heart failure update - dr. stultzdrstultz.com/presentations/2006 08 16 update in heart...

Heart Failure UpdateHeart Failure Update

David Stultz, MDDavid Stultz, MD

August 16, 2006August 16, 2006

(c) 2000-2008 David Stultz, MD

http://www.dilbert.com


OverviewOverview

•• Background on Heart FailureBackground on Heart Failure

•• Established therapies for systolic heartEstablished therapies for systolic heartfailurefailure

•• Recent investigational approaches toRecent investigational approaches tosystolic heart failuresystolic heart failure

•• Quick summary of diastolic heartQuick summary of diastolic heartfailurefailure

•• Lots of Trial Data!Lots of Trial Data! ACC Heart Failure Guidelines will becited where appropriate


What is Heart Failure?What is Heart Failure?

•• Heart failure is a complexHeart failure is a complex clinicalclinical syndromesyndromethat can result from any structural orthat can result from any structural orfunctional cardiac disorder that impairs thefunctional cardiac disorder that impairs theability of the ventricle to fill with or ejectability of the ventricle to fill with or eject

blood.blood.

•• The cardinal manifestations of HF areThe cardinal manifestations of HF aredyspnea and fatigue, which may limitdyspnea and fatigue, which may limitexercise tolerance, and fluid retention, whichexercise tolerance, and fluid retention, whichmay lead to pulmonary congestion andmay lead to pulmonary congestion andperipheral edema.peripheral edema.

ACC 2005


How to classify heart failure?How to classify heart failure?

•• Acute decompensated v ChronicAcute decompensated v Chronic

•• Systolic v Diastolic dysfunctionSystolic v Diastolic dysfunction

•• Low output v High outputLow output v High output

•• Ischemic v NonischemicIschemic v Nonischemic

•• Medical v Device therapyMedical v Device therapy

•• WarmWarm--Dry v ColdDry v Cold--WetWet


Classification of Recommendations

• Class I: Conditions for which there is evidence and/or general agreementthat a given procedure or treatment is beneficial, useful, and effective.

• Class II: Conditions for which there is conflicting evidence and/or adivergence of opinion about the usefulness/efficacy of a procedure ortreatment.• Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.• Class IIb: Usefulness/efficacy is less well established by

evidence/opinion.• Class III: Conditions for which there is evidence and/or general agreement

that a procedure/treatment is not useful/effective and in some cases may beharmful.

Level of Evidence• Level of Evidence A: Data derived from multiple randomized clinical trials or

meta-analyses.• Level of Evidence B: Data derived from a single randomized trial, or

nonrandomized studies.• Level of Evidence C: Only consensus opinion of experts, case studies, or

standard-of-care.


Classification SchemesClassification SchemesNew York Heart AssociationNew York Heart Association

•• Class IClass I -- No symptom limitation withNo symptom limitation withordinary physical activityordinary physical activity

•• Class IIClass II -- Ordinary physical activityOrdinary physical activitysomewhat limitedsomewhat limited by dyspnea (ie, longby dyspnea (ie, longdistance walking,distance walking, climbing 2 flights of stairs)climbing 2 flights of stairs)

•• Class IIIClass III -- Exercise limited by dyspnea at mildExercise limited by dyspnea at mildworkwork loads (ie, short distance walking,loads (ie, short distance walking,climbingclimbing one flight of stairs)one flight of stairs)

•• Class IVClass IV -- Dyspnea at rest or with very littleDyspnea at rest or with very littleexertionexertion


Classification SchemesClassification SchemesACC/AHA StagesACC/AHA Stages

AA High risk for developing heart failureHigh risk for developing heart failure•• Hypertension, diabetes mellitus, CAD, familyHypertension, diabetes mellitus, CAD, family

history of cardiomyopathyhistory of cardiomyopathy

BB Asymptomatic heart failureAsymptomatic heart failure•• Previous MI, LV dysfunction, valvular heartPrevious MI, LV dysfunction, valvular heart

diseasedisease

CC Symptomatic heart failureSymptomatic heart failure•• Structural heart disease, dyspnea and fatigue,Structural heart disease, dyspnea and fatigue,

impaired exercise toleranceimpaired exercise tolerance

DD Refractory endRefractory end--stage heart failurestage heart failure•• Marked symptoms at rest despite maximalMarked symptoms at rest despite maximal

medical therapymedical therapy


Rising prevalence of Heart FailureRising prevalence of Heart Failurewith Agingwith Aging


Rising Discharges for HeartRising Discharges for HeartFailureFailure


Survival in Stage 3 or 4 HeartSurvival in Stage 3 or 4 HeartFailure vs TransplantFailure vs Transplant


Systolic vs Diastolic HeartSystolic vs Diastolic HeartFailureFailure

•• Heart failure with low left ventricularHeart failure with low left ventricularejection fraction vs normal ejectionejection fraction vs normal ejectionfractionfraction

•• Prevalence is approximately equalPrevalence is approximately equal

•• Etiologies are differentEtiologies are different

•• Multiple clinical trials for systolic heartMultiple clinical trials for systolic heartfailurefailure

•• One randomized placebo controlledOne randomized placebo controlledpharmaceutical trial for heart failurepharmaceutical trial for heart failurewith preserved LVEFwith preserved LVEF


Development of SystolicDevelopment of SystolicHeart FailureHeart Failure


Etiologies of Heart FailureEtiologies of Heart Failure


BNP to differentiate etiology ofBNP to differentiate etiology ofacute dyspnea in ER settingacute dyspnea in ER setting

Diagnosis of Heart FailureDiagnosis of Heart Failure


Survival by BNP QuartileSurvival by BNP Quartile


Survival by BNP QuartileSurvival by BNP QuartileACC IIa - Measurement of B-typenatriuretic peptide (BNP)* can be usefulin the evaluation of patients presentingin the urgent care setting in whom theclinical diagnosis of HF is uncertain.(Level of Evidence: A)

ACC IIb - The value of serialmeasurements of BNP to guide therapyfor patients with HF is not wellestablished. (Level of Evidence: C)


Treatment of Heart FailureTreatment of Heart Failure

•• Chronic StableChronic Stable

•• LifestyleLifestyle

•• Risk Factor ModificationRisk Factor Modification

•• PharmacologicalPharmacological

•• Device/NonpharmacologicDevice/Nonpharmacologic

•• Acute DecompensationAcute Decompensation

•• PharmacologicalPharmacological

•• Device/NonpharmacologicDevice/Nonpharmacologic


Pharmacological Treatment ofPharmacological Treatment ofHeart FailureHeart Failure

(Systolic Dysfunction)(Systolic Dysfunction)


A Brief History of DigoxinA Brief History of Digoxin

•• 17851785 -- William WitheringWilliam Witheringpublishespublishes An Account of theAn Account of theFoxglove and some of its Medical UsesFoxglove and some of its Medical Useswhich recounts an anecdote ofwhich recounts an anecdote oftreating a patient with Dropsytreating a patient with Dropsy

•• 19971997 –– DIG trial shows reductionDIG trial shows reductionin hospitalization but no mortalityin hospitalization but no mortalitybenefit of digoxin for heart failurebenefit of digoxin for heart failure

•• Post Hoc DIG AnalysesPost Hoc DIG Analyses

•• 20022002 –– digoxin harmful to women (4%digoxin harmful to women (4%increase in mortality)increase in mortality)

•• 20032003 –– target Digoxin level should betarget Digoxin level should be0.50.5--0.8 ng/mL0.8 ng/mL

•• 20062006 –– survival benefit with Digoxinsurvival benefit with DigoxinLevel 0.5Level 0.5--0.80.8

