Evidence Based Approach in Congestive Heart Failure

Evidence-based Evidence-based medicine: The CHF medicine: The CHF

trialstrialsMoises Auron MDMoises Auron MD

Department of Hospital MedicineDepartment of Hospital MedicineCleveland Clinic Foundation Cleveland Clinic Foundation

September 21, 2007. September 21, 2007.

ObjectivesObjectives

Recognize the evidence supporting the Recognize the evidence supporting the current approach to Chronic Heart current approach to Chronic Heart Failure (CHF) treatment as an Failure (CHF) treatment as an important factor to decrease mortality important factor to decrease mortality and improve survival.and improve survival.

Review each of the most important Review each of the most important trials for pharmacologic therapy of trials for pharmacologic therapy of CHF.CHF.

Review the current alternatives for Review the current alternatives for treatment of CHF in children.treatment of CHF in children.

EpidemiologyEpidemiology PrevalencePrevalence 5 million Americans with chronic heart 5 million Americans with chronic heart

failure; at failure; at age 40, lifetime risk of developing HF age 40, lifetime risk of developing HF is 20%is 20%

IncidenceIncidence 550,000 new cases/year550,000 new cases/year

MorbidityMorbidity 1,099,000 hospital discharges (2004) –rose 1,099,000 hospital discharges (2004) –rose from from 399,000 (1979); Most frequent cause of 399,000 (1979); Most frequent cause of

hospitalization in elderlyhospitalization in elderly

MortalityMortality Causes or contributes to 286,000 deaths/yearCauses or contributes to 286,000 deaths/year

Cost Cost $33.2 billion (2007); $5,912 per Medicare $33.2 billion (2007); $5,912 per Medicare discharge discharge (2001)(2001)

- AHA: Heart Disease and Stroke Statistics - 2007 Update. - AHA: Heart Disease and Stroke Statistics - 2007 Update. Circulation. 2007; 115. Circulation. 2007; 115. - Circulation 2004;109:2685–2691. - Circulation 2004;109:2685–2691.

Cardiorenal Model of HFCardiorenal Model of HF(1940-1960)(1940-1960)

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

DiureticsDiuretics DigitalisDigitalis

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

Cardiorenal Model of HFCardiorenal Model of HF(1940-1960)(1940-1960)

Cardiocirculatory Model Cardiocirculatory Model of HFof HF

(1960 – 1990)(1960 – 1990)

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

Vasodilators Vasodilators V-HeFT 1 (Hydralazine + Nitrate)V-HeFT 1 (Hydralazine + Nitrate)

Inotropic agentsInotropic agents

Cardiocirculatory Model Cardiocirculatory Model of HFof HF

(1960 – 1990)(1960 – 1990)


Initial insights: Initial insights: Vasodilators in Heart Vasodilators in Heart

FailureFailure Rationale for use of organic nitrates and Rationale for use of organic nitrates and

hydralazine in combination: hydralazine in combination: complementary complementary "nitroprusside-like" hemodynamic effect"nitroprusside-like" hemodynamic effect Predominant venodilatory action of organic Predominant venodilatory action of organic

nitrates nitrates Arterial-dilatory effect of hydralazine.Arterial-dilatory effect of hydralazine. This combination leads to a significant This combination leads to a significant

improvement in cardiac function, with a improvement in cardiac function, with a concomitant reduction in right and left concomitant reduction in right and left ventricular filling pressures and augmentation ventricular filling pressures and augmentation of cardiac output. of cardiac output.

Am J Cardiol. 2005 Oct Am J Cardiol. 2005 Oct 10;96(7B):37i-43i. 10;96(7B):37i-43i.

African-american African-american patientspatients

White White patientspatients

NEJM. 1986 Jun 12;314(24):1547-52.NEJM. 1986 Jun 12;314(24):1547-52.J Card Fail. 1999; 5(3):178-87J Card Fail. 1999; 5(3):178-87

VHeFT-I (Vasodilator-Heart VHeFT-I (Vasodilator-Heart Failure Trial)Failure Trial)

Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) vs. Prazosin (20 mg) vs. Prazosin (20 mg) vs. Placebovs. Placebo

N = 642 (male) – on Digoxin and diureticsN = 642 (male) – on Digoxin and diuretics

804 men804 men Hydralazine (300 mg) + Isosorbide Hydralazine (300 mg) + Isosorbide

dinitrate (160 mg) (ISDN-H) vs. dinitrate (160 mg) (ISDN-H) vs. Enalapril (20 mg).Enalapril (20 mg).

Decrease in mortality after 2 years Decrease in mortality after 2 years Enalapril group (18%) vs. ISDN-H group Enalapril group (18%) vs. ISDN-H group

(25%) (25%) 28% reduction in mortality. (28% reduction in mortality. (PP=0.016)=0.016)

African-American population benefit more from African-American population benefit more from ISDN-HISDN-H

VHeFT-II (Vasodilator-Heart VHeFT-II (Vasodilator-Heart Failure Trial)Failure Trial)

N Engl J Med. 1991;325:303-N Engl J Med. 1991;325:303-310. 310.

VHeFT-II VHeFT-II (Vasodilator-Heart (Vasodilator-Heart Failure Trial)Failure Trial)

J Card Fail. 1999; 5(3):178-87J Card Fail. 1999; 5(3):178-87

Vasodilators in Heart Vasodilators in Heart FailureFailure

V-HeFT I showed improvements in LVEF, exercise V-HeFT I showed improvements in LVEF, exercise tolerance, and survival in patients treated with tolerance, and survival in patients treated with isosorbide dinitrate and hydralzaine compared with isosorbide dinitrate and hydralzaine compared with placebo. placebo.

Retrospective analysis of V-HeFT I and V-HeFT II Retrospective analysis of V-HeFT I and V-HeFT II showed that the benefit of this combination was showed that the benefit of this combination was seen mainly in African Americans. seen mainly in African Americans.

