Evidence-based management of CHF

Evidence-based medicine: The CHF trials Moises Auron MD Department of Hospital Medicine Cleveland Clinic Foundation September 21, 2007.

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.

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.

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)

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

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.

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

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

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.

From: Shrier, R. U. Colorado. 2004

Neurohormonal Model of Heart Failure Shah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6.

Renin – Angiotensin – Aldosterone System Modified from Swedberg K. ESC –Heart Failure Lisbon 2005.

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

Alterations in Myocyte Morphology with Ventricular Dysfunction Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000 NEJM. 2003; 348: 2007-18 .

Cardiac hypertrophy From: Tornoci L. Semmelweis U.

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

CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study NEJM 1987; 316: 1429–35.

ACEI Trials Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145

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.

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.

VHeFT-II (Vasodilator-Heart Failure Trial) J Card Fail. 1999; 5(3):178-87

Catecholamines in Heart Failure Am J Cardiol. 1984; 54: 783-6

Relationship between plasma NE and survival in Heart Failure NEJM. 1984: 311: 819-823.

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;

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.

Sir James Black

Nobel Prize 1988

Discovery of Beta-blockers (Propranolol)

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

MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). Lancet 1999; 353 (9169):2001-7.

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.

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

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

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)

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

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

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

Treatment Strategies Amer. J. Cardiol. 1993;71:3C-11C

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.

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.

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.

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.

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.

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.

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.

Vasodilators in Heart Failure: Hydralazine and Isosorbide NEJM. 2004; 351(20): 2112-2114

AHeF-T (African-American Heart Failure Trial)