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Chf

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Chf

  1. 1. Congestive Heart Failure Madi Capoccia DO 5 Jun 2007 Dewitt Army Hospital
  2. 2. Objectives <ul><li>Definition and Epidemiology </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Diagnosis and Classification </li></ul><ul><li>Treatment of Systolic Dysfunction </li></ul><ul><ul><li>Medical Therapy </li></ul></ul><ul><ul><li>Device Therapy </li></ul></ul>
  3. 3. What is CHF? <ul><li>Definition </li></ul><ul><li>Abnormality of cardiac function that leads to the inability of the heart to pump blood to meet the body’s basic metabolic demands or when it can do so only with an elevated filling pressure </li></ul>
  4. 4. Epidemiology <ul><li>Prevalence </li></ul><ul><ul><li>Affects nearly 5 million Americans currently, >500,000 new cases diagnosed each year </li></ul></ul><ul><li>Cost </li></ul><ul><ul><li>Annual direct cost in >10 billion dollars </li></ul></ul><ul><li>Incidence increased with age </li></ul><ul><ul><li>Effects 1-2% of patient from 50-59-years-old and 10% of patient over the age of 75 </li></ul></ul><ul><li>Frequency </li></ul><ul><ul><li>It is the most common inpatient diagnosis in the US for patients over 65 years of age </li></ul></ul><ul><ul><li>Visits to their family practitioner on average 2-3 times per year </li></ul></ul><ul><li>Gender </li></ul><ul><ul><li>Men> women in those between 40 and 75 years of age </li></ul></ul><ul><ul><li>The sexes are equal over 75 years of age </li></ul></ul>
  5. 5. Pathophysiology of Heart Failure <ul><li>Hemodynamic Model </li></ul><ul><li>Neurohumoral Adaptations </li></ul><ul><ul><li>“ double-edged swords” </li></ul></ul><ul><ul><li>Renin-Angiotensin-Aldosterone System </li></ul></ul><ul><ul><li>Sympathetic Nervous System </li></ul></ul><ul><ul><li>Antidiuretic Hormone </li></ul></ul><ul><ul><li>Atrial and B-type Natriuretic Peptides </li></ul></ul><ul><ul><li>Endothelin </li></ul></ul>
  6. 6. Help initially <ul><li>Vasoconstriction </li></ul><ul><ul><li>Redistributes blood to vital organs </li></ul></ul><ul><li>Restoration of Cardiac Output </li></ul><ul><ul><li>Increased myocardial contractility and heart rate </li></ul></ul><ul><ul><li>Expansion of the extracellular fluid volume </li></ul></ul>
  7. 8. Neurohumoral-RAAS
  8. 9. Hurt long-term
  9. 10. Precipitating Causes <ul><li>Common </li></ul><ul><ul><li>CAD (70%) </li></ul></ul><ul><ul><li>Systemic Hypertension </li></ul></ul><ul><ul><li>Idiopathic </li></ul></ul><ul><li>Less Common </li></ul><ul><ul><li>Diabetes Mellitus </li></ul></ul><ul><ul><li>Valvular Disease </li></ul></ul><ul><li>Rare </li></ul><ul><ul><li>Anemia </li></ul></ul><ul><ul><li>Connective Tissue Disease </li></ul></ul><ul><ul><li>Viral Myocarditis </li></ul></ul><ul><ul><li>Hemochromatosis </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Hyper/Hypothyroidism </li></ul></ul><ul><ul><li>Hypertrophic Cardiomyopathy </li></ul></ul><ul><ul><li>Infiltrative Disease including amyloidosis and sarcoidosis </li></ul></ul><ul><ul><li>Mediastinal radiation </li></ul></ul><ul><ul><li>Peripartum cardiomyopathy </li></ul></ul><ul><ul><li>Restrictive pericardial disease </li></ul></ul><ul><ul><li>Tachyarrhythmias </li></ul></ul><ul><ul><li>Toxins </li></ul></ul><ul><ul><li>Trypanosomiasis (Chagas’ disease) </li></ul></ul>