This observation led to the African American Heart This observation led to the African American Heart Failure Trial (A-HeFT).Failure Trial (A-HeFT).

Concomitant use of hydralazine with a nitrate, both Concomitant use of hydralazine with a nitrate, both in an animal model and in patients with CHF, has in an animal model and in patients with CHF, has been shown to prevent the development of nitrate been shown to prevent the development of nitrate tolerance and maintain the favorable hemodynamic tolerance and maintain the favorable hemodynamic effect of nitrates. effect of nitrates. Am J Cardiol. 2005 Oct Am J Cardiol. 2005 Oct

10;96(7B):37i-43i. 10;96(7B):37i-43i.

Vasodilators in Heart Failure: Vasodilators in Heart Failure: Hydralazine and IsosorbideHydralazine and Isosorbide

NEJM. 2004; 351(20): NEJM. 2004; 351(20): 2112-21142112-2114

AHeF-T (African-American AHeF-T (African-American Heart Failure Trial)Heart Failure Trial)

NEJM 2004; 351 (20): 2049-57NEJM 2004; 351 (20): 2049-57-Am J Cardiol 2005; 96 (suppl): 44i– 48iAm J Cardiol 2005; 96 (suppl): 44i– 48i

Compared with V-HeFTCompared with V-HeFT H+I added to conventional CHF H+I added to conventional CHF

treatment. treatment. Post-Hoc analysisPost-Hoc analysis

Beta-blocker increases survival in AA.Beta-blocker increases survival in AA.

AHeF-T AHeF-T (African-American (African-American Heart Failure Trial)Heart Failure Trial)

Congest H Fail. 2004; Congest H Fail. 2004; 10(1):34-710(1):34-7

Neurohormonal Model of Neurohormonal Model of HFHF

(1980 – present)(1980 – present) Heart failure developed and progressed:Heart failure developed and progressed:

Endogenous neurohormonal systems Endogenous neurohormonal systems activated by the initial injury to the heart activated by the initial injury to the heart Deleterious effects on the heart and circulationDeleterious effects on the heart and circulation Independent of the hemodynamic status of the Independent of the hemodynamic status of the

patient.patient.

Amer J Cardiol 1993; 71: 3C-11CAmer J Cardiol 1993; 71: 3C-11C

Neurohumoral Neurohumoral modification in HFmodification in HF

Renin-angiotensin-Renin-angiotensin-aldosterone systemaldosterone system

Sympathetic nervous Sympathetic nervous systemsystem NorepinephrineNorepinephrine

Vasodilators Vasodilators BradykininBradykinin Nitric oxideNitric oxide ProstaglandinsProstaglandins

Natriuretic Natriuretic peptidespeptides

Cytokines Cytokines EndothelinEndothelin Tumor necrosis Tumor necrosis

factorfactor InterleukinsInterleukins

VasopressinVasopressin Matrix Matrix

metalloproteinasesmetalloproteinasesNEJM. 2003; 348 (20): 2007-NEJM. 2003; 348 (20): 2007-1818..NEJM. 1999; 341(8): 577-NEJM. 1999; 341(8): 577-585.585.

From: Shrier, R. U. Colorado. From: Shrier, R. U. Colorado. 20042004

Neurohormonal Model of Heart Failure

Shah M et al. RevShah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6.Cardiovasc Med. 2001; 2 (suppl 2): S2–S6.

Renin – Angiotensin – Renin – Angiotensin – Aldosterone SystemAldosterone System

Modified from Swedberg K. ESC –Heart Modified from Swedberg K. ESC –Heart Failure Lisbon 2005. Failure Lisbon 2005.

Catecholamines in Heart Catecholamines in Heart FailureFailure

Am J Cardiol. 1984; 54: Am J Cardiol. 1984; 54: 783-6783-6

Relationship between Relationship between plasma NE and survival in plasma NE and survival in

Heart FailureHeart Failure

NEJM. 1984: 311: 819-NEJM. 1984: 311: 819-823.823.

CathecolaminesCathecolamines Stimulation of RAAS Stimulation of RAAS further increase further increase

in sympathetic activation.in sympathetic activation. Enhanced sodium and water Enhanced sodium and water

retention, potassium loss, peripheral retention, potassium loss, peripheral vasoconstriction, and oxidative tissue vasoconstriction, and oxidative tissue stress.stress.

NEJM. 1999; 341(8): 577-585.NEJM. 1999; 341(8): 577-585.Congest Heart Fail. 2002 Sep-Congest Heart Fail. 2002 Sep-Oct;8(5):262-9; Oct;8(5):262-9;

CathecolaminesCathecolamines Circulating catecholamines adversely affect Circulating catecholamines adversely affect

cardiac structure and function. cardiac structure and function. Desensitization (via G-protein uncoupling) Desensitization (via G-protein uncoupling)

and down-regulation of and down-regulation of ββ 1-adrenergic 1-adrenergic receptorsreceptors

Myocardial ischemia Myocardial ischemia Enhanced Enhanced cardiomyocyte necrosiscardiomyocyte necrosis

Apoptosis.Apoptosis. Induce and potentiate cardiac arrhythmias Induce and potentiate cardiac arrhythmias

mediated predominantly through mediated predominantly through ββ2-2-adrenergic receptor stimulation.adrenergic receptor stimulation.

Cardiac remodelingCardiac remodeling

Angiotensin II, aldosterone, and Angiotensin II, aldosterone, and catecholamines also function as growth catecholamines also function as growth factors in paracrine fashion. factors in paracrine fashion. Fibroblast activation and the Fibroblast activation and the

induction of myocyte hypertrophy.induction of myocyte hypertrophy. Increase in overall ventricular muscle Increase in overall ventricular muscle

mass and fibrous tissue. mass and fibrous tissue.