Digitalis purpurea


Adjusted outcomes and hazard ratios by SDCsAdjusted outcomes and hazard ratios by SDCs

0.650.65(0.52(0.52--0.82)0.82)

0.740.74(0.60(0.60--0.92)0.92)

0.560.56(0.46(0.46--0.67)0.67)

ReferentReferentHospitalization forHospitalization forworsening heartworsening heartfailurefailure

0.900.90(0.77(0.77--1.04)1.04)

1.021.02(0.89(0.89--1.18)1.18)

0.830.83(0.74(0.74--0.93)0.93)

ReferentReferentAllAll--causecausehospitalizationhospitalization

0.950.95(0.69(0.69--1.31)1.31)

0.860.86(0.63(0.63--1.17)1.17)

0.660.66(0.49(0.49--0.89)0.89)

ReferentReferentWorsening heartWorsening heartfailurefailure

1.211.21(0.99(0.99--1.47)1.47)

0.930.93(0.76(0.76--1.14)1.14)

0.860.86(0.72(0.72--1.02)1.02)

ReferentReferentCardiovascularCardiovascularmortalitymortality

1.161.16(0.96(0.96--1.39)1.39)

0.890.89(0.74(0.74--1.08)1.08)

0.800.80(0.68(0.68--0.94)0.94)

ReferentReferentAllAll--cause mortalitycause mortality

HR (95% CI)HR (95% CI)by SDC 1.2by SDC 1.2ng/mL orng/mL orgreatergreater

HR (95% CI)HR (95% CI)by SDC 0.9by SDC 0.9--1.1 ng/mL1.1 ng/mL

HR** (95% CI)HR** (95% CI)by SDC 0.5by SDC 0.5--0.80.8ng/mLng/mL

PlaceboPlaceboAdjusted outcomes*Adjusted outcomes*

*Adjusted for age; race; body mass index; LVEF; NYHA class; cardiothoracic ratio; number of HF signs and symptoms; systolic BP; heart rate; estimatedglomerular filtration rate; duration of HF; primary cause of HF; history of MI, angina, diabetes, and hypertension; prior use of digoxin; and use of potassium-sparing diuretics, all other diuretics, ACE inhibitors, nitrates, hydralazine, and other vasodilators

**HR-hazard ratio

Rathore SS et al. JAMA 2003 Feb 19; 289(7):871-878


Post hoc DIG analysisPost hoc DIG analysis

64%64% (p(p0.05)0.05)67%67%All CauseAll CauseHospitalizationHospitalization

29%29% (p<0.01)(p<0.01)23%23% (p<0.01)(p<0.01)33%33%HFHFHospitalizationHospitalization

29%29% (p<0.01)(p<0.01)33%33%MortalityMortality

>=1.0>=1.0ng/mLng/mL

0.50.5--0.90.9ng/mLng/mL

placeboplacebo1687 Digoxin1687 Digoxin

3861 placebo3861 placebo

Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M. Digoxin and reduction in mortality andhospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006 Jan;27(2):178-86. Epub 2005 Dec 8.

No interaction between EF>40% or gender


Post hoc DIG analysisPost hoc DIG analysis

64%64% (p(p0.05)0.05)67%67%All CauseAll CauseHospitalizationHospitalization

29%29% (p<0.01)(p<0.01)23%23% (p<0.01)(p<0.01)33%33%HFHFHospitalizationHospitalization

29%29% (p<0.01)(p<0.01)33%33%MortalityMortality

>=1.0>=1.0ng/mLng/mL

0.50.5--0.90.9ng/mLng/mL

placeboplacebo1687 Digoxin1687 Digoxin

3861 placebo3861 placebo

Ahmed A, Rich MW, Love TE, Lloyd-Jones DM, Aban IB, Colucci WS, Adams KF, Gheorghiade M. Digoxin and reduction in mortality andhospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006 Jan;27(2):178-86. Epub 2005 Dec 8.

No interaction between EF>40% or gender

ACC III - Digoxin should not be used inpatients with low EF, sinus rhythm, andno history of HF symptoms, because inthis population, the risk of harm is notbalanced by any known benefit. (Levelof Evidence: C)


Diuretics in Heart FailureDiuretics in Heart Failure

•• Loop diuretics used for volume controlLoop diuretics used for volume controland relief of symptomsand relief of symptoms

•• Thiazide diuretics may be added inThiazide diuretics may be added inconjunctionconjunction

•• No trial data!No trial data! ACC I - Diuretics and salt restriction areindicated in patients with current orprior symptoms of HF and reducedLVEF who have evidence of fluidretention (see Table 4). (Level ofEvidence: C)


Diuretic Action SitesDiuretic Action Sites


Vasodilators in Heart FailureVasodilators in Heart Failure

•• VHEFT 1 showed 27% relative reductionVHEFT 1 showed 27% relative reductionin mortality with vasodilatorsin mortality with vasodilators•• Digoxin + diureticsDigoxin + diuretics

•• Placebo vs. isosorbide + hydralazinePlacebo vs. isosorbide + hydralazine

•• VHEFT 2 showed 7% absolute (25% vsVHEFT 2 showed 7% absolute (25% vs18%) mortality benefit of ACE over18%) mortality benefit of ACE overisordil/hydralazineisordil/hydralazine•• Enalapril 10mg bid vs isosorbide dinitrateEnalapril 10mg bid vs isosorbide dinitrate

40mg qid + hydralazine 75mg qid40mg qid + hydralazine 75mg qid

Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, et al. A comparison ofenalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991 Aug1;325(5):303-10.


ACE inhibitors in HeartACE inhibitors in HeartFailureFailure

•• 1991 SOLVD1991 SOLVD –– enalapril 10mg bid vsenalapril 10mg bid vsplacebo for patients with chronic EFplacebo for patients with chronic EF<=35%<=35%

•• 2569 patients, average 41 month followup2569 patients, average 41 month followup

69% (p=0.006)69% (p=0.006)74%74%HospitalizationHospitalization

35.2% (p=0.004)35.2% (p=0.004)39.7%39.7%DeathDeath

EnalaprilEnalaprilPlaceboPlacebo

SOLVD Investigators. Effect of analapril on survival in patients with reduced left ventricular ejection fractions and congestive heart

failure. N Engl J Med 1881; 325: 293-302.


ACE inhibitors in HeartACE inhibitors in HeartFailureFailure

•• 1991 SOLVD1991 SOLVD –– enalapril 10mg bid vsenalapril 10mg bid vsplacebo for patients with chronic EFplacebo for patients with chronic EF<=35%<=35%

•• 2569 patients, average 41 month followup2569 patients, average 41 month followup

69% (p=0.006)69% (p=0.006)74%74%HospitalizationHospitalization

35.2% (p=0.004)35.2% (p=0.004)39.7%39.7%DeathDeath

EnalaprilEnalaprilPlaceboPlacebo

SOLVD Investigators. Effect of analapril on survival in patients with reduced left ventricular ejection fractions and congestive heart

failure. N Engl J Med 1881; 325: 293-302.

