Evidence-based management of CHF

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Evidence that supports the current management of Chronic Systolic Heart Failure.

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Evidence-based management of CHF

  1. 1. Evidence-based medicine: The CHF trials Moises Auron MD Department of Hospital Medicine Cleveland Clinic Foundation September 21, 2007.
  2. 2. Objectives <ul><li>Recognize the evidence supporting the current approach to Chronic Heart Failure (CHF) treatment as an important factor to decrease mortality and improve survival. </li></ul><ul><li>Review each of the most important trials for pharmacologic therapy of CHF. </li></ul>
  3. 3. Epidemiology <ul><li>Prevalence  5 million Americans with chronic heart failure; at age 40, lifetime risk of developing HF is 20% </li></ul><ul><li>Incidence 550,000 new cases/year </li></ul><ul><li>Morbidity 1,099,000 hospital discharges (2004) –rose from 399,000 (1979); Most frequent cause of hospitalization in elderly </li></ul><ul><li>Mortality Causes or contributes to 286,000 deaths/year </li></ul><ul><li>Cost $33.2 billion (2007); $5,912 per Medicare discharge (2001) </li></ul>- AHA: Heart Disease and Stroke Statistics - 2007 Update. Circulation. 2007; 115. - Circulation 2004;109:2685–2691.
  4. 4. Cardiorenal Model of HF (1940-1960) Am J Cardiol 1993; 71: 3C-11C
  5. 5. <ul><li>Diuretics </li></ul><ul><li>Digitalis </li></ul>Am J Cardiol. 1993;71:3C-11C Cardiorenal Model of HF (1940-1960)
  6. 6. Cardiocirculatory Model of HF (1960 – 1990) Am J Cardiol 1993; 71: 3C-11C
  7. 7. <ul><li>Vasodilators </li></ul><ul><ul><li>V-HeFT 1 (Hydralazine + Nitrate) </li></ul></ul><ul><li>Inotropic agents </li></ul>Cardiocirculatory Model of HF (1960 – 1990) Am J Cardiol. 1993;71:3C-11C
  8. 8. Vasodilators in Heart Failure <ul><li>Rationale for use of organic nitrates and hydralazine in combination: complementary &quot;nitroprusside-like&quot; hemodynamic effect </li></ul><ul><ul><li>Predominant venodilatory action of organic nitrates </li></ul></ul><ul><ul><li>Arterial-dilatory effect of hydralazine. </li></ul></ul><ul><ul><li>This combination leads to a significant improvement in cardiac function, with a concomitant reduction in right and left ventricular filling pressures and augmentation of cardiac output. </li></ul></ul>Am J Cardiol 2005 Oct 10;96(7B):37i-43i.
  9. 9. VHeFT-I (Vasodilator-Heart Failure Trial) African-american patients White patients NEJM. 1986 Jun 12;314(24):1547-52. J Card Fail. 1999; 5(3):178-87 Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) vs. Prazosin (20 mg) vs. Placebo N = 642 (male) – on Digoxin and diuretics
  10. 10. Neurohormonal Model of HF (1980 – present) <ul><li>Heart failure developed and progressed: </li></ul><ul><ul><li>Endogenous neurohormonal systems activated by the initial injury to the heart </li></ul></ul><ul><ul><ul><li>Deleterious effects on the heart and circulation </li></ul></ul></ul><ul><ul><ul><li>Independent of the hemodynamic status of the patient. </li></ul></ul></ul>Am J Cardiol 1993; 71: 3C-11C
  11. 11. Biologically Active Substances in HF <ul><li>Renin-angiotensin-aldosterone system </li></ul><ul><li>Sympathetic nervous system </li></ul><ul><ul><li>Norepinephrine </li></ul></ul><ul><li>Vasodilators </li></ul><ul><ul><li>Bradykinin </li></ul></ul><ul><ul><li>Nitric oxide </li></ul></ul><ul><ul><li>Prostaglandins </li></ul></ul><ul><li>Natriuretic peptides </li></ul><ul><li>Cytokines </li></ul><ul><ul><li>Endothelin </li></ul></ul><ul><ul><li>Tumor necrosis factor </li></ul></ul><ul><ul><li>Interleukins </li></ul></ul><ul><li>Vasopressin </li></ul><ul><li>Matrix metalloproteinases </li></ul>NEJM. 2003; 348 (20): 2007-18 . NEJM. 1999; 341(8): 577-585.
  12. 12. From: Shrier, R. U. Colorado. 2004
  13. 13. Neurohormonal Model of Heart Failure Shah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6.