Consequences of Neurohormonal Consequences of Neurohormonal ActivationActivation

Maladaptive hypertrophy Maladaptive hypertrophy energy energy starvation starvation necrosis necrosis

ApoptosisApoptosis Increased interstitial fibrosisIncreased interstitial fibrosis Myocyte elongation Myocyte elongation progressive progressive

dilatation of the ventricledilatation of the ventricle

Katz, AM. Heart Failure. Lippincott Williams & Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000Wilkins, 2000

CARDIAC CARDIAC REMODELINGREMODELING

Alterations in Myocyte Morphology with Alterations in Myocyte Morphology with Ventricular DysfunctionVentricular Dysfunction

Katz, AM. Heart Failure. Lippincott Williams & Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000Wilkins, 2000NEJM. 2003; 348: 2007-18NEJM. 2003; 348: 2007-18..

Cardiac hypertrophyCardiac hypertrophy

From: Tornoci L. Semmelweis U. From: Tornoci L. Semmelweis U.

CONSENSUS: Cooperative North CONSENSUS: Cooperative North Scandinavian Enalapril Survival Scandinavian Enalapril Survival

StudyStudy

NEJM 1987; 316: 1429–35.NEJM 1987; 316: 1429–35.

N = 253

NYHA IV on diuretics and digoxin

Enalapril 20 mg BID vs Placebo

Pro

bab

ilit

y of

death

Pro

bab

ilit

y of

death

ACEI TrialsACEI Trials

Adapted from Yan AT, et al. Ann Intern Med. 2005; Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145142: 132-145

ACEI TrialsACEI Trials CONSENSUS = Cooperative North Scandinavian CONSENSUS = Cooperative North Scandinavian

Enalapril Survival StudyEnalapril Survival Study SOLV-D = Studies of Left Ventricular DysfunctionSOLV-D = Studies of Left Ventricular Dysfunction ATLAS = Assessment of Treatment with Lisinopril And ATLAS = Assessment of Treatment with Lisinopril And

Survival TrialSurvival Trial SAVE = Survival and Ventricular EnlargementSAVE = Survival and Ventricular Enlargement AIRE = Acute Infarction Ramipril EfficacyAIRE = Acute Infarction Ramipril Efficacy TRACE = Trandolapril Cardiac EvaluationTRACE = Trandolapril Cardiac Evaluation

- NEJM 1987; 316: 1429-35.- NEJM 1987; 316: 1429-35.- Eur Heart J. 1999; 20(2):136-9.Eur Heart J. 1999; 20(2):136-9.- NEJM. 1991; 325: 293-302.- NEJM. 1991; 325: 293-302.- NEJM. 1992; 327: 685-91. NEJM. 1992; 327: 685-91. - Circulation 1999 Dec 7; 100(23):2312-8.- Circulation 1999 Dec 7; 100(23):2312-8.- Eur Heart J 2000 Dec; 21(23):1967-78.Eur Heart J 2000 Dec; 21(23):1967-78.- NEJM. 1992;327:669-77. NEJM. 1992;327:669-77. - NEJM. 1995; 333: 1670-6. NEJM. 1995; 333: 1670-6. - Lancet. 1993; 342: 821-8.Lancet. 1993; 342: 821-8.

ACE Inhibitors in HFACE Inhibitors in HF Mortality Mortality ↓↓ 20%–25% (P< 0.001)20%–25% (P< 0.001) Death plus hospitalizationDeath plus hospitalization ↓ ↓ 30%–35%30%–35%

HOWEVER…..HOWEVER…..

~ 50% will still die within 5 years~ 50% will still die within 5 years 30% may be rehospitalized for CHF 30% may be rehospitalized for CHF

withinwithin threethree monthsmonths- JAMA. 1995;273:1450–1456- JAMA. 1995;273:1450–1456- AHA. 2001 Heart and Stroke Statistical Update. 2000- AHA. 2001 Heart and Stroke Statistical Update. 2000- Am J Cardiol. 1999;83(Suppl 2A):1A–39A.- Am J Cardiol. 1999;83(Suppl 2A):1A–39A.

Sir James BlackSir James Black

Nobel Prize 1988Nobel Prize 1988 Discovery of Beta-Discovery of Beta-

blockers blockers (Propranolol)(Propranolol)

Potential effects of Potential effects of ββ--blockers in cardiac blockers in cardiac

remodelingremodeling ↓ ↓ Heart rateHeart rate ↓ ↓ VO2VO2 Modulation of β-Modulation of β-

receptorsreceptors Protection from Protection from

catecholamine catecholamine toxicitytoxicity

↓ ↓ RAASRAAS Anti-ischemic and Anti-ischemic and

anti-arrhythmic effectanti-arrhythmic effect

Improvement in Improvement in synthesis of synthesis of myocardial proteinsmyocardial proteins

Peripheral Peripheral vasodilationvasodilation

Decrease of heart Decrease of heart workwork

Antioxidant actionAntioxidant action Anti-inflammatory Anti-inflammatory

actionactionEur Rev Med Pharmacol Sci. 2002; Eur Rev Med Pharmacol Sci. 2002; 6: 115-126.6: 115-126.

Lancet 1999; 353 Lancet 1999; 353 (9169):2001-7.(9169):2001-7.

MERIT-HF MERIT-HF (Metoprolol CR/XL (Metoprolol CR/XL Randomized Intervention Trial in Randomized Intervention Trial in

CHF).CHF).

34%34%

P=0.00P=0.006262

N = 3991N = 3991NYHA II-IVNYHA II-IV

MERIT-HF MERIT-HF (Metoprolol CR/XL (Metoprolol CR/XL Randomized Intervention Trial Randomized Intervention Trial

in CHF).in CHF). Post-hoc analysis in Post-hoc analysis in NYHA IVNYHA IV (n=795) (n=795)

J Am Coll Cardiol. 2001; J Am Coll Cardiol. 2001; 38:932.38:932.

