Advances in the Management of Heart Failure

Daniel P. Fishbein, M.D.Professor of Medicine

Medical Director, Heart Failure and Cardiac Transplantation

University of Washington Medical Center

The Scope of the Problem - CHF

• 5 million patients with CHF (10 million by 2020)• 500,000 new cases/year • 1,000,000 hospitalizations/year• Incidence doubles with each decade after age 45• CHF is leading DRG• $29 - 50 billion annual cost; 60% of this cost is spent on

hospitalization for ADHF• CHF “epidemic” driven by aging U.S. population, improved

survival of ACS, improved long-term survival• 50% of patients have preserved left ventricular ejection

fraction

What is Heart Failure?

• Heart failure is a syndrome caused by an abnormality of cardiac function that is characterized by impaired exercised tolerance due to shortness of breath and/or fatigue, SOB at rest, systemic and pulmonary venous, and an increase in mortality due to progressive pump failure or ventricular arrhythmias

• Final common pathway for a number of cardiac/cardiovascular diseases

• Heart Failure with Reduced Ejection Fraction (HFrEF)• Heart Failure with Preserved Ejection Fraction

(HFpEF); aka diastolic dysfunction

How do we describe heart failure?• Etiology: ischemic, idiopathic, post-viral,

hypertensive, toxic, valvular• NYHA Functional Class

- FC I: no symptoms- FC II: symptoms with more than usual activity- FC III: symptoms with minimal activity- FC IV: symptoms at rest

• ACC/AHA Stage: course of disease• Clinical assessment:

– “wet” or “dry– “cold” or “warm”

Clinical Assessment of Hemodynamics

Cold handsLow BPLow pulse prTachycardiaConfusionAgitation

PND, Orthopnea, Edema, JVD, Rales, Effusions

LV=left ventricular, MI=myocardial infarctionAdapted from Yancy CW et al. Prim Care Spec Ed 2002;6:15-19.

High Risk: Hypertension, coronary artery disease, diabetes, family history of cardiomyopathy

Asymptomatic LVD: Previous MI, LV systolic dysfunction, asymptomatic valvular disease

Symptomatic HF: Known structuralheart disease, shortness of breath and

fatigue, reduced exercise tolerance

RefractoryEnd-Stage HF:

Marked symptomsat rest despite maximal

medical therapy

A

B

C

D

Heart Failure Disease Progression: ACC/AHA Heart Failure Stages

Causes of Heart Failure with Reduced EF• Coronary artery disease• Ischemic cardiomyopathy• Hypertensive heart disease• Idiopathic cardiomyopathy• Familial cardiomyopathy• Valvular Cardiomyopathy

– Aortic stenosis– Aortic insufficiency– Mitral regurgitation

• Viral/post-viral/lymphocytic myocarditis• Alcohol-related cardiomyopathy• Thyroid disease (hypo or hyper)• Restrictive/hypertrophic cardiomyopathy• Sarcoid• Cardio-toxic substances: anthracyclines, herceptin, cyclophosphamide,

methamphetamines, cocaine• Giant cell myocarditis• Amyloid, hemochromatosis, eosinophilic myocarditis• SLE, systemic sclerosis

Heart Failure Symptoms• Shortness of breath and/or fatigue with activity• Shortness of breath at rest• Shortness of breath with recumbency (orthopnea) or at night

(PND) – probably the most specific symptoms for heart failure• Edema • Fatigue • Chest pain• Abdominal swelling, liver pain• Poor appetite• Weight loss• Syncope• Stroke

Heart Failure Signs• Rales • Evidence of pleural effusions• Elevated jugular venous pressure – the most

specific physical finding for congestion• S3 – specific for LV dysfunction• Edema - when combined with JVP, specific for HF• MR murmur• Hepatomegaly• Ascites• Cool extremities• Low pulse pressure• Tachycardia

CHF Initial Evaluation• Consider in patients with unexplained SOB especially with

JVD, edema, evidence of pulmonary congestion, or unexplained tachycardia.

• Obtain an echocardiogram: ventricular dimensions, LV and RV function, assessment of valvular regurgitation and stenosis, assessment of PA and RA pressures.