  14. 14. Renin – Angiotensin – Aldosterone System Modified from Swedberg K. ESC –Heart Failure Lisbon 2005.
  15. 15. Consequences of Neurohormonal Activation <ul><li>Maladaptive hypertrophy  energy starvation  necrosis </li></ul><ul><li>Apoptosis </li></ul><ul><li>Increased interstitial fibrosis </li></ul><ul><li>Myocyte elongation  progressive dilatation of the ventricle </li></ul>Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000 CARDIAC REMODELING
  16. 16. Alterations in Myocyte Morphology with Ventricular Dysfunction Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000 NEJM. 2003; 348: 2007-18 .
  17. 17. Cardiac hypertrophy From: Tornoci L. Semmelweis U.
  18. 18. CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study NEJM 1987; 316: 1429–35. N = 253 NYHA IV on diuretics and digoxin Enalapril 20 mg BID vs Placebo Probability of death
  19. 19. CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study NEJM 1987; 316: 1429–35.
  20. 20. ACEI Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145
  21. 21. ACEI Trials <ul><li>CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study </li></ul><ul><li>SOLV-D = Studies of Left Ventricular Dysfunction </li></ul><ul><li>ATLAS = Assessment of Treatment with Lisinopril And Survival Trial </li></ul><ul><li>SAVE = Survival and Ventricular Enlargement </li></ul><ul><li>AIRE = Acute Infarction Ramipril Efficacy </li></ul><ul><li>TRACE = Trandolapril Cardiac Evaluation </li></ul><ul><li>- NEJM 1987; 316: 1429-35. </li></ul><ul><li>Eur Heart J. 1999; 20(2):136-9. </li></ul><ul><li>- NEJM. 1991; 325: 293-302. </li></ul><ul><li>NEJM. 1992; 327: 685-91. </li></ul><ul><li>- Circulation 1999 Dec 7; 100(23):2312-8. </li></ul><ul><li>Eur Heart J 2000 Dec; 21(23):1967-78. </li></ul><ul><li>NEJM. 1992;327:669-77. </li></ul><ul><li>NEJM. 1995; 333: 1670-6. </li></ul><ul><li>Lancet. 1993; 342: 821-8. </li></ul>
  22. 22. ACE Inhibitors in HF <ul><li>Mortality ↓ 20%–25% (P< 0.001) </li></ul><ul><li>Death plus hospitalization ↓ 30%–35% </li></ul><ul><li> HOWEVER….. </li></ul><ul><li>~ 50% will still die within 5 years </li></ul><ul><li>30% may be rehospitalized for CHF within three months </li></ul>- JAMA. 1995;273:1450–1456 - AHA. 2001 Heart and Stroke Statistical Update. 2000 - Am J Cardiol. 1999;83(Suppl 2A):1A–39A.
  23. 23. <ul><li>804 men </li></ul><ul><li>Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) (ISDN-H) vs. Enalapril (20 mg). </li></ul><ul><li>Decrease in mortality after 2 years </li></ul><ul><ul><li>Enalapril group (18%) vs. ISDN-H group (25%) </li></ul></ul><ul><ul><li>28% reduction in mortality. ( P =0.016) </li></ul></ul><ul><ul><ul><li>African-American population benefit more from ISDN-H </li></ul></ul></ul>VHeFT-II (Vasodilator-Heart Failure Trial) N Engl J Med. 1991;325:303-310.
  24. 24. VHeFT-II (Vasodilator-Heart Failure Trial) J Card Fail. 1999; 5(3):178-87
  25. 25. Catecholamines in Heart Failure Am J Cardiol. 1984; 54: 783-6
  26. 26. Relationship between plasma NE and survival in Heart Failure NEJM. 1984: 311: 819-823.