ACC I - Angiotensin converting enzymeinhibitors should be used in patientswith a reduced EF and no symptomsof HF, even if they have not experiencedMI. (Level of Evidence: A)


--Blockers inBlockers inHeart FailureHeart Failure

•• Improves survival in chronicImproves survival in chronicheart failureheart failure

A.A. 1999 MERIT1999 MERIT--HF (Toprol XL)HF (Toprol XL)

–– EF <=40%, NYHA 2EF <=40%, NYHA 2--44

B.B. 1999 CIBIS II (bisoprolol)1999 CIBIS II (bisoprolol)

–– EF <=35%, NYHA 3EF <=35%, NYHA 3--44

C.C. 2001 COPERNICUS (Coreg)2001 COPERNICUS (Coreg)

–– EF <25%EF <25%


--Blockers inBlockers inHeart FailureHeart Failure

•• Improves survival in chronicImproves survival in chronicheart failureheart failure

A.A. 1999 MERIT1999 MERIT--HF (Toprol XL)HF (Toprol XL)

–– EF <=40%, NYHA 2EF <=40%, NYHA 2--44

B.B. 1999 CIBIS II (bisoprolol)1999 CIBIS II (bisoprolol)

–– EF <=35%, NYHA 3EF <=35%, NYHA 3--44

C.C. 2001 COPERNICUS (Coreg)2001 COPERNICUS (Coreg)

–– EF <25%EF <25%ACC I - Beta-blockers and ACEIs should beused in all patients with a recent or remotehistory of MI regardless of EF or presence ofHF (see Table 3). (Level of Evidence: A)

Beta-blockers are indicated in all patientswithout a history of MI who have a reducedLVEF with no HF symptoms (see Table 3 andtext). (Level of Evidence: C)


Spironolactone in HeartSpironolactone in HeartFailureFailure

•• 1999 RALES trial1999 RALES trial

•• 1663 patients with NYHA 31663 patients with NYHA 3--4 and EF <35%4 and EF <35%

•• Excluded creatinine >2.5 mg/dL or K+ >5Excluded creatinine >2.5 mg/dL or K+ >5mmol/Lmmol/L

•• Mean 24 month followupMean 24 month followup

•• 25mg qd spironolactone vs placebo25mg qd spironolactone vs placebo

•• NoNo --Blocker useBlocker use

•• All cause mortalityAll cause mortality

•• 46% placebo46% placebo

•• 35% spironolactone (p<0.001)35% spironolactone (p<0.001)Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity andmortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep2;341(10):709-17.


Spironolactone in HeartSpironolactone in HeartFailureFailure

•• 1999 RALES trial1999 RALES trial

•• 1663 patients with NYHA 31663 patients with NYHA 3--4 and EF <35%4 and EF <35%

•• Excluded creatinine >2.5 mg/dL or K+ >5Excluded creatinine >2.5 mg/dL or K+ >5mmol/Lmmol/L


•• 25mg qd spironolactone vs placebo25mg qd spironolactone vs placebo

•• NoNo --Blocker useBlocker use


•• 46% placebo46% placebo

•• 35% spironolactone (p<0.001)35% spironolactone (p<0.001)Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity andmortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep2;341(10):709-17.

ACC I - Addition of an aldosterone antagonist is reasonable in selectedpatients with moderately severe to severe symptoms of HF and reducedLVEF who can be carefully monitored for preserved renal function andnormal potassium concentration. Creatinine should be less than orequal to 2.5 mg/dL in men or less than or equal to 2.0 mg/dL in womenand potassium should be less than 5.0 mEq/L. Under circumstanceswhere monitoring for hyperkalemia or renal dysfunction is notanticipated to be feasible, the risks may outweigh the benefits ofaldosterone antagonists. (Level of Evidence: B)


Angiotensin ReceptorAngiotensin ReceptorBlockersBlockers

•• 2001 Val2001 Val--HeFTHeFT

•• 5010 patients with NYHA class 25010 patients with NYHA class 2--4, EF<40%4, EF<40%

•• 2 year followup2 year followup

•• Valsartan titrated to 160mg bid vs placeboValsartan titrated to 160mg bid vs placebo

•• On top of ACE,On top of ACE, --blockers, diuretics, digoxinblockers, diuretics, digoxin

•• No difference in all cause mortality (19.7% vsNo difference in all cause mortality (19.7% vs19.4%)19.4%)

•• Combined Death/CHF hospitalization favoredCombined Death/CHF hospitalization favoredvalsartan (28.8% vs 32.1%, p=0.009)valsartan (28.8% vs 32.1%, p=0.009)

•• 2000 ELITE2000 ELITE--22

•• No difference between captopril and losartanNo difference between captopril and losartanCohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan inchronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75.


Angiotensin ReceptorAngiotensin ReceptorBlockersBlockers

•• 2001 Val2001 Val--HeFTHeFT

•• 5010 patients with NYHA class 25010 patients with NYHA class 2--4, EF<40%4, EF<40%

•• 2 year followup2 year followup

•• Valsartan titrated to 160mg bid vs placeboValsartan titrated to 160mg bid vs placebo

•• On top of ACE,On top of ACE, --blockers, diuretics, digoxinblockers, diuretics, digoxin

•• No difference in all cause mortality (19.7% vsNo difference in all cause mortality (19.7% vs19.4%)19.4%)

•• Combined Death/CHF hospitalization favoredCombined Death/CHF hospitalization favoredvalsartan (28.8% vs 32.1%, p=0.009)valsartan (28.8% vs 32.1%, p=0.009)

•• 2000 ELITE2000 ELITE--22

•• No difference between captopril and losartanNo difference between captopril and losartanCohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan inchronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75.

ACC IIa - Angiotensin II receptorblockers are reasonable to use asalternatives to ACEIs as first-linetherapy for patients with mild tomoderate HF and reduced LVEF,especially for patients already takingARBs for other indications. (Level ofEvidence: A)


ARBARB’’s Revisiteds Revisited•• 2003 CHARM program2003 CHARM program

•• CHARMCHARM--AddedAdded•• 2548 patients, median followup 41 months2548 patients, median followup 41 months

•• Candesartan 32mg daily added to ACE and otherCandesartan 32mg daily added to ACE and othercontemporary therapycontemporary therapy

•• Reduction in death (23.7% v 27.3%, p=0.021)Reduction in death (23.7% v 27.3%, p=0.021)

•• Reduction in CHF hospitalization (24.2% v 28%,Reduction in CHF hospitalization (24.2% v 28%,p=0.018)p=0.018)

•• CHARMCHARM--AlternativeAlternative•• Patients intolerant of ACE benefited from ARB overPatients intolerant of ACE benefited from ARB over

placeboplaceboMcMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; CHARM Investigatorsand Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function takingangiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003 Sep 6;362(9386):767-71.

Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigatorsand Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerantto angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep 6;362(9386):772-6.


ARBARB’’s Revisiteds Revisited•• 2003 CHARM program2003 CHARM program

•• CHARMCHARM--AddedAdded•• 2548 patients, median followup 41 months2548 patients, median followup 41 months

•• Candesartan 32mg daily added to ACE and otherCandesartan 32mg daily added to ACE and othercontemporary therapycontemporary therapy

•• Reduction in death (23.7% v 27.3%, p=0.021)Reduction in death (23.7% v 27.3%, p=0.021)

•• Reduction in CHF hospitalization (24.2% v 28%,Reduction in CHF hospitalization (24.2% v 28%,p=0.018)p=0.018)

•• CHARMCHARM--AlternativeAlternative•• Patients intolerant of ACE benefited from ARB overPatients intolerant of ACE benefited from ARB over

placeboplaceboMcMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; CHARM Investigatorsand Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function takingangiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003 Sep 6;362(9386):767-71.

Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigatorsand Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerantto angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep 6;362(9386):772-6.