• History, exam, ECG, CXR, Echo, TFTs, chemistries, BUN, creatinine, BNP, CBC with differential, UA, transferrin saturation and ferritin, consider plasma light chains, SPEP and UPEP especially in patients without ventricular dilation

• Evaluation for CAD– Coronary angiography– SPECT– Stress PET– Dobutamine stress echo– CT angiography

Diagnostic and Therapeutic Goals in Patients Presenting with Heart Failure

• Identify underlying cause(s) of heart failure especially those that may be reversible/treatable : CAD/ischemia, valvular disease, uncontrolled HTN, thyroid abnormalities, alcohol, drugs, iron overload.

• Identify conditions that may worsen heart failure: atrial arrhythmia, infection, sleep apnea, urinary obstruction, dietary and medication non-adherence, thyroid abnormalities, alcohol or drug use, meds (NSAIDS, COX 2, TZDs, CCBs, BBs).

• Improve symptoms• Prevent/reverse ventricular remodeling• Prevent arrhythmic death (SCD)• Secondary prevention of AMI• Prevent stroke• Improve survival

Heart Failure PathophysiologyMyocardial Injury Fall in LV Performance

Cardiac output

Activation of RAAS and SNS( ET1, AVP, cytokines)

Myocardial Toxicity Gene Expression

Peripheral Vasoconstriction Na/Water Retention

Remodeling andProgressive

Worsening ofLV Function Heart Failure SymptomsMorbidity and Mortality

Effect of ACEI in Patients with CHF

CONSENSUS*NYHA Class IV

SOLVD Treatment†

NYHA Class II-III

*Risk reduction 40% (P=0.003).†Risk reduction 16% (P=0.0036).Reprinted with permission from CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435; SOLVD Investigators. N Engl J Med. 1991;325:293-302.

Placebo(n=126)

Enalapril(n=126)

Enalapril(n=1285)

60

80

40

20

0

Placebo(n=1284)

Mor

talit

y (%

)

126 18 30 36 420 24 48

Months

CONSENSUS and SOLVD

ACEI in Patients with Systolic DysfunctionGarg et al. JAMA 1995;273:1450-6

• > 32 randomized trials of ACEI including enalapril, captopril, ramipril, quinapril and lisinopril

• 23% reduction in all-cause mortality largely due to reduction in death from progressive heart failure (HR 0.69)

• 35% reduction in mortality or HF hospitalization• Similar effects were observed among different ACEI• Benefit was seen across various subgroups but

greatest in patients with the lowest ejection fraction

High vs Low Dose Lisinopril: ATLASPacker et al. Circulation 1999;100: 2312 - 8

• 3164 patients with FC II – IV heart failure and LVEF 30%

• Low (2.5-5 mg qd) vs high (32.5 vs 35 mg qd) dose lisinopril

• Median follow-up 45.7 months• Hazard Ratios:

All-cause mortality 0.92 P = 0.128CV mortality 0.90 P = 0.073Mortality and Hosp 0.88 P = 0.002Mortality and CHF Hosp 0.85 P < 0.001

• ~30% of patients stopped drug and 20% started on open label during course of study

ARBs versus placebo in patients with chronic HF

Lee V C et al. Ann Intern Med 2004;141:693-704

ARBs versus ACEI in patients with chronic HF

Lee V C et al. Ann Intern Med 2004;141:693-704

ARB and ACEI combinations versus ACE inhibitors in patients with chronic HF

Lee V C et al. Ann Intern Med 2004;141:693-704

ACEI and ARB in Chronic Heart Failure• Cornerstone of heart failure therapy• ACEI should be use first – improve survival, decrease

hospitalization, inhibit remodeling, improve symptoms, improve functional class, inexpensive, well tolerated

• Benefits of ACEI appear to be class-specific• ACEI should be uptitrated every 2-3 weeks to target

dose (enalapril 10 mg bid or equivalent)• ARBs should be used in patients intolerant to ACEI

(cough, angioedema) (losartan 50 mg bid or equivalent)• The benefits of ARBS are nearly equivalent to ACEI• The benefit of adding and ARB to background ACEI and

-blockade has not been clearly established.