  27. 27. Norepinephrine <ul><li>Stimulation of RAAS  further increase in sympathetic activation. </li></ul><ul><ul><li>Enhanced sodium and water retention, potassium loss, peripheral vasoconstriction, and oxidative tissue stress. </li></ul></ul><ul><li>Circulating catecholamines adversely affect cardiac structure and function. </li></ul><ul><ul><li>Desensitization (via G-protein uncoupling) and down-regulation of β 1-adrenergic receptors </li></ul></ul><ul><ul><li>Myocardial ischemia  Enhanced cardiomyocyte necrosis </li></ul></ul><ul><ul><li>Apoptosis. </li></ul></ul><ul><ul><li>Induce and potentiate cardiac arrhythmias mediated predominantly through β 2-adrenergic receptor stimulation. </li></ul></ul><ul><ul><li>Angiotensin II, aldosterone, and catecholamines also function as growth factors in paracrine fashion. </li></ul></ul><ul><ul><ul><li>Fibroblast activation and the induction of myocyte hypertrophy. </li></ul></ul></ul><ul><ul><ul><li>Increase in overall ventricular muscle mass and fibrous tissue. </li></ul></ul></ul>NEJM. 1999; 341(8): 577-585. Congest Heart Fail. 2002 Sep-Oct;8(5):262-9;
  28. 28. Potential effects of β -blockers in cardiac remodeling <ul><li>↓ Heart rate </li></ul><ul><li>↓ VO2 </li></ul><ul><li>Modulation of β-receptors </li></ul><ul><li>Protection from catecholamine toxicity </li></ul><ul><li>↓ RAAS </li></ul><ul><li>Anti-ischemic and anti-arrhythmic effect </li></ul><ul><li>Improvement in synthesis of myocardial proteins </li></ul><ul><li>Peripheral vasodilation </li></ul><ul><li>Decrease of heart work </li></ul><ul><li>Antioxidant action </li></ul><ul><li>Anti-inflammatory action </li></ul>Eur Rev Med Pharmacol Sci. 2002; 6: 115-126.
  29. 29. Sir James Black <ul><li>Nobel Prize 1988 </li></ul><ul><li>Discovery of Beta-blockers (Propranolol) </li></ul>
  30. 30. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). Lancet 1999; 353 (9169):2001-7. 34% P=0.0062 N = 3991 NYHA II-IV
  31. 31. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). Lancet 1999; 353 (9169):2001-7.
  32. 32. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). <ul><li>Post-hoc analysis in NYHA IV (n=795) </li></ul>J Am Coll Cardiol. 2001; 38:932.
  33. 33. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). <ul><li>Post-hoc analysis in NYHA IV (n=795) </li></ul>J Am Coll Cardiol. 2001; 38:932. <ul><li>Number of hospital days: 15 vs. 26 </li></ul>
  34. 34. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) NEJM 2001; 344(22): 1651-8. 35% (P = 0.0014) N = 2289 NYHA III-IV Carvedilol 25 mg BID vs. Placebo
  35. 35. Beta-Blockers: Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145 No difference (P= 0.16) Benefit in non-black patients All cause mortality Bucindolol 50 – 100 mg BID vs. placebo BEST (24 mos) Absolute risk ↓ 6% favor carvedilol (P= 0.0017) All-cause mortality Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID COMET (58 mos) Early termination. ↓ in mortality rate 38% (P < 0.001) All cause mortality, exercise tolerance, QOL. Carvedilol 25 – 50 mg BID vs. placebo US Carvedilol (6 mos) ↓ in overall mortality 35% (P = 0.0014). Not worsening HF when initiating Rx. All-cause mortality Carvedilol 25 mg BID vs. placebo COPERNICUS (10.4 mos) Early termination; ↓ in mortality 32% (P< 0.001) All-cause mortality Bisoprolol 10 mg/d vs. placebo CIBIS II (16 mos) Overall ↓ in mortality 34% (P = 0.0062) All-cause mortality Metoprolol succinate 200 mg Qday vs. placebo MERIT (12 mos)