ACC IIb - The addition of an ARB maybe considered in persistentlysymptomatic patients with reducedLVEF who are already being treatedwith conventional therapy. (Level ofEvidence: B)


Device Therapy in Heart FailureDevice Therapy in Heart Failure

Device Therapy in ChronicDevice Therapy in ChronicSystolic Heart FailureSystolic Heart Failure


ICD for primary prevention hasICD for primary prevention hasmortality benefit for ischemicmortality benefit for ischemic

cardiomyopathycardiomyopathy•• 2002 MADIT II2002 MADIT II

•• Post MIPost MI

•• LVEF <30%LVEF <30%

•• ConventionalConventional

treatment vs.treatment vs.ICDICD


ICDICD’’s beneficial in primarys beneficial in primaryprevention for patients withprevention for patients with

Low EF regardless of etiologyLow EF regardless of etiology•• 2004 SCD2004 SCD--HEFTHEFT

•• 2521 patients with NYHA 22521 patients with NYHA 2--3,3,LVEF<35%LVEF<35%

•• ICD v amiodarone v placeboICD v amiodarone v placebo


•• 3 years: 17.1% v 24% v 22.3%3 years: 17.1% v 24% v 22.3%

•• 5 years: 28.9% v 34.1% v 35.8%5 years: 28.9% v 34.1% v 35.8%

Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE,Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 Jan20;352(3):225-37. Erratum in: N Engl J Med. 2005 May 19;352(20):2146.


ICDICD’’s beneficial in primarys beneficial in primaryprevention for patients withprevention for patients with

Low EF regardless of etiologyLow EF regardless of etiology•• 2004 SCD2004 SCD--HEFTHEFT

•• 2521 patients with NYHA 22521 patients with NYHA 2--3,3,LVEF<35%LVEF<35%

•• ICD v amiodarone v placeboICD v amiodarone v placebo


•• 3 years: 17.1% v 24% v 22.3%3 years: 17.1% v 24% v 22.3%

•• 5 years: 28.9% v 34.1% v 35.8%5 years: 28.9% v 34.1% v 35.8%

Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE,Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005 Jan20;352(3):225-37. Erratum in: N Engl J Med. 2005 May 19;352(20):2146.

ACC IIa - Placement of an implantable cardioverter-defibrillator is reasonable in patients with LVEF of 30% to35% of any origin with NYHA functional class II or IIIsymptoms who are taking chronic optimal medical therapyand who have reasonable expectation of survival with goodfunctional status of more than 1 year. (Level of Evidence: B)


Cardiac Resynchronization improves combined HFCardiac Resynchronization improves combined HFworsening/Death in patients with low EF and wide QRSworsening/Death in patients with low EF and wide QRS

•• 2002 MIRACLE2002 MIRACLE

•• 453 patients453 patients

•• EF <35%EF <35%

•• QRS >130msQRS >130ms

•• CardiacCardiacResynchronizatiResynchronization vs placeboon vs placebo

•• No mortalityNo mortalitybenefitbenefitdemonstrateddemonstrated


Cardiac Resynchronization improves combined HFCardiac Resynchronization improves combined HFworsening/Death in patients with low EF and wide QRSworsening/Death in patients with low EF and wide QRS

•• 2002 MIRACLE2002 MIRACLE


•• EF <35%EF <35%


•• CardiacCardiacResynchronizatiResynchronization vs placeboon vs placebo

•• No mortalityNo mortalitybenefitbenefitdemonstrateddemonstrated

ACC I - Patients with LVEF less than orequal to 35%, sinus rhythm, and NYHAfunctional class III or ambulatory classIV symptoms despite recommended,optimal medical therapy and who havecardiac dyssynchrony, which iscurrently defined as a QRS durationgreater than 0.12 ms, should receivecardiac resynchronization therapyunless contraindicated. (Level ofEvidence: A)


Pharmacological Treatment of AcutePharmacological Treatment of AcuteDecompensated Heart FailureDecompensated Heart Failure


NonpharmacologicalNonpharmacological/Device Therapy/Device Therapyfor Acute Decompensated Heartfor Acute Decompensated Heart

FailureFailure


Effect of Natrecor on PCWPEffect of Natrecor on PCWP


http://www.columbiasurgery.org/pat/cardiac/news_rematch.html

Thoratec HeartmateThoratec Heartmate2004 REMATCH2004 REMATCH

HF patients requiring inotropesHF patients requiring inotropes


http://www.columbiasurgery.org/pat/cardiac/news_rematch.html

Thoratec HeartmateThoratec Heartmate2004 REMATCH2004 REMATCH

HF patients requiring inotropesHF patients requiring inotropes

ACC IIa - Consideration of an LV assistdevice as permanent or “destination”therapy is reasonable in highly selectedpatients with refractory end-stage HFand an estimated 1-year mortality over50% with medical therapy. (Level ofEvidence: B)


New Directions in HeartNew Directions in HeartFailureFailure

•• Pathophysiologic implication ofPathophysiologic implication ofneurohormonal treatmentneurohormonal treatment

•• New medicationsNew medications

•• New devicesNew devices

•• Recognition of ComorbiditiesRecognition of Comorbidities


ReninRenin--AngiotensinAngiotensin systemsystem


Preventing Heart FailurePreventing Heart Failure

•• 2003 HOPE trial2003 HOPE trial

•• >=55 years old with>=55 years old with•• CAD, CVA or PAD orCAD, CVA or PAD or

•• Diabetes + at least 1 risk factorDiabetes + at least 1 risk factor•• HTN, HLP, smoking, microalbuminuriaHTN, HLP, smoking, microalbuminuria

•• Excluded EF <40%, uncontrolled HTN, CVA or MIExcluded EF <40%, uncontrolled HTN, CVA or MIin past 4 weeksin past 4 weeks

•• Ramipril 10mg daily vs placeboRamipril 10mg daily vs placebo


•• 4.5 year followup4.5 year followup

Arnold JM, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, Lonn E, Pogue J, Bosch J; HOPE Investigators. Prevention ofHeart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003 Mar 11;107(9):1284-90.


HOPE resultsHOPE results

•• New onset heart failureNew onset heart failure•• 9.0% with ramipril vs 11.5%9.0% with ramipril vs 11.5%

placebo (p<0.0001)placebo (p<0.0001)

•• Reduced risk of HFReduced risk of HFwhether or not there waswhether or not there wasan interim myocardialan interim myocardialinfarctioninfarction

•• Reduced risk for patientsReduced risk for patientswith SBP above medianwith SBP above median(139mmHg) and below(139mmHg) and belowmedianmedian

•• ConclusionConclusion –– RamiprilRamiprilreduces development ofreduces development ofHF in atHF in at--risk patientsrisk patients

Arnold JM, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, Lonn E, Pogue J, Bosch J; HOPE Investigators. Prevention ofHeart Failure in Patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003 Mar 11;107(9):1284-90.

ACC IIa - Angiotensin converting enzymeinhibitors can be useful to prevent HF inpatients at high risk for developing HF whohave a history of atherosclerotic vasculardisease, diabetes mellitus, or hypertensionwith associated cardiovascular risk factors.(Level of Evidence: A)


Neurohumoral vasoconstriction leading toNeurohumoral vasoconstriction leading torenal sodium and water retentionrenal sodium and water retention


New Directions in ChronicNew Directions in ChronicSystolic Heart FailureSystolic Heart Failure


EPHESUSEPHESUS


•• AcuteAcuteMyocardialMyocardialInfarctionInfarction

•• EF <40% andEF <40% and•• Heart FailureHeart Failure

(Rales) or(Rales) or

•• DiabetesDiabetes

•• EplerenoneEplerenone25mg daily vs25mg daily vsplaceboplacebo

Rate of Cardiac Death

Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, MullanyCJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr. ACC/AHA guidelines for the management of patients with ST-elevationmyocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004. Available atwww.acc.org/clinical/guidelines/stemi/index.pdf.