  10. 11. Systolic vs. Diastolic <ul><li>Diastolic dysfunction </li></ul><ul><ul><li>EF normal or increased </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Due to chronic replacement fibrosis & ischemia-induced decrease in distensibility </li></ul></ul><ul><li>Systolic dysfunction </li></ul><ul><ul><li>EF < 40% </li></ul></ul><ul><ul><li>Usually from coronary disease </li></ul></ul><ul><ul><li>Due to ischemia-induced decrease in contractility </li></ul></ul><ul><li>Most common is a combination of both </li></ul>
  11. 12. Subtypes of Systolic Heart Failure <ul><li>High output </li></ul><ul><ul><li>Severe anemia </li></ul></ul><ul><ul><li>AV malformations </li></ul></ul><ul><ul><li>hyperthyroidism </li></ul></ul><ul><li>Low cardiac output </li></ul><ul><li>Right Heart Failure </li></ul><ul><ul><li>Peripheral edema </li></ul></ul><ul><li>Left Heart Failure </li></ul><ul><ul><li>Pulmonary congestion </li></ul></ul><ul><li>Biventricular Failure </li></ul><ul><ul><li>Systemic and pulmonary congestion </li></ul></ul>
  12. 13. Evaluation <ul><li>History: risk factors for ischemic heart disease, family history </li></ul><ul><li>Physical exam: S3, JVD more specific signs of HF than rales, peripheral edema </li></ul>
  13. 14. Exam <ul><li>Major Criteria </li></ul><ul><ul><li>Paroxysmal nocturnal dyspnea </li></ul></ul><ul><ul><li>Neck Vein Distention </li></ul></ul><ul><ul><li>Rales </li></ul></ul><ul><ul><li>Cardiomegaly </li></ul></ul><ul><ul><li>Pulmonary Edema </li></ul></ul><ul><ul><li>S3 Gallop </li></ul></ul><ul><ul><li>Hepatojugular Reflex </li></ul></ul><ul><li>Minor Criteria </li></ul><ul><ul><li>Ankle edema </li></ul></ul><ul><ul><li>Nocturnal Cough </li></ul></ul><ul><ul><li>Dyspnea on ordinary exertion </li></ul></ul><ul><ul><li>Hepatomegaly </li></ul></ul><ul><ul><li>Pleural Effusion </li></ul></ul><ul><ul><li>Tachycardia >120bpm </li></ul></ul>
  14. 15. Confirming the Presence of Heart Failure <ul><li>CXR-cardiomegaly and pulmonary edema; Kerley’s B Lines </li></ul><ul><li>Laboratory Values </li></ul><ul><li>BNP </li></ul><ul><ul><li>Maybe inc by age, female gender, CRI, pulm disease, hyperthyroid, obesity, steroid use </li></ul></ul><ul><li>Electrocardiogram/ECHO </li></ul><ul><ul><li>Anterior Q waves, LBBB, LVH </li></ul></ul>
  15. 16. Negative Prognostic Factors <ul><li>Clinical </li></ul><ul><ul><li>Increased Age, Diabetes, Smoking </li></ul></ul><ul><li>Laboratory </li></ul><ul><ul><li>Hyponatremia, Elevated neurohormones </li></ul></ul><ul><li>Hemodynamic </li></ul><ul><ul><li>Reduced EF, Increased Pulm Cap Wedge Pressure </li></ul></ul><ul><li>Electrophysiological </li></ul><ul><ul><li>A-fib, A-flutter, Ventricular ectopy, V-tach </li></ul></ul>
  16. 17. Classification of Heart Failure: ACC/AHA Stage vs NYHA Class
  17. 18. Principles of Treatment <ul><li>Systolic HF </li></ul><ul><li> Preload </li></ul><ul><li> Afterload </li></ul><ul><li> Ionotropy </li></ul><ul><li> Neurohumoral </li></ul><ul><li>activity </li></ul><ul><li>ACE-I, Beta-blockers, and aldosterone antagonist are the mainstay of treatment </li></ul>