  36. 36. Beta-Blockers: Trials <ul><li>MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in CHF </li></ul><ul><li>CIBIS: Cardiac Insufficiency Bisoprolol Study </li></ul><ul><li>COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival </li></ul><ul><li>COMET: Carvedilol or Metoprolol European Trial </li></ul><ul><li>United States Carvedilol Heart Failure Study Group </li></ul><ul><li>BEST: Beta-blocker Evaluation of Survival Trial (Bucindolol) </li></ul><ul><li>CAPRICORN: Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction </li></ul>Lancet 1999; 353 (9169):2001-7. J Am Coll Cardiol. 2001; 38:932. Lancet 1999 Jan 2;353(9146):9-13. Am Heart J 2002 Feb;143(2):301-7. Eur Heart J 2001 Jun; 22(12):1021-31. NEJM 2001; 344(22): 1651-8. Circulation 2002; 106(17):2194-9. Lancet 2003; 362(9377):7-13. Circulation 1996; 94:2793-9. Circulation 1996; 94:2800-6. Circulation 1996; 94:2807-16. NEJM 1996; 334:1349-55. Lancet. 2001;357:1385-90. NEJM 2001; 344(22):1659-67
  37. 37. COMET (Carvedilol or Metoprolol European Trial) Lancet 2003; 362(9377):7-13. 6% P= 0.017 Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID N = 3029 NYHA II-IV
  38. 38. Not all Beta Blocker are the Same!!! <ul><li>BEST Trial (Bucindolol) </li></ul><ul><li>COMET Trial (Metoprolol Tartrate vs Carvedilol) </li></ul><ul><li>Atenolol - not proven in heart failure </li></ul><ul><li>Labetalol – not proven in heart failure </li></ul><ul><li>Metoprolol Tartrate – no trials showing increased survival compared to placebo </li></ul>
  39. 39. Treatment Strategies Amer. J. Cardiol. 1993;71:3C-11C
  40. 40. Neurohormones in HF: Aldosterone <ul><li>↑ 20-fold in CHF </li></ul><ul><li>Aldosterone escape phenomenon </li></ul><ul><li>As well secretion can be independent of [AT II] </li></ul><ul><li>Extraadrenal production </li></ul><ul><ul><li>Endothelial cells </li></ul></ul><ul><ul><li>Vascular smooth muscle in the heart and blood vessels </li></ul></ul>NEJM. 1999; 341(8): 577-585. Int J Clin Pract. 2006 Jul;60(7):835-46. NEJM. 2001 Dec; 345(23): 1689-1697.
  41. 41. Neurohormones in HF: Aldosterone NEJM. 1999; 341(8): 577-585. Int J Clin Pract. 2006 Jul;60(7):835-46. NEJM. 2001 Dec; 345(23): 1689-1697.
  42. 42. RALES (Randomized Aldactone® Evaluation Study) 34% (P = 0.001) <ul><ul><li>N = 1664 </li></ul></ul><ul><ul><li>Class IV or class III (EF < 35%) with hx. < 6 mos of class IV CHF </li></ul></ul><ul><ul><li>Spironolactone 25 mg/d vs. placebo </li></ul></ul><ul><li>- Am J Cardiol 1996 Oct 15; 78(8):902-7. </li></ul><ul><li>NEJM 1999; Sep 2; 341(10):709-17. </li></ul><ul><li>NEJM 2003; Apr 3; 348(14):1309-21. </li></ul>
  43. 43. EPHESUS (Eplerenone In Heart Failure Post Acute Myocardial Infarction) NEJM 2003; Apr 3; 348(14):1309-21. <ul><ul><li>N= 6642 </li></ul></ul><ul><ul><li>MI < 2 wk; EF < 40% with evidence of HF and/or DM. </li></ul></ul><ul><ul><li>Eplerenone 50 mg/d vs. placebo </li></ul></ul>
  44. 44. <ul><li>ACC/AHA guidelines - Spironolactone 25-50 mg-day in: </li></ul><ul><ul><li>NYHA IV </li></ul></ul><ul><ul><li>Creatinine < 2.5 mg/dL </li></ul></ul><ul><ul><li>Serum potassium < 5 mEq/L. </li></ul></ul><ul><li>Endocrine side effects: gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido </li></ul><ul><ul><li>Non-selective binding to androgen and progesterone receptors. </li></ul></ul>RALES (Randomized Aldactone® Evaluation Study) - Am J Cardiol 1996 Oct 15; 78(8):902-7. - NEJM 1999; Sep 2; 341(10):709-17.
  45. 45. Neurohormones in HF: Angiotensin II <ul><li>High mortality in CHF patients despite being on ACEI and BB </li></ul><ul><li>Potent vasoconstrictor and growth-stimulating hormone </li></ul><ul><li>May contribute to the impairment of left ventricular function and the progression of heart failure: </li></ul><ul><ul><li>increased impedance of left ventricular emptying </li></ul></ul><ul><ul><li>adverse long-term structural effects on the heart and vasculature </li></ul></ul><ul><ul><li>activation of other neurohormones (NE, ET1, aldosterone) </li></ul></ul><ul><li>Physiologically active levels in patient on ACEI </li></ul><ul><ul><li>Incomplete supression of ATII production </li></ul></ul><ul><li>Intolerance to ACEI (cough due to increase in bradykinins). </li></ul><ul><ul><li>Needs an alternative therapeutic choice </li></ul></ul>NEJM. 1999; 341(8): 577-585. ACC/AHA Heart Failure Guidelines 2005.
