Evidence-based management of CHF

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    Evidence-based management of CHF - Presentation Transcript

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

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