  18. 19. Treatment of Systolic Heart Failure <ul><li>ACE Inhibitors- </li></ul><ul><ul><li>Works to inhibit the over stimulation of the RAS that leads to myocardial hypertrophy and fibrosis </li></ul></ul><ul><ul><li>Causes balanced vasodilation </li></ul></ul><ul><ul><li>Decrease the rate of morbidity & mortality in all pts with systolic heart failure </li></ul></ul><ul><ul><li>-If treating acute HF, can start after BP tolerates and pulmonary edema is relieved </li></ul></ul>
  19. 20. ACE-I <ul><li>SOLVD-Enalapril 20mg/day (41 mo) </li></ul><ul><li>2569 Patients with and EF <35% </li></ul><ul><ul><li>Earlier stages of HF even asymptomatic </li></ul></ul><ul><ul><li>NYHA Class II-III </li></ul></ul><ul><li>All cause mortality dec by 16% </li></ul><ul><li>Morality rate from HF dec by 16% </li></ul><ul><li>CONSENSUS-Enalapril 2.5-40mg (188 days) vs placebo </li></ul><ul><li>Pts were already taking digoxin and diuretics </li></ul><ul><li>253 Patient with NYHA Class IV </li></ul><ul><li>Dec mortality at: </li></ul><ul><ul><li>6 months -40% </li></ul></ul><ul><ul><li>1 Year – 27% </li></ul></ul>
  20. 22. Angiotensin-Receptor Blockers <ul><ul><li>Comparable to ACE inhibitors </li></ul></ul><ul><ul><li>Reduce all-cause mortality </li></ul></ul><ul><ul><li>Suitable alternative for patient with adverse events (angioedema, cough, hyperkalemia) occur with ace-i </li></ul></ul>
  21. 23. ACE + ARB <ul><li>CHARM-Added (Lancet 2003) </li></ul><ul><ul><li>2548 NYHA II-IV; LVEF < 40% </li></ul></ul><ul><ul><li>CV death, hospital admission </li></ul></ul><ul><ul><li>NNT=25 </li></ul></ul><ul><ul><li>Second study found no benefit </li></ul></ul><ul><li>But 23% discontinued due to side effects (increased cr, hypotension, hyperkalemia) </li></ul><ul><li>Currently Ace + Arb is not recommended </li></ul>
  22. 24. Beta-Blockers <ul><li>34% reduction in all mortality with use of beta-blockers </li></ul><ul><li>Decrease Cardiac Sympathetic Activity </li></ul><ul><li>Use in stable, chronic disease (start as early as discharge-IMPACT-HF) </li></ul><ul><li>Titrate slowly </li></ul><ul><li>Contraindications-bradycardia, heart block or hemodynamic instability </li></ul><ul><li>Mild asthma was not a contraindication </li></ul><ul><li>Work irrespective of the etiology of the heart failure </li></ul>
  23. 25. Beta- blocker therapy-which to pick? <ul><li>Three beta-blockers : </li></ul><ul><li>Bisoprolol (Zebeta) -Trial CIBIS-II </li></ul><ul><li>Metoprolol (Toprol XL) –Trial MERIT-HF (sustained release) </li></ul><ul><li> Carvedilol (Coreg) Trial-COPERNICUS </li></ul><ul><li>6 RCT’s with > 9,000 pts already taking ACE-I showed a significant reduction in total mortality and sudden death (NNT 24, and 35 over 1-2 years) regardless of severity </li></ul><ul><li>Carvedilol vs. Metoprolol (COMET 2003) </li></ul><ul><ul><li>3029 pts; carvedilol 25mg bid vs. metoprolol 50 mg bid </li></ul></ul><ul><ul><li>Patient with NYHA Classes II-IV </li></ul></ul><ul><ul><li>Carvedilol –greater reduction in mortality (NNT, 18 over 5 years) and cardiovascular mortality (NNT, 16 over 5 years) than metoprolol but hypotension was greater in carvedilol (14 vs 11 percent) </li></ul></ul>
  24. 26. Initial and Target Doses of beta-blockers for HF Medication Starting Dose Target Dosage Bisoprolol 1.25mg daily 10mg daily Carvedilol 3.125mg bid 25mg bid Metoprolol CR/XL 12.5-25mg daily 200mg daily