EPHESUSEPHESUS


•• AcuteAcuteMyocardialMyocardialInfarctionInfarction

•• EF <40% andEF <40% and•• Heart FailureHeart Failure

(Rales) or(Rales) or

•• DiabetesDiabetes

•• EplerenoneEplerenone25mg daily vs25mg daily vsplaceboplacebo

Rate of Cardiac Death

ACC I - Long-term aldosterone blockadeshould be prescribed for post-STEMI patientswithout significant renal dysfunction(creatinine should be less than or equal to 2.5mg/dL in men and less than or equal to 2.0mg/dL in women) or hyperkalemia (potassiumshould be less than or equal to 5.0 mEq/L)who are already receiving therapeutic dosesof an ACE inhibitor, have an LVEF of lessthan or equal to 0.40, and have eithersymptomatic heart failure or diabetes. (Levelof Evidence: A)

Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, MullanyCJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr. ACC/AHA guidelines for the management of patients with ST-elevationmyocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). 2004. Available atwww.acc.org/clinical/guidelines/stemi/index.pdf.


Isosorbide/Hydralazine isIsosorbide/Hydralazine isbeneficial in African Americansbeneficial in African Americans

•• 2004 A2004 A--HeFTHeFT

•• 1050 self1050 self--classified Africanclassified African--AmericansAmericans

•• NYHA class 3NYHA class 3--44•• LVEF<=35% orLVEF<=35% or

•• LVEF <=40% with LV dilatationLVEF <=40% with LV dilatation

•• BiDil (20mg isordil + 37.5mgBiDil (20mg isordil + 37.5mghydralazine) tid vs placebohydralazine) tid vs placebo

•• On top of standard tx including ACE,On top of standard tx including ACE, --blockers, diureticsblockers, diuretics

Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med2004; 351:2049-2057.


AA--HeFT resultsHeFT results


•• BiDil improved mortality and 1BiDil improved mortality and 1stst HF hospitalizationHF hospitalization

16.4% (p=0.001)16.4% (p=0.001)24.4%24.4%11stst HFHFhospitalizationhospitalization

6.2% (p=0.01)6.2% (p=0.01)10.2%10.2%AllAll--causecausemortalitymortality

BiDilBiDilplaceboplacebo



AA--HeFT resultsHeFT results


•• BiDil improved mortality and 1BiDil improved mortality and 1stst HF hospitalizationHF hospitalization

16.4% (p=0.001)16.4% (p=0.001)24.4%24.4%11stst HFHFhospitalizationhospitalization

6.2% (p=0.01)6.2% (p=0.01)10.2%10.2%AllAll--causecausemortalitymortality

BiDilBiDilplaceboplacebo


ACC IIa - The addition of isosorbide dinitrate andhydralazine to a standard medical regimen for HF,including ACEIs and beta-blockers, is reasonable andcan be effective in blacks with NYHA functional class IIIor IV HF. Others may benefit similarly, but this has notyet been tested. (Level of Evidence: A)

The addition of a combination of hydralazine and anitrate is reasonable for patients with reduced LVEFwho are already taking an ACEI and beta-blocker forsymptomatic HF and who have persistent symptoms.(Level of Evidence: A)


New Directions in AcuteNew Directions in AcuteDecompensated Heart FailureDecompensated Heart Failure


Arginine Vasopressin ReceptorArginine Vasopressin ReceptorAntagonistsAntagonists

•• New class of medicationsNew class of medications

•• Blocks effect of antidiuretic hormone (ADH)Blocks effect of antidiuretic hormone (ADH)

•• Facilitates Aquaresis (net loss of water without electrolytes)Facilitates Aquaresis (net loss of water without electrolytes)

•• Used in conjunction with other diureticsUsed in conjunction with other diuretics

•• ReceptorsReceptors•• V(1A) (vascular and myocardial effects)V(1A) (vascular and myocardial effects)

•• V(2) receptors (renal effects)V(2) receptors (renal effects)

•• Conivaptan (IV) is a a V(1A) + V(2) nonselective antagonist,Conivaptan (IV) is a a V(1A) + V(2) nonselective antagonist,approved for use in hyponatremia (SIADH)approved for use in hyponatremia (SIADH)

•• Tolvaptan (oral) is a V(2) selective antagonistTolvaptan (oral) is a V(2) selective antagonist


InIn--hospital outcomes of oral tolvaptan andhospital outcomes of oral tolvaptan andplacebo in ACTIV in CHFplacebo in ACTIV in CHF

2296.52296.54127.34127.3(<0.001)(<0.001)

4175.24175.2(<0.001)(<0.001)

4056.2 (0.02)4056.2 (0.02)Urine volumeUrine volume,,hospitalhospital day 1day 1,,mean mL (p vsmean mL (p vsplacebo)placebo)

1.901.903.203.20(0.06)(0.06)

2.80 (0.002)2.80 (0.002)3.30 (0.006)3.30 (0.006)Weight lossWeight loss vsvsbaseline, atbaseline, atdischargedischarge,,median kg (p vsmedian kg (p vsplacebo)placebo)

0.600.602.05 (0.009)2.05 (0.009)2.10 (0.002)2.10 (0.002)1.80 (0.002)1.80 (0.002)Weight lossWeight loss vsvsbaseline,baseline,hospitalhospital day 1day 1,,median kg (p vsmedian kg (p vsplacebo)placebo)

PlaceboPlacebo(n=80)(n=80)

Tolvaptan 90Tolvaptan 90mg/daymg/day(n=77)(n=77)



OutcomeOutcome

319 patients319 patients

Gheorghiade M et al. JAMA 2004; 291:1963-1971.


Adenosine A1 receptorAdenosine A1 receptorantagonistsantagonists

•• Elevated levels of plasma adenosine inElevated levels of plasma adenosine inheart failureheart failure

•• Adenosine lowers renal cortical blood flowAdenosine lowers renal cortical blood flow

•• Small phase 2 trial completedSmall phase 2 trial completed

•• Adenosine A1 receptor blockade can causeAdenosine A1 receptor blockade can causenatriuresis and diuresis without impact onnatriuresis and diuresis without impact onK+ excretion or GFRK+ excretion or GFR

Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, AbrahamWT. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretictherapy. Circulation. 2002 Mar 19;105(11):1348-53. Erratum in: Circulation 2002 Sep 24;106(13):1743.


UltrafiltrationUltrafiltration

•• Peripheral or centralPeripheral or centralvenous access optionsvenous access options

•• Catheter options includeCatheter options includeperipheral IVs, midlinesperipheral IVs, midlinesor centralor central

•• Fluid removalFluid removaladjustable from 10 toadjustable from 10 to500 ml/hour in 10500 ml/hour in 10ml/hour incrementsml/hour increments

•• Blood flow settable fromBlood flow settable from10 to 40 ml/min in 510 to 40 ml/min in 5ml/min incrementsml/min increments

•• Total extracorporealTotal extracorporealblood volume of 33 mlblood volume of 33 ml

http://www.chfsolutions.com/


Primary and secondary end points,Primary and secondary end points,ultrafiltrationultrafiltration vsvs standardstandard diuresisdiuresis inin

UNLOADUNLOAD

Costanzo MR. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

0.0150.015131333••Need forNeed for vasoactivevasoactive drugs (%)drugs (%)

0.0180.018121211••K<3.5K<3.5 mEqmEq/L (%)/L (%)

0.0010.0013.33.34.64.6••Net fluid loss (mean L)Net fluid loss (mean L)

0.350.356.1, n=836.1, n=836.4, n=806.4, n=80••DyspneaDyspnea score, primary endscore, primary endpoint (mean)point (mean)

0.0010.0013.1, n=843.1, n=845.0, n=835.0, n=83••Weight loss, primary end pointWeight loss, primary end point

(mean kg)(mean kg)

48 hours48 hours

ppDiuresisDiuresisUltrafiltrationUltrafiltrationEnd pointsEnd points

K=potassiumED=emergency department


Primary and secondary end points,Primary and secondary end points,ultrafiltrationultrafiltration vsvs standardstandard diuresisdiuresis inin