Number of hospital days: Number of hospital days: 15 vs. 2615 vs. 26

COPERNICUS COPERNICUS (Carvedilol (Carvedilol Prospective Randomized Prospective Randomized

Cumulative Survival)Cumulative Survival)

NEJM 2001; 344(22): 1651-8.NEJM 2001; 344(22): 1651-8.

35% (P = 35% (P = 0.0014) 0.0014)

N = 2289N = 2289NYHA NYHA III-IVIII-IV

Carvedilol 25 mg BID vs. PlaceboCarvedilol 25 mg BID vs. Placebo

COMET COMET (Carvedilol or (Carvedilol or Metoprolol European Metoprolol European

Trial)Trial)

Lancet 2003; Lancet 2003; 362(9377):7-13.362(9377):7-13.

6%6%P= P= 0.0170.017

Carvedilol 25 Carvedilol 25 mg BID vs. mg BID vs. Metoprolol Metoprolol tartrate 50 tartrate 50 mg BIDmg BID

N = 3029N = 3029NYHA II-NYHA II-IVIV

Beta-Blockers: TrialsBeta-Blockers: TrialsMERIT MERIT

(12 mos)(12 mos)Metoprolol succinate 200 mg Qday Metoprolol succinate 200 mg Qday vs. placebovs. placebo

All-cause All-cause mortalitymortality

Overall Overall ↓ in ↓ in mortality 34%mortality 34% (P = (P = 0.0062)0.0062)

CIBIS IICIBIS II

(16 mos)(16 mos)Bisoprolol 10 mg/d vs. placeboBisoprolol 10 mg/d vs. placebo All-cause All-cause

mortalitymortalityEarly termination; Early termination; ↓ ↓ in mortality 32%in mortality 32% (P< 0.001)(P< 0.001)

COPERNICUCOPERNICUSS

(10.4 mos)(10.4 mos)

Carvedilol 25 mg BID vs. placeboCarvedilol 25 mg BID vs. placebo All-cause All-cause mortalitymortality

↓ ↓ in overall in overall mortality 35%mortality 35% (P = (P = 0.0014). Not 0.0014). Not worsening HF when worsening HF when initiating Rx.initiating Rx.

COMETCOMET

(58 mos)(58 mos)Carvedilol 25 mg BID vs. Metoprolol Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BIDtartrate 50 mg BID


Absolute risk Absolute risk ↓ 6%↓ 6% favor carvedilol (P= favor carvedilol (P= 0.0017)0.0017)

US US CarvedilolCarvedilol

(6 mos)(6 mos)

Carvedilol 25 – 50 mg BID vs. Carvedilol 25 – 50 mg BID vs. placeboplacebo

All cause All cause mortality, mortality, exercise exercise tolerance, QOL.tolerance, QOL.

Early termination.Early termination. ↓ ↓ in mortality rate in mortality rate 38%38% (P < 0.001) (P < 0.001)

BESTBEST

(24 mos)(24 mos)Bucindolol 50 – 100 mg BID vs. Bucindolol 50 – 100 mg BID vs. placeboplacebo

All cause All cause mortalitymortality

No differenceNo difference (P= (P= 0.16)0.16)

Benefit in non-black Benefit in non-black patientspatients


Beta-Blockers: TrialsBeta-Blockers: Trials MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in CHFMERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in CHF CIBIS: Cardiac Insufficiency Bisoprolol StudyCIBIS: Cardiac Insufficiency Bisoprolol Study COPERNICUS: Carvedilol Prospective Randomized Cumulative SurvivalCOPERNICUS: Carvedilol Prospective Randomized Cumulative Survival COMET: Carvedilol or Metoprolol European TrialCOMET: Carvedilol or Metoprolol European Trial United States Carvedilol Heart Failure Study GroupUnited States Carvedilol Heart Failure Study Group BEST: Beta-blocker Evaluation of Survival Trial (Bucindolol)BEST: Beta-blocker Evaluation of Survival Trial (Bucindolol) CAPRICORN: Carvedilol Post-Infarct Survival Control in Left Ventricular CAPRICORN: Carvedilol Post-Infarct Survival Control in Left Ventricular

DysfunctionDysfunction

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

Not all Beta Blocker are the Not all Beta Blocker are the Same!!!Same!!!

BEST Trial (Bucindolol)BEST Trial (Bucindolol) COMET Trial (Metoprolol Tartrate vs COMET Trial (Metoprolol Tartrate vs

Carvedilol)Carvedilol) Atenolol - not proven in heart failureAtenolol - not proven in heart failure Labetalol – not proven in heart failureLabetalol – not proven in heart failure Metoprolol Tartrate – no trials Metoprolol Tartrate – no trials

showing increased survival compared showing increased survival compared to placebo to placebo

Treatment StrategiesTreatment Strategies


Neurohormones in HF: Neurohormones in HF: AldosteroneAldosterone

↑ ↑ 20-fold in CHF20-fold in CHF Aldosterone escape Aldosterone escape

phenomenonphenomenon As well secretion As well secretion

can be independent can be independent of [AT II]of [AT II]

Extraadrenal Extraadrenal productionproduction Endothelial cellsEndothelial cells Vascular smooth Vascular smooth

muscle in the heart muscle in the heart and blood vesselsand blood vessels

NEJM. 1999; 341(8): 577-585.NEJM. 1999; 341(8): 577-585.Int J Clin Pract. 2006 Int J Clin Pract. 2006 Jul;60(7):835-46. Jul;60(7):835-46. NEJM. 2001 Dec; 345(23): NEJM. 2001 Dec; 345(23): 1689-1697.1689-1697.