  25. 27. Aldosterone Antagonists <ul><li>Spironolactone (Aldactone; RALES 1999) </li></ul><ul><ul><li>Pts 1,663 Class III/IV, ACE, Loop,Dig, EF < 35% </li></ul></ul><ul><ul><li>Decreased all cause mortality of 30%, NNT=10 </li></ul></ul><ul><ul><li>Hyperkalemia, gynecomastia </li></ul></ul><ul><li>Eplerenone (Inspra; EPHESUS 2003 ) </li></ul><ul><ul><li>Pts 6,642 asym LV dysfunction, DM, or after MI </li></ul></ul><ul><ul><li>Dec CV mortality of 13%, NNT=43 </li></ul></ul><ul><ul><li>Newer more selective inhibitor; fewer side effects </li></ul></ul><ul><ul><li>More pts on beta-blockers </li></ul></ul>
  26. 28. Hydralazine (Apresoline) and isosorbide dinitrate (Sorbitrate) <ul><li>Hydralazine </li></ul><ul><li>Reduces systemic vascular resistance by preferentially dilating arterioles </li></ul><ul><li>Isosorbide Dinitrate </li></ul><ul><li>Preferential Venodilator-reduces ventricular filling pressure and treat pulmonary congestion </li></ul><ul><li>Reduces mortality – upto 28% </li></ul><ul><li>Poor tolerability->30% drop out of study </li></ul><ul><li> flushing, headaches, gi upset, less frequently can cause positive ANA titers and lupus-like syndrome </li></ul>
  27. 29. Hydralazine (Apresoline) and isosorbide dinitrate (Sorbitrate) <ul><li>African-American Heart Failure Trial (A-HeFT) </li></ul><ul><ul><li>advanced HF and a fixed dose of isosorbide dinitrate and hydralazine </li></ul></ul><ul><ul><li>Added to Standard B-blocker/Ace-I therapy </li></ul></ul><ul><ul><li>Some survival improvement </li></ul></ul>
  28. 30. Digoxin <ul><li>May relieve symptoms, does not reduce mortality </li></ul><ul><li>Pts taking digoxin are less likely to be hospitalized (25% reduction) </li></ul><ul><li>More admissions for suspected digoxin toxicity </li></ul>
  29. 31. Loop Diuretics <ul><li>Mainstay of symptomatic treatment </li></ul><ul><ul><li>Improve fluid retention </li></ul></ul><ul><ul><li>Increase exercise tolerance </li></ul></ul><ul><ul><li>No effects on morbidity or mortality </li></ul></ul>
  30. 32. Antiplatelet Therapy and Anticoagulation <ul><li>Increased risk of Thromboembolic events, 1.6-3.2% per year </li></ul><ul><li>Antiplatelet therapy (aspirin) in not useful in patient in sinus rhythm </li></ul><ul><li>Coumadin for patient with atrial fibrillation or a previous thromboembolic event </li></ul>
  31. 33. Nesiritide (Natrecor) <ul><li>Recombinant form of human BNP </li></ul><ul><li>Causes venous and arterial vasodilation </li></ul><ul><ul><li>has been shown to improve dyspnea and global assessments at 3 hours after initiation in pts with Acute HF. </li></ul></ul><ul><ul><li>Risks- deleterious effect on renal function and decreased 30 day survival </li></ul></ul>
  32. 34. Nonpharmacological Management <ul><li>Sodium Restriction to 2g/day </li></ul><ul><li>Risk Factor Management </li></ul><ul><li>Exercise </li></ul><ul><ul><li>Decreases mortality (NNT=4) </li></ul></ul><ul><ul><li>Decreases hospitalizations (NNT=5) </li></ul></ul><ul><li>Multidisciplinary, Disease-Management Approach </li></ul><ul><ul><li>CHAMP – Cardiovascular Hospital Atherosclerosis Management Program </li></ul></ul><ul><ul><li>ASA, beta-blocker, Nitrates, ACE-I, Statin, Exercise, Smoking Cessation, Dietary counseling (use increased by 80%) </li></ul></ul>