  46. 46. Angiotensin II Receptor Blockage: Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145 Absolute risk ↓ 7% (P<0.001) Trend toward lower all-cause mortality (P= 0.11) CV death or hospitalization for heart failure Candesartan 32 mg/d vs. placebo N = 2028 NYHA II-IV EF < 40% Intolerance to ACEI CHARM – Alternative (33.7 mos) Absolute risk ↓ 4% (P=0.011) Trend toward lower all-cause mortality (P= 0.086) CV death or hospitalization for heart failure Candesartan 32 mg/d vs. placebo N = 2548 NYHA II-IV EF < 40% On ACEI CHARM-Added (41 mos) Similar mortality (P > 0.2) Absolute risk ↓3.3% (P<0.002) in composite end-point. (Decreased admissions) ↑ LVID ↓EF  ↑ Benefit All-cause mortality; mortality or cardiac arrest or hospitalization for HF Valsartan 160 mg BID vs. Placebo N = 5010 NYHA II-IV EF < 40%; LV dilatation Val-HeFT (23 mos) No superiority of one agent vs. other (P = 0.16) All-cause mortality Losartan 50 mg/d vs. Captopril 50 mg TID. N = 3152 Age > 60 y/o NYHA II-IV EF < 40% ELITE II (18.5 mos)
  47. 47. <ul><li>ELITE: Evaluation of Losartan in the Elderly </li></ul><ul><li>Val-HeFT: Valsartan heart failure trial </li></ul><ul><li>CHARM: Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity </li></ul>Angiotensin II Receptor Blockage: Trials Lancet. 1997;349: 747-52. Lancet. 2000;355: 1582-7. NEJM 2001 Dec 6; 345(23):1667-75. Circulation 2002 Nov 5; 106(19):2454-8. J Am Coll Cardiol 2004 Jun 2; 43(11):2022-7. Lancet 2003; Sep 6; 362(9386):759-66. Lancet 2003; Sep 6; 362(9386):767-71. Circulation 2004 Oct 12; 110(15):2180-3.
  48. 48. Vasodilators in Heart Failure <ul><li>V-HeFT I showed improvements in LVEF, exercise tolerance, and survival in patients treated with isosorbide dinitrate and hydralzaine compared with placebo. </li></ul><ul><li>Retrospective analysis of V-HeFT I and V-HeFT II showed that the benefit of this combination was seen mainly in African Americans. </li></ul><ul><li>This observation led to the African American Heart Failure Trial (A-HeFT). </li></ul><ul><li>Concomitant use of hydralazine with a nitrate, both in an animal model and in patients with CHF, has been shown to prevent the development of nitrate tolerance and maintain the favorable hemodynamic effect of nitrates. </li></ul>Am J Cardiol. 2005 Oct 10;96(7B):37i-43i.
  49. 49. Vasodilators in Heart Failure: Hydralazine and Isosorbide NEJM. 2004; 351(20): 2112-2114
  50. 50. AHeF-T (African-American Heart Failure Trial) <ul><li>NEJM 2004; 351 (20): 2049-57 </li></ul><ul><li>Am J Cardiol 2005; 96 (suppl): 44i– 48i </li></ul>
  51. 51. <ul><li>Compared with V-HeFT </li></ul><ul><ul><li>H+I added to conventional CHF treatment. </li></ul></ul><ul><li>Post-Hoc analysis </li></ul><ul><ul><li>Beta-blocker increases survival in AA. </li></ul></ul>AHeF-T (African-American Heart Failure Trial) Congest H Fail. 2004; 10(1):34-7
  52. 52. Summary of Major Therapeutic Options for Systolic Heart Failure 2005 ACC/AHA Guidelines.
  53. 53. Stages of Heart Failure and Treatment options NEJM 2003; 348 (20): 2007-18.
  54. 54. Other research endeavors in CHF <ul><li>Stem cell transplantation </li></ul><ul><li>Ultrafiltration (UNLOAD) - Completed </li></ul><ul><li>Vasopressin antagonists </li></ul><ul><ul><li>Acute and Chronic Therapeutic Impact of Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF) </li></ul></ul><ul><ul><li>SALT ( Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) - Completed </li></ul></ul><ul><ul><li>EVEREST </li></ul></ul><ul><li>Thyroid hormone analog </li></ul><ul><ul><li>(3,5- diiodothyropropionic acid [DITPA]) </li></ul></ul><ul><li>Endothelin receptors antagonists </li></ul><ul><li>Neutral endopeptidase inhibitors </li></ul><ul><li>Metalloproteinases inhibitors </li></ul>Pediatr Cardiol. 2006 Sep-Oct; 27(5): 533-51.

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