Neurohormones in HF: Neurohormones in HF: AldosteroneAldosterone

NEJM. 1999; 341(8): 577-585.NEJM. 1999; 341(8): 577-585.Int J Clin Pract. 2006 Int J Clin Pract. 2006 Jul;60(7):835-46. Jul;60(7):835-46. NEJM. 2001 Dec; 345(23): NEJM. 2001 Dec; 345(23): 1689-1697.1689-1697.

RALES (Randomized Aldactone® RALES (Randomized Aldactone® Evaluation Study)Evaluation Study)

34% (P = 34% (P = 0.001)0.001)

N = 1664N = 1664Class IV or Class IV or class III (EF class III (EF < 35%) with < 35%) with hx. < 6 mos hx. < 6 mos of class IV of class IV CHFCHF

SpironolactonSpironolactone 25 mg/d vs. e 25 mg/d vs. placeboplacebo

- Am J Cardiol 1996 Oct 15; - Am J Cardiol 1996 Oct 15; 78(8):902-7.78(8):902-7.- NEJM 1999; Sep 2; NEJM 1999; Sep 2; 341(10):709-17.341(10):709-17.- NEJM 2003; Apr 3; NEJM 2003; Apr 3; 348(14):1309-21.348(14):1309-21.

EPHESUSEPHESUS (Eplerenone In Heart (Eplerenone In Heart Failure Post Acute Myocardial Failure Post Acute Myocardial

Infarction)Infarction)

NEJM 2003; Apr 3; NEJM 2003; Apr 3; 348(14):1309-21.348(14):1309-21.

N= 6642 N= 6642 MI < 2 wk; EF < 40% with evidence of HF MI < 2 wk; EF < 40% with evidence of HF and/or DM.and/or DM.Eplerenone 50 mg/d vs. placeboEplerenone 50 mg/d vs. placebo

ACC/AHA guidelines - Spironolactone 25-ACC/AHA guidelines - Spironolactone 25-50 mg-day in:50 mg-day in: NYHA IV NYHA IV Creatinine < 2.5 mg/dL Creatinine < 2.5 mg/dL Serum potassium < 5 mEq/L.Serum potassium < 5 mEq/L.

Endocrine side effects: gynecomastia, Endocrine side effects: gynecomastia, breast pain, menstrual irregularities, breast pain, menstrual irregularities, impotence, and decreased libidoimpotence, and decreased libido Non-selective binding to androgen and Non-selective binding to androgen and

progesterone receptors. progesterone receptors.

Spironolactone in Heart Spironolactone in Heart FailureFailure

- Am J Cardiol 1996 Oct 15; - Am J Cardiol 1996 Oct 15; 78(8):902-7.78(8):902-7.- NEJM 1999; Sep 2; - NEJM 1999; Sep 2; 341(10):709-17.341(10):709-17.

Neurohormones in HF: Neurohormones in HF: Angiotensin IIAngiotensin II

High mortality in CHF patients despite being on ACEI High mortality in CHF patients despite being on ACEI and BBand BB

Potent vasoconstrictor and growth-stimulating hormonePotent vasoconstrictor and growth-stimulating hormone May contribute to the impairment of left ventricular May contribute to the impairment of left ventricular

function and the progression of heart failure:function and the progression of heart failure: increased impedance of left ventricular emptyingincreased impedance of left ventricular emptying adverse long-term structural effects on the heart and adverse long-term structural effects on the heart and

vasculaturevasculature activation of other neurohormones (NE, ET1, aldosterone)activation of other neurohormones (NE, ET1, aldosterone)

Physiologically active levels in patient on ACEIPhysiologically active levels in patient on ACEI Incomplete supression of ATII productionIncomplete supression of ATII production

Intolerance to ACEI (cough due to increase in Intolerance to ACEI (cough due to increase in bradykinins). bradykinins). Needs an alternative therapeutic choiceNeeds an alternative therapeutic choice

NEJM. 1999; 341(8): 577-585.NEJM. 1999; 341(8): 577-585.ACC/AHA Heart Failure Guidelines ACC/AHA Heart Failure Guidelines 2005. 2005.

Angiotensin II Receptor Angiotensin II Receptor Blockage: TrialsBlockage: Trials

ELITE IIELITE II

(18.5 mos)(18.5 mos)N = 3152N = 3152

Age > 60 Age > 60 y/oy/o

NYHA II-IVNYHA II-IV

EF < 40%EF < 40%

Losartan 50 mg/d Losartan 50 mg/d vs. Captopril 50 vs. Captopril 50 mg TID. mg TID.

All-cause mortalityAll-cause mortality No superiority of No superiority of one agent vs. otherone agent vs. other

(P = 0.16)(P = 0.16)

Val-HeFTVal-HeFT

(23 mos)(23 mos)N = 5010N = 5010


EF < 40%; EF < 40%;

LV LV dilatationdilatation

Valsartan 160 mg Valsartan 160 mg BID vs. PlaceboBID vs. Placebo

All-cause mortality; All-cause mortality; mortality or cardiac mortality or cardiac arrest or arrest or hospitalization for hospitalization for HFHF

Similar mortality (P > Similar mortality (P > 0.2)0.2)

Absolute risk ↓3.3% Absolute risk ↓3.3% (P<0.002) in (P<0.002) in composite end-point. composite end-point. (Decreased (Decreased admissions)admissions)

↑ ↑ LVID ↓EF LVID ↓EF ↑ ↑ BenefitBenefit

CHARM-CHARM-AddedAdded

(41 mos)(41 mos)

N = 2548N = 2548


EF < 40%EF < 40%

On ACEIOn ACEI

Candesartan 32 Candesartan 32 mg/d vs. placebomg/d vs. placebo

CV death or CV death or hospitalization for hospitalization for heart failureheart failure

Absolute risk ↓ 4%Absolute risk ↓ 4% (P=0.011)(P=0.011)