  33. 35. Device Therapy <ul><li>Implantable Cardioverter-Defibrillators (ICD) </li></ul><ul><li>Cardiac Resynchronization Therapy (CRT) </li></ul><ul><li>Left Ventricular Assist Devices (LVAD) </li></ul>
  34. 36. ICD <ul><li>SCD-HeFT (sudden cardiac death) </li></ul><ul><li>2521 patients with depressed LV systolic function and Class II-III HF </li></ul><ul><li>Randomized to standard therapy vs. standard therapy plus ICD vs. standard therapy plus amiodarone </li></ul><ul><li>23% reduction in mortality with ICD </li></ul><ul><li>No difference in mortality with amiodarone </li></ul><ul><li>Results did not vary based on etiology of LV dysfunction </li></ul>
  35. 37. ICD <ul><li>Recommended in pts with EF<30% and mild to moderate symptoms of HF </li></ul><ul><li>Survival with good functional capacity is anticipated for > 1 year </li></ul>
  36. 38. CRT <ul><li>COMPANION Trial </li></ul><ul><li>1520 patients most with Class III-IV HF, QRS duration >120 ms </li></ul><ul><li>Randomized in 1:2:2 ratio to standard therapy vs standard therapy plus CRT vs standard therapy plus CRT with device that also defibrillated </li></ul><ul><li>34% reduction in death or any hospitalization with CRT </li></ul><ul><li>40% reduction when combined with ICD </li></ul>
  37. 39. Left Ventricular Assist Devices (LVAD) <ul><li>REMATCH Trial- </li></ul><ul><li>1 yr survival 52% (LVAD) vs 24% (rx) </li></ul><ul><li>2 yr survival 23% vs 8% </li></ul><ul><li>End-Stage (Class IV) </li></ul><ul><li>HF pts ineligible for transplant due to: </li></ul><ul><ul><li>>65yo </li></ul></ul><ul><ul><li>DM with EOD </li></ul></ul><ul><ul><li>CRI </li></ul></ul>
  38. 41. Diastolic Dysfunction <ul><li>Acute Management is the SAME </li></ul><ul><li>Chronic Management is CONTROVERSIAL </li></ul><ul><ul><li>Diuretics-dec fluid volume </li></ul></ul><ul><ul><li>CCB-promote left ventricular relaxation </li></ul></ul><ul><ul><li>ACE-I-promote regression of left ventricular hypertrophy </li></ul></ul><ul><ul><li>Beta-blockers/antiarrhytmic agents-control heart rate or maintain atrial contraction </li></ul></ul>
  39. 42. <ul><li>QUESTIONS? </li></ul>
  40. 43. Recent Inservice Exam Questions <ul><li>1. Which one of the following is considered a contraindication to the use of beta-blockers for congestive heart failure? </li></ul><ul><ul><li>A) Mild Asthma </li></ul></ul><ul><ul><li>B) Symptomatic Heart Block </li></ul></ul><ul><ul><li>C) New York Heart Association (NYHA) Class III heart failure </li></ul></ul><ul><ul><li>D) NYHA Class I heart failure in a patient with a history of a previous myocardial infarction </li></ul></ul><ul><ul><li>E) An ejection fraction <30% </li></ul></ul>
  41. 44. <ul><li>1. Answer B </li></ul><ul><li>According to several randomized, controlled trial, mortality rates are improved in patient with heart failure who receive beta blockers in addition to diuretics, ACE inhibitors, and occasionally, digoxin. Contraindications to beta blocker use include hemodynamic instability, heart block, bradycardia, and severe asthma. Beta-blockers may be tried in patients with mild asthma or COPD as long as them are monitored for potential exacerbations. B-blocker use has been shown to be effective in patient with NYHA Class II or III heart failure. There is no absolute threshold ejection fraction . B-blockers have also been shown to decrease mortality in patients with a previous history of myocardial infarction, regardless of their NYHA classification </li></ul>