Aldosterone Blockade: Rationale

• Aldosterone levels associated with mortality in HF • Aldosterone is produced in tissues other than the

kidney including heart and blood vessels• Aldosterone production is not completely inhibited

by ACEI or ARB• Aldosterone has multiple non-renal effects

including SNS activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, vascular injury and decreased arterial compliance, reactive oxygen species, alterations in ion channels, prolonged ventricular repolarization

Pitt, B. et al. N Engl J Med 1999;341:709-717

Spironolactone 25 mg qd in patients with advanced heart failure – The Rales Trial

HR= 0.70

HR SCD = 0.71

HR CV H = 0.70

Eplerenone 25 – 50 mg qd in Patients with Recent AMI, EF 40% and CHF or Diabetes – The EPHESUS Trial

Months Since Randomization

Cumulative Incidence (%)

22

0

2

20

16

18

14

12

10

8

6

4

Total Mortality RR = 0.85; P = 0.008

SCD RR = 0.79; P = 0.03

Placebo

Eplerenone

3633302724211815129630

EMPHASIS-HF: Eplerenone in Mild HF and LVEF ≤ 35%

Zannad F et al. N Engl J Med 2011;364:11-21.

Aldosterone Blockade in Chronic Heart Failure• Improve survival, decrease SCD, decrease HF

hospitalization, improve symptoms and decrease ventricular remodeling in patients with FC III-IV symptoms or HF complicating recent MI

• Probably a class effect, fewer side effects with eplerenone• Indicated in patients with NYHA FC 2-4 HF symptoms

and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration

• Creatinine ≤ 2.5 mg/dL in men and 2.0 mg/dL in women; potassium < 5.0 mEq/L

• In EPHESUS and RALES, potassium measured at 48 hours, one, four and five weeks and every three months – study drug decreased or held for K > 5.5 mmol/L

Rates of Hyperkalemiaand DeathAfter Publicationof RALES

500% inspironolactone Rx(p<0.001)

275% inhosp for hyperkalemia(p<0.001)

285% in deathdue to hyperkalemia(p<0.001)

(Juurlink, et al. NEJM 2004;351:543)

Digoxin

• Mild positive inotrope• Autonomic effects, sympathoinhibitory, plasma

NE, plasma renin levels• Improves exercise tolerance and sxs in CHF• DIG Trial - ~7000 pts with mild – moderate CHF

randomized to dig or placebo. No difference in mortality but fewer hospitalizations in pts with more severe HF

• Increased mortality with higher dig levels• Use as adjunctive therapy in patients with

persistent FC III-IV sxs with target dig levels < 0.8 – 1.0 ng/dL

DIG Trial - Mortality

N Engl J Med 1997; 336:525-33

DIG Trial –HF Hospitalization

N Engl J Med 1997; 336:525-33

Rathore, S. S. et al. N Engl J Med 2002;347:1403-1411

The DIG Trial: Survival by Gender

HR = 1.23

The DIG Trial: Event Rates Adjusted for Digoxin Levels (Dose Matters!)

Mortality Mortality and Hospitalization

Adams et al. JACC 2005; 46: 497 - 504

BETA BLOCKER TRIALS IN CHF

Drug Patients Mortality

(%)

USCHFSG Carvedilol 1,094 65

CIBIS-II Bisoprolol 2,647 32

MERIT-HF Metroprolol XL 3,991 34

Copernicus Carvedilol 2,289 35

BEST Bucindolol 2,708 8.5

Lancet 1999; 353:9-13

CIBIS II

HR =0.68

PlaceboMetoprolol CR/XL

MERIT-HF

Lancet 1999; 353:2001- 07

Follow-up (months)

Cum

ulat

ive

mor

talit

y (%

) HR = 0.65

HR SCD = 0.60

Packer, M. et al. N Engl J Med 2001;344:1651-1658

COPERNICUS

HR = 0.65

HR SCD = 0.67

Not all -blockers Work

BEST Xamoterol Study Group

Lancet 1990;336:1-6N Engl J Med 2001; 344: 1659-67

Carvedilol vs Metoprolol: LV FunctionMetra M et al. Circulation. 2000;102:546–551.

0

2

4

6

8

10

12

14

16

Ab

solu

te C

han

ge

Fro

mB

asel

ine

LVE

F u

nit

s (%

)

-40

-35

-30

-25

-20

-15

-10

-5

0

mL

/m2

LVEF LV EDV LV ESV

Metoprolol†

(n=61)Carvedilol

(n=61)

***

***

**

***

***

***

*

*P<.05; **P<.01; ***P<.001.

†Metoprolol tartrate.