Trend toward lower Trend toward lower all-cause mortality (P= all-cause mortality (P= 0.086)0.086)

CHARM – CHARM – AlternativAlternativee

(33.7 mos)(33.7 mos)

N = 2028N = 2028


EF < 40%EF < 40%

Intolerance Intolerance to ACEIto ACEI

Candesartan 32 Candesartan 32 mg/d vs. placebomg/d vs. placebo

CV death or CV death or hospitalization for hospitalization for heart failureheart failure

Absolute risk ↓ 7%Absolute risk ↓ 7% (P<0.001)(P<0.001)

Trend toward lower Trend toward lower all-cause mortality (P= all-cause mortality (P= 0.11)0.11)


ELITE: Evaluation of Losartan in the ELITE: Evaluation of Losartan in the ElderlyElderly

Val-HeFT: Valsartan heart failure Val-HeFT: Valsartan heart failure trialtrial

CHARM: Candesartan in Heart CHARM: Candesartan in Heart Failure Assessment of Reduction in Failure Assessment of Reduction in Mortality and MorbidityMortality and MorbidityLancet. 1997;349: 747-52. Lancet. 1997;349: 747-52.

Lancet. 2000;355: 1582-7. Lancet. 2000;355: 1582-7. NEJM 2001 Dec 6; 345(23):1667-75.NEJM 2001 Dec 6; 345(23):1667-75.Circulation 2002 Nov 5; 106(19):2454-8.Circulation 2002 Nov 5; 106(19):2454-8.J Am Coll Cardiol 2004 Jun 2; J Am Coll Cardiol 2004 Jun 2;

43(11):2022-7.43(11):2022-7.Lancet 2003; Sep 6; 362(9386):759-66.Lancet 2003; Sep 6; 362(9386):759-66.Lancet 2003; Sep 6; 362(9386):767-71.Lancet 2003; Sep 6; 362(9386):767-71.Circulation 2004 Oct 12; 110(15):2180-Circulation 2004 Oct 12; 110(15):2180-

3.3.

Angiotensin II Receptor Angiotensin II Receptor Blockage: TrialsBlockage: Trials

2005 ACC/AHA 2005 ACC/AHA Guidelines. Guidelines.

Summary of Major Therapeutic Options for Systolic Heart Failure

Electrical consequences of Electrical consequences of heart failureheart failure

www.HRSonline.org/professional_education/www.HRSonline.org/professional_education/learning_categories/articleslearning_categories/articles

Electrical therapy of Electrical therapy of CHF: TrialsCHF: TrialsCOMPANIOCOMPANIO

NN

(35 mo)(35 mo)

N = 1520N = 1520

NYHA III-IVNYHA III-IV

EF < 35%, stableEF < 35%, stable

QRS=120 msecQRS=120 msec

PR>150 msecPR>150 msec

1:2:2 ratio1:2:2 ratio-Medical RxMedical Rx-Medical Rx + PMMedical Rx + PM-Medical Rx + Medical Rx + PM/ICDPM/ICD

All-cause All-cause mortality of mortality of hospitalizationhospitalization

↓ ↓ composite composite end-point 20% end-point 20% (P= 0.015 and (P= 0.015 and 0.011) 0.011) Improvement in Improvement in NYHA, 6 min. NYHA, 6 min. walk distance, walk distance, and SBP. and SBP.

CARE – HFCARE – HF

(29.4 mo)(29.4 mo)N = 813 N = 813

NYHA III-IVNYHA III-IV

EF< 35%EF< 35%

Cardiac Cardiac dysynchronydysynchrony

Medical Rx vs. BiV Medical Rx vs. BiV pacingpacing

Time to death Time to death (all-cause) or (all-cause) or hospitalization hospitalization (CV)(CV)

↓ ↓ composite composite end-point 29% end-point 29% (P< 0.001)(P< 0.001)

33% ↓ mortality 33% ↓ mortality (P <0.002)(P <0.002)

↑ ↑ LVEF 7% at LVEF 7% at 18 mo18 mo

MADITMADIT

(27 mo)(27 mo)N = 156N = 156

NYHA I-III; prior NYHA I-III; prior MIMI

EF < 35%; EF < 35%; Documented VT; Documented VT; inducible VTinducible VT

Medical Rx vs. ICDMedical Rx vs. ICD All-cause All-cause mortalitymortality

↓ ↓ overall overall mortality 61% mortality 61% (P= 0.009)(P= 0.009)

MADIT IIMADIT II

(20 mo)(20 mo)N = 1232N = 1232

EF < 30%; Prior MIEF < 30%; Prior MI3:2 ratio ICD vs. 3:2 ratio ICD vs. Medical RxMedical Rx


↓ ↓ in overall in overall mortality 28% (P mortality 28% (P = 0.016)= 0.016)

SCD-HeFTSCD-HeFT

(45 mo)(45 mo)N = 2521N = 2521

NYHA II-IIINYHA II-III

EF < 35%EF < 35%

1:1:1 Medical Rx + 1:1:1 Medical Rx + placebo; Medical Rx placebo; Medical Rx + amiodarone; + amiodarone; Medical Rx + ICDMedical Rx + ICD


Amiodarone=plaAmiodarone=placebocebo

ICD ↓ absolute ICD ↓ absolute risk 7.2% in risk 7.2% in mortality (P= mortality (P= 0.007)0.007)

Electrical therapy in Electrical therapy in CHF: TrialsCHF: Trials

COMPANION: Comparison of Medical Therapy, COMPANION: Comparison of Medical Therapy, Pacing, and Defibrillation in Heart FailurePacing, and Defibrillation in Heart Failure

CARE-HF: Cardiac resynchronization in Heart CARE-HF: Cardiac resynchronization in Heart FailureFailure