  42. 45. <ul><li>2. Which one of the following serologic tests would be the most helpful for detecting left ventricular dysfunction? </li></ul><ul><ul><li>A) B -type natriuetic peptide (BNP) </li></ul></ul><ul><ul><li>B) Troponin-T </li></ul></ul><ul><ul><li>C) C-reactive protein (CRP) </li></ul></ul><ul><ul><li>D) D dimer </li></ul></ul><ul><ul><li>E) Cardiac interleukin-2 </li></ul></ul>
  43. 46. <ul><li>2. Answer A. </li></ul><ul><li>Β NP is a 32-amino acid polypeptide secreted from the cardiac ventricles in response to ventricular volume expansion and pressure overload. The major source of BNP is the cardiac ventricles, and because of its minimal presence in storage granules, its release is directly proportional to ventricular dysfunction. It is a simple and rapid test that reliably predicts the prescence or absence of heart failure. </li></ul>
  44. 47. <ul><li>3. Which one of the following is a risk factor for perioperative arrhythmias? </li></ul><ul><ul><li>A) Supraventricular Tachycardia </li></ul></ul><ul><ul><li>B) Congestive Heart Failure </li></ul></ul><ul><ul><li>C) Age >60 </li></ul></ul><ul><ul><li>D) Premature Atrial Contractions </li></ul></ul><ul><ul><li>E) Past history of hyperthyroidism </li></ul></ul>
  45. 48. <ul><li>3. Answer B </li></ul><ul><li>Significant predictors of intraoperative and perioperative ventricular arrhythmias include preoperative ventricular (not supraventricular) ectopy, CHF, and tobacco use. Age and history of hyperthyroidism are not significant predictors of perioperative ventricular arrhythmias. </li></ul>
  46. 49. <ul><li>4. Which one of the following is preferred for chronic treatment of congestive heart failure due to left ventricular systolic dysfunction? </li></ul><ul><ul><li>A) Diuretics </li></ul></ul><ul><ul><li>B) Digoxin </li></ul></ul><ul><ul><li>C) Calcium Channel Blockers </li></ul></ul><ul><ul><li>D) ACE inhibitors </li></ul></ul><ul><ul><li>E) Hydralazine (Apresoline) plus isosorbide dinitrate (Isordil, Sorbitrate) </li></ul></ul>
  47. 50. <ul><li>4. Answer D </li></ul><ul><ul><li>ACE-I are the preferred drugs for CHF due to LV systolic dysfunction, because they are associated with the lowest mortality. The combination of hydralazine/isosorbide dinitrate is a reasonable alternative, and diuretics should be used cautiously. It is not known whether Digoxin affects mortality, although it can help with symptoms. </li></ul></ul>
  48. 51. <ul><li>5. A 72-year-old male with class III CHF due to systolic dysfunction asks if he can take ibuprofen for his “aches and pains.” </li></ul>
  49. 52. <ul><ul><li>A) NSAIDs are a good choice for pain relief, as they decrease systemic vascular resistance </li></ul></ul><ul><ul><li>B) NSAIDs are a good choice for pain relief, as they augment the effect of his diuretic </li></ul></ul><ul><ul><li>C) High-dose aspirin (325mg/day) is preferable to other NSAIDs for patients talking ACE-I </li></ul></ul><ul><ul><li>D) NSAIDs, including high-dose aspirin, should be avoided in CHF patient because they can cause fluid retention </li></ul></ul>
