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Secondary Prevention after ACS - Role of Beta Blockers


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Dr. Pramudjo Abdulgani, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013.
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Secondary Prevention after ACS - Role of Beta Blockers

  1. 1. Secondary Prevention After ACS Role of Beta Blockers Pramudjo Abdulgani Pekanbaru
  2. 2. Power of Prevention “An ounce of prevention is worth a pound of cure” Benjamin Franklin, 1736
  3. 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:
  4. 4. 4 Centers for Disease Control and Prevention. Available at:,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. 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. 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. 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. 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. 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. 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. 11 ββββ-blocker Recommendations
  12. 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. 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. 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. 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. 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. 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. 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. 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. 20. Beta 2 – on bronchial and vascular smooth muscle - relaxation Increased in heart failure Beta 3 – mediate vasodilatation by release of nitric oxide
  21. 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. 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. 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. 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. 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. 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. 27. Bisoprolol still WONDER us !!!
  28. 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. 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. 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. 31. THANK YOUTHANK YOUTHANK YOUTHANK YOU a man with a hammer, everything looks like a nail....