UNLOADUNLOAD

Costanzo MR. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

0.0090.00944442121••Unscheduled office/ED visits (%)Unscheduled office/ED visits (%)

0.0220.0223.83.81.41.4••RehospitalizationRehospitalization days (mean)days (mean)

0.0220.02232321818••RehospitalizationRehospitalization (%)(%)

90 days90 days

ppDiuresisDiuresisUltrafiltrationUltrafiltrationEnd pointsEnd points

K=potassiumED=emergency department


Calcium sensitizationCalcium sensitizationLevosimendenLevosimenden

•• Novel agent which improvesNovel agent which improvesmyocardial contractility withoutmyocardial contractility withoutincreasing intracellular calcium or cincreasing intracellular calcium or c--AMPAMP

•• Improves myocardial sensitivity toImproves myocardial sensitivity tocalciumcalcium

•• Vasodilator action by opening ATPVasodilator action by opening ATPsensitive K+ channelssensitive K+ channels


Early Levosimenden TrialsEarly Levosimenden Trials

•• Advanced decompensated heart failure (IV)Advanced decompensated heart failure (IV)•• 2003 LIDO (vs dobutamine)2003 LIDO (vs dobutamine)11

•• Improved PCWP and cardiac indexImproved PCWP and cardiac index

•• Improved 1 month (7.8% v 17%)and 6 month (26% v 38%) mortalityImproved 1 month (7.8% v 17%)and 6 month (26% v 38%) mortality

•• Improves BNP and inflammatory cytokines vs dobutamineImproves BNP and inflammatory cytokines vs dobutamine22

•• Improves PCWP and Cardiac Index in sepsisImproves PCWP and Cardiac Index in sepsis--inducedinducedcardiac dysfunction vs dobutaminecardiac dysfunction vs dobutamine33

•• Class 3Class 3--4 Heart Failure (oral)4 Heart Failure (oral)•• Improves inotropic parameters and increases heart rateImproves inotropic parameters and increases heart rate44

1 Follath F et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (theLIDO study): a randomised double-blind trial. Lancet. 2002 Jul 20;360(9328):196-202.2 Avgeropoulou C et al. The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels inpatients with advanced decompensated heart failure in comparison to dobutamine. Eur J Heart Fail. 2005 Aug;7(5):882-7.3 Morelli A, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive CareMed. 2005 May;31(5):638-44. Epub 2005 Apr 6.4 Poder P, Eha et al. Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severecongestive heart failure: a dosing interval study. J Clin Pharmacol. 2004 Oct;44(10):1143-50.


Later Levosimenden TrialsLater Levosimenden Trials•• 2005 REVIVE2005 REVIVE--22

•• Acute decompensated HF (EF<=35%), vs placebo; 600 patientsAcute decompensated HF (EF<=35%), vs placebo; 600 patients•• ““Clinical ImprovementClinical Improvement”” better at 24h and 5d with levosimendenbetter at 24h and 5d with levosimenden•• 90 day mortality rate favored placebo (11% v 15%, p=NS)90 day mortality rate favored placebo (11% v 15%, p=NS)

•• 2005 SURVIVE2005 SURVIVE•• Acute decompensated HF (EF<=30%), vs dobutamine; 1327 patientsAcute decompensated HF (EF<=30%), vs dobutamine; 1327 patients•• No significant survival advantage up to 6 monthsNo significant survival advantage up to 6 months

•• 2006 PERSIST (phase 2), Orion company sponsored2006 PERSIST (phase 2), Orion company sponsored•• Severe Heart failure patients (outpatient, oral)Severe Heart failure patients (outpatient, oral)•• No benefit vs placeboNo benefit vs placebo•• No plans for phase 3 trialNo plans for phase 3 trial

•• Subsequent trials have identified higher rates of atrialSubsequent trials have identified higher rates of atrialfibrillation, ventricular tachycardia, and hypotension withfibrillation, ventricular tachycardia, and hypotension withlevosimendenlevosimenden

Packer, M et al. Radnomize Evaluations of Levosimendan (REVIVE-2). Presented at AHA Scientific Sessions 2005, Dallas, TX.Mebazaa, A et al. SURVIVE. Presented at AHA Scientific Sessions 2005, Dallas, TX.Orion Pharmaceuticals. Results of PERSIST study with oral levosimendan. June 6, 2006. Available at:http://www.orion.fi/english/investors/stockreleases.shtml/a05?24526.


Endothelin Antagonists inEndothelin Antagonists inAcute Decompensated HeartAcute Decompensated Heart

FailureFailure•• 2005 VERITAS2005 VERITAS

•• TezosentanTezosentan –– IV dual endothelin receptorIV dual endothelin receptorantagonist v placebo on top of usual careantagonist v placebo on top of usual care

•• Largest study in acute decompensated HFLargest study in acute decompensated HF–– 1400 patients1400 patients

•• No difference in dyspnea at 24hNo difference in dyspnea at 24h

•• No difference in worsening heart failure orNo difference in worsening heart failure ormortality at 7 days (26% v 26%)mortality at 7 days (26% v 26%)

•• No mortality benefit at 6 monthsNo mortality benefit at 6 months

McMurray J et al. Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS). Presented atACC Scientific Sessions 2005, Orlando, FL.


New Evidence in Device Therapy forNew Evidence in Device Therapy forHeart Failure with Systolic DysfunctionHeart Failure with Systolic Dysfunction


Cardiac ResynchronizationCardiac Resynchronizationimproves mortality with EF<35%improves mortality with EF<35%

and wide QRSand wide QRS•• 2005 CARE2005 CARE--HFHF

•• 813 patients with NYHA 3813 patients with NYHA 3--4, LVEF4, LVEF<=35%, QRS>=120ms<=35%, QRS>=120ms

•• 29.4 month followup29.4 month followup

•• Cardiac resynchronization (BiCardiac resynchronization (Bi--VVpacing) vs standard medical therapypacing) vs standard medical therapy

•• All cause mortality 20% v 30% (p<0.002)All cause mortality 20% v 30% (p<0.002)

Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure(CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med.2005 Apr 14;352(15):1539-49. Epub 2005 Mar 7.


Cardiac Resynchronization forCardiac Resynchronization forNYHA class 2 patients?NYHA class 2 patients?

•• 50 patients Class 2 v 50 patients Class 350 patients Class 2 v 50 patients Class 3--44

•• NYHA class 2, LVEF <=35%NYHA class 2, LVEF <=35%


•• Class 2 patientsClass 2 patients

•• EF improved from 25% to 33%EF improved from 25% to 33%

•• Only 8% had worsening HF symptomsOnly 8% had worsening HF symptoms

•• Results comparable to Class 3Results comparable to Class 3--4 patients4 patients

Bleeker GB, Schalij MJ, Holman ER, Steendijk P, van der Wall EE, Bax JJ. Cardiac resynchronization therapy in patients withsystolic left ventricular dysfunction and symptoms of mild heart failure secondary to ischemic or nonischemic cardiomyopathy. Am JCardiol. 2006 Jul 15;98(2):230-5. Epub 2006 May 19.