  50. 53. <ul><li>5. Answer D </li></ul><ul><ul><li>If possible, NSAIDs should be avoided in patients with heart failure. They cause sodium and water retention, as well as an increase in systemic vascular resistance which may lead to cardiac decompensation. NSAIDs may negate or decrease entirely the beneficial unloading effects of ACE inhibition. </li></ul></ul>
  51. 54. References <ul><li>REFERENCES : 1  Hunt S.A.,  Baker D.W.,  Chin M.H.,  Cinquegrani M.P.,  Feldman A.M.,  Francis G.S.,  Ganiats T.G.,  Goldstein S.,  Gregoratos G.,  Jessup M.L,  ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure) . J Am Coll Cardiol (2001) 38 : pp 2101-2113 .   </li></ul><ul><li>2  Packer M.,  Cohn J.N.,  Consensus recommendations for the management of chronic heart failure . Am J Cardiol (1999) 83 : pp 1A-38A . 3  Pitt B.,  Williams G.,  Remme W.,  Martinez F.,  Lopez-Sendon J.,  Zannad F.,  Neaton J.,  Roniker B.,  Hurley S.,  Burns D,  The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction Eplerenone Post-AMI Heart Failure Efficacy and Survival Study . Cardiovasc Drugs Ther (2001) 15 : pp 79-87 .   4  Pitt B.,  Zannad F.,  Remme W.J.,  Cody R.,  Castaigne A.,  Perez A.,  Palensky J.,  Wittes J.,  The effect of spironolactone on morbidity and mortality in patients with severe heart failure Randomized Aldactone Evaluation Study Investigators . N Engl J Med (1999) 341 : pp 709-717 .   </li></ul><ul><li>5  SOLVD Investigators Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure The SOLVD Investigators . N Engl J Med (1991) 325 : pp 293-302 .     </li></ul>
  52. 55. <ul><li>  CONSENSUS Trial Study Group Effects of enalapril on mortality in severe congestive heart failure Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group . N Engl J Med (1987) 316 : pp 1429-1435 .   7  Hjalmarson A.,  Goldstein S.,  Fagerberg B.,  Wedel H.,  Waagstein F.,  Kjekshus J.,  Wikstrand J.,  El Allaf D.,  Vitovec J.,  Aldershvile J,  Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF) MERIT-HF Study Group . JAMA (2000) 283 : pp 1295-1302 .   8  CIBIS-II Investigators The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial . Lancet (1999) 353 : pp 9-13 .   9  Packer M.,  Bristow M.R.,  Cohn J.N.,  Colucci W.S.,  Fowler M.B.,  Gilbert E.M.,  Shusterman N.H.,  The effect of carvedilol on morbidity and mortality in patients with chronic heart failure U.S. Carvedilol Heart Failure Study Group . N Engl J Med (1996) 334 : pp 1349-1355 .   10  Packer M.,  Fowler M.B.,  Roecker E.B.,  Coats A.J.,  Katus H.A.,  Krum H.,  Mohacsi P.,  Rouleau J.L.,  Tendera M.,  Staiger C,  Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study . Circulation (2002) 106 : pp 2194-2199 .   </li></ul>
  53. 56. <ul><li>11  Fonarow G., Gheorghiade, M., Abraham, W., Importance of In-Hospital Initiabtion of Evidence-Based Medical Therapies for Heart Failure-A Review. J Am Coll Cardiol (2004) 94 : pp 1155-1159 </li></ul><ul><li>12 Chavey WE 2 nd , The Importance of Beta Blocker in the Treatment of Heart Failure Am Fam Physician - (2000) 62(11): 2453-62  </li></ul>

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