Discharge)

1. ASA2. Clopidogrel3. Heparin/LMWH4. GP IIb/IIIa inhibitors5. Beta-blockers6. Nitrates7. ACE inhibitors

1. ASA2. Clopidogrel3. Beta-blockers4. ACE Inhibitors5. Statins6. Risk factor + Lifestyle ∆’s

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NitratesCalcium 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

WalnutsGarlic

ACE Inhibitors

Aspirin Coumadin

Gene Therapy

Olive Oil

Weight Loss

Fish Oils

VegetablesL-Arginine

StentsNiacin

Statins

Fibrates

Resins

Anti-Oxidants

Lasers

Acupuncture

Platelet antagonists

Phlebotomy

Fiber

Thyroid Hormones

Soy Beans

?

Potential Therapies for Atherosclerosis

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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.

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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

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• 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:

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Class I

Benefit >>> Risk

Procedure or treatment SHOULD

be performed or administered

Class IIa

Benefit >> RiskAdditional studies with

focused objectives needed

IT IS REASONABLE to perform procedure or administer treatment

Class IIb

Benefit ≥ RiskAdditional studies with

broad objectives needed; Additional

registry data would be helpful

Procedure or treatment MAY BE CONSIDERED

Class III

Risk ≥ BenefitNo 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 trialsB: Single trial, non-randomized studiesC: Expert opinion

Level of Evidence

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ββββ-blocker Recommendations

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 fraction40%) with heart failure or prior myocardial infarction, unless contraindicated. (Use should be limited tocarvedilol, 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 ventricularfunction 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

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Phase of Treatment

Acute treatment

Secondaryprevention

Overall

Total #Patients

28,970

24,298

53,268

0.5 1.0 2.0RR of death

β-blockerbetter

RR (95% CI)

Placebobetter

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

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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

Pro

port

ion

Eve

nt-f

ree

n=975

n=984

ββββ-blocker Evidence: Post MI with Left Ventricular Dysfunction

Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN)

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Months

Sur

viva

l

US Carvedilol Study* 1

Carvedilol(n=696)

Placebo(n=398)

Risk Reduction=65%P<.001

0 3 6 9 12

Months of Follow-up

Sur

viva

l

MERIT-HF3

0 3 6 9 12 15 18 21

Placebo(n=2001)

Metoprolol CR/XL(n=1990)

P=.0062Risk Reduction=34%

Time After Inclusion (months)

Sur

viva

l

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<.0001Risk Reduction=34%

1.0

0.8

0.6

06 2112 24

1.0

0.8

0.6

0

1.0

0.8

0.6

0

3 9 15 18

Months

P=.0014S

urvi

val

Carvedilol (n=1156)

Placebo(n=1133)

0 3 6 9 12 15 18 210

Risk Reduction=35%

1.0

0.8

0.6

COPERNICUS4

ββββ-blocker Evidence: Benefit in HF and LVSD

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Study DrugHF

SeverityPatients

(n)Follow-up

(years)Mean

DosageEffects 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 7.5mg/day

All cause mortality↓↓↓↓34% (P<0.0001)

BEST Bucindolol* Moderate-Severe

2,708 2.0 152mg/day

All cause mortality ↓↓↓↓10% (p=NS)

MERIT-HF Metoprolol succinate #

Mild-Moderate

3,991 1.0 159mg/day

All cause mortality↓↓↓↓34% (P=0.0062)

MDC Metprolol tartrate*

Mild-Moderate

383 1.0 108mg/day

Death or Need for Tx ↓↓↓↓30% (P=NS)

CAPRICORN Carvedilol Mild 1,989 1.3 40mg/day

All cause mortality ↓↓↓↓23% (P =0.03)

US Carvedilol Carvedilol Mild-Moderate

1,094 0.5 45mg/day

All-cause mortality†↓↓↓↓65% (P=.0001)

COPERNICUS Carvedilol Severe 2,289 0.9 37mg/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

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-morbiditi es, patient preference and cost. 8

Avoid beta-blockers if history of asthma or bronchospasm. Contraindicated in decompensated heart failure or critical peripheral vascular disea se.9

Do not combine a beta blocker with verapamil and us e caution with diltiazem. 9

Sudden withdrawal may cause exacerbation of angina 9

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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)

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

� Beta 2 – on bronchial and vascular smooth

muscle - relaxation

� Increased in heart failure

� Beta 3 – mediate vasodilatation by release of

nitric oxide

Distribution of Beta-Receptors

Beta - 1 Beta - 2Myocardium (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 terminalsEye

Anti-ischaemic Effects of

betablockade

� Negative inotropic, chronotropic and

dromotropic effect

� Decreases myocardial oxygen demand

� Decrease in heart rate – long diastolic

myocardial perfusion

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

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 +++(*)

Βeta-2 blockadeAlpha-

blockadeΒeta-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

Trial Evidence

CIBIS I - Bisoprolol improves LV functionCIBIS II -1999MERIT - 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 benefitCOMET study, 2003 - suggests Carvedilol vs Metoprolol increases mortality.SENIORS, 2005 - Placebo vs Nebivolol

Bisoprolol still WONDER us !!!

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 ClopidogrelBeta-blocker

Secondary PreventionClass 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

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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

THANK YOUTHANK YOUTHANK YOUTHANK YOU

.....to a man with a hammer, everything looks like a nail....