Predicting Responders toPredicting Responders toCRTCRT

•• Currently a QRS width of >120ms isCurrently a QRS width of >120ms isused as a marker of LV dyssynchronyused as a marker of LV dyssynchrony

•• Echocardiographic parameters areEchocardiographic parameters areuseful to determine dyssynchronyuseful to determine dyssynchrony

•• Paradoxical septal motionParadoxical septal motion

•• Tissue doppler imagingTissue doppler imaging

•• SpeckleSpeckle

•• StrainStrain


Risk Stratification for ICDsRisk Stratification for ICDsMicrovolt T Wave AlternansMicrovolt T Wave Alternans

Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung ES, Menon S, Nallamothu BK, Chan PS. Prognostic utilityof microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol. 2006 May2;47(9):1820-7. Epub 2006 Apr 19.http://www.nature.com/ncpcardio/journal/v2/n10/images/ncpcardio0323-F1.gif


Risk Stratification for ICDsRisk Stratification for ICDsMicrovolt T Wave AlternansMicrovolt T Wave Alternans

Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung ES, Menon S, Nallamothu BK, Chan PS. Prognostic utilityof microvolt T-wave alternans in risk stratification of patients with ischemic cardiomyopathy. J Am Coll Cardiol. 2006 May2;47(9):1820-7. Epub 2006 Apr 19.http://www.nature.com/ncpcardio/journal/v2/n10/images/ncpcardio0323-F1.gif

•• Ischemic Cardiomyopathy, EF <=35%Ischemic Cardiomyopathy, EF <=35%•• Observational Cohort StudyObservational Cohort Study


ComorbiditiesComorbidities in Heart Failurein Heart Failure


Anemia is associated with increasedAnemia is associated with increasedmortality in Heart Failuremortality in Heart Failure


Treating anemia improvesTreating anemia improvesfunction in heart failurefunction in heart failure

•• Treatment with erythropoietin 15,000Treatment with erythropoietin 15,000--30,00030,000IU/week over 3 months improved anemiaIU/week over 3 months improved anemiaand function in small study of 26 patientsand function in small study of 26 patients

•• Patients with LVEF<=40%, NYHA 3Patients with LVEF<=40%, NYHA 3--4, Hgb4, Hgb

1010--11.5g% treated with epogen and IV iron11.5g% treated with epogen and IV ironover 8 months have improved EF, improvedover 8 months have improved EF, improvedfunction, decreased need for diuretics, andfunction, decreased need for diuretics, anddecreased hospitalizations (n=32)decreased hospitalizations (n=32)

Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients withmoderate to severe chronic heart failure. Circulation. 2003 Jan 21;107(2):294-9.

Silverberg DS, Wexler D, Sheps D, Blum M, Keren G, Baruch R, Schwartz D, Yachnin T, Steinbruch S, Shapira I, Laniado S, IainaA.. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin andintravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001 Jun 1;37(7):1775-80.


Treating anemia improvesTreating anemia improvesfunction in heart failurefunction in heart failure

•• Treatment with erythropoietin 15,000Treatment with erythropoietin 15,000--30,00030,000IU/week over 3 months improved anemiaIU/week over 3 months improved anemiaand function in small study of 26 patientsand function in small study of 26 patients

•• Patients with LVEF<=40%, NYHA 3Patients with LVEF<=40%, NYHA 3--4, Hgb4, Hgb

1010--11.5g% treated with epogen and IV iron11.5g% treated with epogen and IV ironover 8 months have improved EF, improvedover 8 months have improved EF, improvedfunction, decreased need for diuretics, andfunction, decreased need for diuretics, anddecreased hospitalizations (n=32)decreased hospitalizations (n=32)

Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients withmoderate to severe chronic heart failure. Circulation. 2003 Jan 21;107(2):294-9.

Silverberg DS, Wexler D, Sheps D, Blum M, Keren G, Baruch R, Schwartz D, Yachnin T, Steinbruch S, Shapira I, Laniado S, IainaA.. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin andintravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001 Jun 1;37(7):1775-80.

ACC IIb - The benefit of enhancingerythropoiesis in patients with HF andanemia is not established. (Level ofEvidence: C)


Cardiorenal SyndromeCardiorenal Syndrome

•• Concomitant Cardiac and RenalConcomitant Cardiac and Renaldysfunction leading to diureticdysfunction leading to diureticresistance and volume overloadresistance and volume overload

•• No formal standard definitionNo formal standard definition•• Rise in creatinine of 0.3 mg/dLRise in creatinine of 0.3 mg/dL

•• 1/31/3--1/2 of heart failure patients1/2 of heart failure patientsdevelop renal insufficiency (GFRdevelop renal insufficiency (GFR<60mL/min/1.73m2) in clinical trials<60mL/min/1.73m2) in clinical trials

•• Worse renal function = worse prognosisWorse renal function = worse prognosis

Geisberg C, Butler J. Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med. 2006 May;73(5):485-91.


Risk Factors for WorseningRisk Factors for WorseningRenal Function in the SOLVDRenal Function in the SOLVD

trialstrials•• Old ageOld age

•• Low EFLow EF

•• Baseline Renal dysfunctionBaseline Renal dysfunction

•• Low systolic blood pressureLow systolic blood pressure

•• Diabetes MellitusDiabetes Mellitus

•• HypertensionHypertension

•• Use of antiplatelet tx, diuretics, orUse of antiplatelet tx, diuretics, or --BlockersBlockers

Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J. Predictors of decreased renal function in patients with heart failure duringangiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD). Am Heart J. 1999Nov;138(5 Pt 1):849-55.


Treatment of CardiorenalTreatment of CardiorenalSyndromeSyndrome

•• ACE inhibitorsACE inhibitors

•• Start when patient is not dehydrated,Start when patient is not dehydrated,cautious use with creatinine >2.0cautious use with creatinine >2.0

•• DiureticsDiuretics

•• May lead to higher mortality, pump failureMay lead to higher mortality, pump failure

•• Diuretic resistance is a marker forDiuretic resistance is a marker foradvanced diseaseadvanced disease


New Horizons in SurgicalNew Horizons in SurgicalTreatment for Heart FailureTreatment for Heart Failure


•• EF <35%, scheduled primary offEF <35%, scheduled primary off--pump CABGpump CABG•• Epicardial autologous stem cellEpicardial autologous stem cell

transplantation (CD34+); injection sitestransplantation (CD34+); injection sitesdetermined by predetermined by pre--operativeoperativeechocardiogram, catheterization, and nuclearechocardiogram, catheterization, and nuclearstress imaging.stress imaging.

•• 20 patients randomized (placebo v stem cell)20 patients randomized (placebo v stem cell)•• Average baseline EF 30%, median 1 bypassAverage baseline EF 30%, median 1 bypass

graftgraft

•• 6 month FU6 month FU•• Mean EF improved in stem cell group (46% v 37%,Mean EF improved in stem cell group (46% v 37%,

p<0.001)p<0.001)Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel HC Jr, Kormos R, Benetti F. Surgical treatment for congestive heart failure withautologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg. 2005 Dec;130(6):1631-8.Epub 2005 Oct 26.

Stem Cell TherapyStem Cell Therapy


Update on Anticoagulation TrialsUpdate on Anticoagulation Trials


Anticoagulation Does NotAnticoagulation Does NotReduce Thromboembolic RiskReduce Thromboembolic Risk

in HFin HF•• 2004 WATCH2004 WATCH11

•• 1587 patients with HF and LVEF <35%; 23 months FU1587 patients with HF and LVEF <35%; 23 months FU•• ASA (162mg/d) v clopidogrel v Warfarin (INR 2.5ASA (162mg/d) v clopidogrel v Warfarin (INR 2.5--3)3)•• Similar rates of death, MI and strokeSimilar rates of death, MI and stroke

•• 2004 WASH2004 WASH22

•• 279 patients with HF; 27 months FU279 patients with HF; 27 months FU•• Placebo v ASA v WarfarinPlacebo v ASA v Warfarin•• No differences in primary endpoint of death, nonfatal MI, orNo differences in primary endpoint of death, nonfatal MI, or

nonfatal strokenonfatal stroke

•• 2006 HELAS2006 HELAS33

•• Ischemic/nonischemic cardiomyopathyIschemic/nonischemic cardiomyopathy•• 115 patients, ASA v Warfarin; 2.5 years FU115 patients, ASA v Warfarin; 2.5 years FU•• No differences in the primary composite end point of death, MI,No differences in the primary composite end point of death, MI,

hospitalization, HF exacerbation, or hemorrhagehospitalization, HF exacerbation, or hemorrhage

1 Massie BM et al. Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH). Presented at ACC Scientific Sessions 2004,New Orleans, LA.2 Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart Failure (WASH): A randomized trial comparingantithrombotic strategies for patients with heart failure. Am Heart J 2004; 148:157-64.3 Cokkinos DV, Haralabopoulos GC, Kostis JB, et al. Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study.Eur J Heart Fail 2006; 8:428-432.