SCD-HeFT: Sudden Cardiac Death in Heart SCD-HeFT: Sudden Cardiac Death in Heart Failure TrialFailure Trial

MADIT: Multicenter Automatic Defibrillator MADIT: Multicenter Automatic Defibrillator Implantation TrialImplantation Trial

NEJM 2004 May 20; 350(21):2140-50.NEJM 2004 May 20; 350(21):2140-50.NEJM. 2005 Apr 14; 352(15):1539-49.NEJM. 2005 Apr 14; 352(15):1539-49.NEJM 2005 Jan 20; 352(3):225-37.NEJM 2005 Jan 20; 352(3):225-37.NEJM. 1996 Dec 26; 335 (26): 1933-40.NEJM. 1996 Dec 26; 335 (26): 1933-40.NEJM. 2002 Mar 21; 346(12):877-83. NEJM. 2002 Mar 21; 346(12):877-83. JACC. 2004; 43(8): 1459-65JACC. 2004; 43(8): 1459-65

Stages of Heart Failure and Treatment Stages of Heart Failure and Treatment optionsoptions

NEJM 2003; 348 (20): NEJM 2003; 348 (20): 2007-18.2007-18.

Other research Other research endeavors in CHFendeavors in CHF

Stem cell transplantationStem cell transplantation Ultrafiltration (UNLOAD) - CompletedUltrafiltration (UNLOAD) - Completed Vasopressin antagonists Vasopressin antagonists

Acute and Chronic Therapeutic Impact of Vasopressin 2 Acute and Chronic Therapeutic Impact of Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF)Antagonist in Congestive Heart Failure (ACTIV in CHF)

SALT (Study of Ascending Levels of Tolvaptan in SALT (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) - CompletedHyponatremia 1 and 2) - Completed

EVERESTEVEREST Thyroid hormone analog Thyroid hormone analog

(3,5- diiodothyropropionic acid [DITPA]) (3,5- diiodothyropropionic acid [DITPA]) Endothelin receptors antagonistsEndothelin receptors antagonists Neutral endopeptidase inhibitorsNeutral endopeptidase inhibitors Metalloproteinases inhibitorsMetalloproteinases inhibitors

Pediatr Cardiol. 2006 Sep-Oct; Pediatr Cardiol. 2006 Sep-Oct; 27(5): 533-51. 27(5): 533-51.

Vasopressin stimulationVasopressin stimulation

V2 receptor (coll.tubule)V2 receptor (coll.tubule)

Water retentionWater retention

V1A receptor (vascular smooth muscle)V1A receptor (vascular smooth muscle)

Increase in systemic vascular resistanceIncrease in systemic vascular resistance

Low cardiac outputLow cardiac output

Activation of the carotid sinus and aortic arch baroreceptorsActivation of the carotid sinus and aortic arch baroreceptors

↑↑ADHADH

Thirst.Thirst.

↓Na

Hyponatremia in HFHyponatremia in HF

N = 203N = 203

Na > 137 = 373 dNa > 137 = 373 d

Na < 137 = 164 dNa < 137 = 164 d

Lee WH, Packer M. Circulation. 1986; Lee WH, Packer M. Circulation. 1986; 73(2): 257-267.73(2): 257-267.

Vasopressin antagonistsVasopressin antagonists

V1A receptor blockage V1A receptor blockage reduction reduction in SVR in SVR afterload reduction afterload reduction improve myocardial fximprove myocardial fx

V2 receptor blockage V2 receptor blockage increased increased free water excretion free water excretion correction of correction of hyponatremia and volume overloadhyponatremia and volume overload

J Am Coll Cardiol 2005 Nov J Am Coll Cardiol 2005 Nov 15;46(10):1785-91.15;46(10):1785-91.

Tolvaptan investigatorsTolvaptan investigators

CirculationCirculation. 2003;107:2690-2696.. 2003;107:2690-2696.

Circulation. 2003;107:2690-2696.Circulation. 2003;107:2690-2696.

Tolvaptan investigatorsTolvaptan investigators

ACTIV TrialACTIV TrialN = 319LVEF < 40% NYHA III-IV

- 1.6

- 2.8

JAMA. 2004;291:1963-1971JAMA. 2004;291:1963-1971

EVERESTEVEREST N= 4133 patients N= 4133 patients LVEF < 40 % LVEF < 40 % Randomly assigned to tolvaptan (30 mg/day) vs. Randomly assigned to tolvaptan (30 mg/day) vs.

placebo placebo Minimum of 60 days.Minimum of 60 days. The primary end point was a composite score of The primary end point was a composite score of

changes from baseline in patient-assessed global changes from baseline in patient-assessed global clinical statusclinical status

and body weight at day 7 or dischargeand body weight at day 7 or discharge Secondary end points included patient-assessed Secondary end points included patient-assessed

changes in dyspnea at day 1, global clinical status at changes in dyspnea at day 1, global clinical status at day 7 or discharge, body weight at days 1 and 7 or day 7 or discharge, body weight at days 1 and 7 or discharge, and peripheral edema at day 7 or discharge, and peripheral edema at day 7 or discharge for patients manifesting edema at baseline.discharge for patients manifesting edema at baseline.

EVERESTEVEREST EVEREST Clinical Status EVEREST Clinical Status

Weight loss -day 1- (1.7 - 1.8 vs. 1.0 kg Weight loss -day 1- (1.7 - 1.8 vs. 1.0 kg placebo) - P <0.001. placebo) - P <0.001.

Weight loss -day 7 or D/C- (3.3-3.8 vs. 2.7-2.8 Weight loss -day 7 or D/C- (3.3-3.8 vs. 2.7-2.8 kg placebo) - P <0.001. kg placebo) - P <0.001.

Dyspnea - improvement at day one (72-77% vs. 65-Dyspnea - improvement at day one (72-77% vs. 65-71%placebo) – P <0.001. 71%placebo) – P <0.001.