Anticoagulation Does NotAnticoagulation Does NotReduce Thromboembolic RiskReduce Thromboembolic Risk

in HFin HF•• 2004 WATCH2004 WATCH11

•• 1587 patients with HF and LVEF <35%; 23 months FU1587 patients with HF and LVEF <35%; 23 months FU•• ASA (162mg/d) v clopidogrel v Warfarin (INR 2.5ASA (162mg/d) v clopidogrel v Warfarin (INR 2.5--3)3)•• Similar rates of death, MI and strokeSimilar rates of death, MI and stroke

•• 2004 WASH2004 WASH22

•• 279 patients with HF; 27 months FU279 patients with HF; 27 months FU•• Placebo v ASA v WarfarinPlacebo v ASA v Warfarin•• No differences in primary endpoint of death, nonfatal MI, orNo differences in primary endpoint of death, nonfatal MI, or

nonfatal strokenonfatal stroke

•• 2006 HELAS2006 HELAS33

•• Ischemic/nonischemic cardiomyopathyIschemic/nonischemic cardiomyopathy•• 115 patients, ASA v Warfarin; 2.5 years FU115 patients, ASA v Warfarin; 2.5 years FU•• No differences in the primary composite end point of death, MI,No differences in the primary composite end point of death, MI,

hospitalization, HF exacerbation, or hemorrhagehospitalization, HF exacerbation, or hemorrhage

1 Massie BM et al. Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH). Presented at ACC Scientific Sessions 2004,New Orleans, LA.2 Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart Failure (WASH): A randomized trial comparingantithrombotic strategies for patients with heart failure. Am Heart J 2004; 148:157-64.3 Cokkinos DV, Haralabopoulos GC, Kostis JB, et al. Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study.Eur J Heart Fail 2006; 8:428-432.

ACC IIb - The usefulness of anticoagulation isnot well established in patients with HF whodo not have atrial fibrillation or a previousthromboembolic event. (Levelof Evidence: B)

Update on Anticoagulation TrialsUpdate on Anticoagulation Trials


Diastolic Heart FailureDiastolic Heart Failure

A Few Words on DiastolicA Few Words on DiastolicHeart FailureHeart Failure……


Development of DiastolicDevelopment of DiastolicHeart FailureHeart Failure


Diagnostic Criteria forDiagnostic Criteria forDiastolic Heart FailureDiastolic Heart Failure


ACC 2005


CHARMCHARM--preserved trialpreserved trial

•• 3025 patients, median followup 363025 patients, median followup 36monthsmonths

•• Candesartan titrated to 32mg daily vsCandesartan titrated to 32mg daily vsplaceboplacebo

15.9 (p=0.047)15.9 (p=0.047)18.318.3CHFCHFHospitalizationHospitalization

11.211.211.311.3CV DeathCV Death

candesartancandesartanplaceboplacebo

Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigatorsand Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: theCHARM-Preserved Trial. Lancet. 2003 Sep 6;362(9386):777-81.


Prognosis of Diastolic v SystolicPrognosis of Diastolic v SystolicHeart FailureHeart Failure

•• Canadian 1 year studyCanadian 1 year study•• 2802 patients with new HF and documented EF2802 patients with new HF and documented EF

•• Compared 1570 pts with EF<40% with 880 ptsCompared 1570 pts with EF<40% with 880 ptswith EF>50%with EF>50%

•• Groups clinically not distinguishable at admissionGroups clinically not distinguishable at admission

•• 1 year mortality 22% (diastolic) v 25% (systolic)1 year mortality 22% (diastolic) v 25% (systolic)

•• American 15 year studyAmerican 15 year study•• 4596 patients discharged with HF4596 patients discharged with HF

•• 2429 pts with EF <50%, 2167 pts with EF >=50%2429 pts with EF <50%, 2167 pts with EF >=50%

•• At 5 years, mortality hazard ratio for diastolic HFAt 5 years, mortality hazard ratio for diastolic HFwas 0.96 (CI 0.92was 0.96 (CI 0.92--1.00); better for <65 yrs age (0.87)1.00); better for <65 yrs age (0.87)

Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med2006; 355:260-269.Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl JMed 2006; 355:251-259.


In Summary:In Summary:The OldThe Old

•• DigoxinDigoxin•• For relief of symptomsFor relief of symptoms

•• DiureticsDiuretics•• As needed for volume control and symptomsAs needed for volume control and symptoms

•• ACE InhibitorsACE Inhibitors•• All patients with systolic dysfunctionAll patients with systolic dysfunction•• To prevent HF in high risk populationTo prevent HF in high risk population•• ARB ok if ACE intoleranceARB ok if ACE intolerance

•• --BlockersBlockers•• For all patients with systolic dysfunctionFor all patients with systolic dysfunction

•• AldactoneAldactone•• For class NYHA 3For class NYHA 3--4 patients4 patients


The Recent NewThe Recent New

•• Isordil/HydralazineIsordil/Hydralazine

•• African Americans, on top of other therapyAfrican Americans, on top of other therapy

•• ARBARB’’s in addition to ACEs in addition to ACE

•• ARBARB’’s for diastolic heart failures for diastolic heart failure

•• ACE may prevent heart failureACE may prevent heart failure

•• ICD for EF <35%ICD for EF <35%

•• BiVentricularBiVentricular pacingpacing

•• EF<35%, QRS 120ms, NYHA 3EF<35%, QRS 120ms, NYHA 3--44


The NewThe New

•• Ultrafiltration for decompensated heart failureUltrafiltration for decompensated heart failure

•• LVAD as a destination therapy for refractory heartLVAD as a destination therapy for refractory heartfailurefailure

•• AVP receptor antagonistsAVP receptor antagonists

•• Adenosine AAdenosine A11 antagonistsantagonists

•• Stem cell therapyStem cell therapy

•• Predicting risk of sudden cardiac death by microvoltPredicting risk of sudden cardiac death by microvolttt--wave alternanswave alternans

•• Recognition that diastolic and systolic heart failureRecognition that diastolic and systolic heart failurehave similar (bad) prognosishave similar (bad) prognosis


ReferencesReferences

•• Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TGHunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M,, Jessup M,Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA,Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, YancyStevenson LW, YancyCW. ACC/AHA 2005 guideline update for the diagnosis and managemeCW. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heartnt of chronic heartfailure in the adult: a report of the American College of Cardiofailure in the adult: a report of the American College of Cardiology/American Heartlogy/American HeartAssociation Task Force on Practice Guidelines (Writing CommitteeAssociation Task Force on Practice Guidelines (Writing Committee to Update the 2001to Update the 2001Guidelines for the Evaluation and Management of Heart Failure).Guidelines for the Evaluation and Management of Heart Failure). American College ofAmerican College ofCardiologyCardiology


heart failure update - dr. stultzdrstultz.com/presentations/2006 08 16 update in heart...

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