EVEREST Outcome EVEREST Outcome Median follow up - 10 months - Median follow up - 10 months - no difference in all no difference in all

cause mortalitycause mortality or in a combined endpoint of or in a combined endpoint of cardiovascular death or HF hospitalization.cardiovascular death or HF hospitalization.

Baseline Na < 134 mEq/L Baseline Na < 134 mEq/L Tolvaptan ↑ Na at seven Tolvaptan ↑ Na at seven days or D/C (5.5 vs. 1.9 mEq/L placebo)days or D/C (5.5 vs. 1.9 mEq/L placebo)

JAMA. 2007 Mar 28;297(12):1319-31. JAMA. 2007 Mar 28;297(12):1319-31. JAMA. 2007 Mar 28;297(12):1332-43. JAMA. 2007 Mar 28;297(12):1332-43.

NesiritideNesiritide Decreases PCWP -6 to -10 mmHg vs 2 mmHg placebo.Decreases PCWP -6 to -10 mmHg vs 2 mmHg placebo. Improved clinical status (60 and 67 % vs. 14 % Improved clinical status (60 and 67 % vs. 14 %

placebo).placebo). No difference when compared to intravenous No difference when compared to intravenous

nitroglycerin.nitroglycerin. Pooled analysis 3 RCT (N = 862) comparing nesiritide Pooled analysis 3 RCT (N = 862) comparing nesiritide

with noninotropic vasodilator therapy with noninotropic vasodilator therapy increase in increase in 30-day mortality among patients receiving nesiritide 30-day mortality among patients receiving nesiritide (7.2 vs. 4 %, P = 0.059). (7.2 vs. 4 %, P = 0.059).

Less likely to provoke ventricular arrhythmias (vs. Less likely to provoke ventricular arrhythmias (vs. dobutamine) dobutamine)

Does not reduce the length of stay compared to Does not reduce the length of stay compared to dobutamine, but…. lower readmission rate for any dobutamine, but…. lower readmission rate for any cause or for HFcause or for HF N Engl J Med 2000 Jul 27;343(4):246-53 N Engl J Med 2000 Jul 27;343(4):246-53

JAMA 2002 Mar 27;287(12):1531-40 JAMA 2002 Mar 27;287(12):1531-40 Am Heart J. 2006 Dec;152(6):1084-90Am Heart J. 2006 Dec;152(6):1084-90

NesiritideNesiritide Initial iv bolus of 2 mcg/kg, followed by a continuous infusion Initial iv bolus of 2 mcg/kg, followed by a continuous infusion

of 0.01 mcg/kg/minof 0.01 mcg/kg/min Dose is increased if, after 3 to 24 hours, to target the desired Dose is increased if, after 3 to 24 hours, to target the desired

therapeutic response:therapeutic response: increase in urine outputincrease in urine output symptomatic improvementsymptomatic improvement reduction in cardiac filling pressuresreduction in cardiac filling pressures

Infusion is usually increased by 0.005 mcg/kg/min, preceded Infusion is usually increased by 0.005 mcg/kg/min, preceded by a bolus of 1 mcg/kg, up to a maximum of 0.03 mcg/kg/min. by a bolus of 1 mcg/kg, up to a maximum of 0.03 mcg/kg/min.

If hypotension occurs, the infusion should be discontinued If hypotension occurs, the infusion should be discontinued and restarted when the blood pressure has stabilized, at a and restarted when the blood pressure has stabilized, at a 30% lower dose without bolus. 30% lower dose without bolus.

Continue iv diuretics Continue iv diuretics ACE inhibitors can be given in combination with nesiritide – if ACE inhibitors can be given in combination with nesiritide – if

hypotension use ACEI rather than nesiritide hypotension use ACEI rather than nesiritide

Clev Clin J Med 2002 Mar;69(3):252-6

CaveatsCaveats AgeAge

Most trials include people 10 years Most trials include people 10 years younger than in general populationyounger than in general population

EFEF Little evidence for efficacy in patients Little evidence for efficacy in patients

with near-normal EFwith near-normal EF Gender Gender

Few women have been included in trialsFew women have been included in trials

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept 2006: 242-2452006: 242-245

CaveatsCaveats

Devices:Devices: Inclusion criteria Inclusion criteria

EF < 35% EF < 35% QRS width > 120 ms.QRS width > 120 ms.

Actual EF in the population studied is Actual EF in the population studied is << 25% 25%

Actual mean QRS is 150 ms. Actual mean QRS is 150 ms.

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept 2006: 242-2452006: 242-245

CaveatsCaveats Redefinition of the primary variable after Redefinition of the primary variable after

unblinding is considered unacceptableunblinding is considered unacceptable Post-hoc analysis does not have protection Post-hoc analysis does not have protection

against type I erroragainst type I error Additional data-derived analyses on endpoints Additional data-derived analyses on endpoints

other than the one defined prospectively as other than the one defined prospectively as the primary one, might be useful in the primary one, might be useful in suggesting hypotheses for further studies.suggesting hypotheses for further studies. the conclusions should not be considered in the the conclusions should not be considered in the

same manner as the principal hypothesis of the same manner as the principal hypothesis of the study design. study design.

Zanolla L. Eur J Heart Failure. 5 (2003): 717–Zanolla L. Eur J Heart Failure. 5 (2003): 717–723.723.

Thank youThank you

Dr. Shanti Gunawardena.Dr. Shanti Gunawardena. Dr. Mark E. Dunlap.Dr. Mark E. Dunlap. Dr. James C. Pile.Dr. James C. Pile. Dr. David J. Mansour.Dr. David J. Mansour. Dr. Holly B. Perzy.Dr. Holly B. Perzy.

Evidence Based Approach in Congestive Heart Failure

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