150 HF patients on diuretics, ACE inhibitors, +/- digoxin were randomized to double-blind treatment; 122 had EF/hemodynamic assessments at baseline and after 13–15 months of treatment. Achieved doses Metoprolol 124 mg/d vs Carvedilol 49 mg/day

b-Blockers – Time Course of Improvement

0

5

10

15

20

25

30

35

40

45

0 1 day 1 month 3 months 18months

LVE

F %

Hall et al JACC 1995; 25:1154-61

-Blocker Dose: MOCHABristow, M. R. et al. Circulation 1996;94:2807-2816

Change in LVEF 6 Month Mortality

Time (years)

Mo

rtal

ity

(%)

0

10

20

30

40

0 1 2 3 4 5

Metoprolol tartrate (85 mg qd)

Carvedilol (42 mg qd)

hazard ratio 0.83, 95% CI 0.74-0.93, P = 0.0017

Number at risk

Carvedilol 1511 1367 1259 1155 1002 383Metoprolol 1518 1359 1234 1105 933 352

Primary endpoint of mortality

-Blockers in Heart Failure

• Cornerstone of chronic HF therapy• mortality by 35%, sudden and heart failure related

death• Improve LVEF 8-12%• Benefits may be limited to the BB demonstrated in

clinical trials to be effective – these are the BB that should be used to treat heart failure: carvedilol, metoprolol succinate, bisoprolol

• Should be used in combination with ACEI or ARB• Initiate at low dose and up-titrate to target doses used

clinical trials: carvedilol 25 mg bid; metoprolol succinate 150 mg daily; bisoprolol 10 mg daily

Diuretics• No randomized controlled clinical trials to guide therapy• Goals: improve symptoms by relieving pulmonary and

systemic venous congestion without impairing systemic perfusion or renal function and while maintaining normal electrolytes

• Most patients need a loop diuretic• Furosemide, bumetanide, torsemide• Need to achieve a threshold dose that results in diuresis• If patients remain volume overloaded, increase the

frequency of dosing, especially if using furosemide• In diuretic resistant patients, adding a thiazide or

metolazone may be helpful but is associated with more hypokalemia

African-American Heart Failure Trial• African-American patients with NYHA FC III – IV

symptoms of heart failure for three months, LVEF 35%, treated with optimal medical therapy

• Randomized to placebo vs fixed-dose combination of isosorbide dinitrate and hydralazine 20/37.5 mg tid increasing to 40/75 mg tid

• Primary endpoint composite score composed of death, first CHF hospitalization and change in QOL

• 1050 patients enrolled – Age 57, Men 59%, FC III 95%, LVEF 24%, ischemic 23%, hypertensive 38%, weight 93 kg, SBP 126 mm Hg, BB 74%, ACE/ARB 86%

A-HeFT

NEJM 2004;351:2049 -57

HR 0.57

Hydralazine and Isosorbide

• Recommended for African Americans who remain symptomatic despite optimal medical therapy

• Reasonable for patients who have persistent symptoms despite optimal medical therapy

• Reasonable for patients with severe HF symptoms who are intolerant of ACEI or ARB, especially when this therapy is limited by hypotension or renal insufficiency

• No trials data addressing the use of Hyd/ISDN in non-African American patients with persistent symptoms or in patients with ACEI or ARB intolerance

• Compliance difficult - tid dosing and side effects

PARAGIGM - HF• Enalapril 10 mg bid vs valsartan 160 mg plus

sacubitril 40 mg bid• Sacubitril is an neprilysin inhibitor• Neprilysin is a neutral endopeptidase that

degrades several endogenous vasoactive peptides including natriuretic peptides, bradykinin, and adrenomedullin

• Inhibition of neprilysin increases levels of these peptides and counters neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling

PARADIGM-HF: Enalapril vs Valsartan and Neprilysin Inhibitor Sacubitril

Pitt B et al. N Engl J Med 2014;370:1383-1392.

Sudden Cardiac Death In CHF

• ~ 50% of deaths in patients with CHF are due to SCD • SCD is the primary mode of death in patients with less severe

CHF• SCD risk factors: CAD, poor LV function, history of syncope,

symptomatic ventricular arrhythmias• Primary prevention strategies are limited by the lack of specific

predictors of SCD – ambient ectopy, EP testing, signal averaged ECG are not useful screening studies. It has not yet been possible to identify those patients without a prior history of symptomatic arrhythmias who are at highest risk

• Conventional antiarrhythmic drugs increase risk of SCD• ACEI, beta-blockers, and aldosterone receptor antagonists

decrease SCD risk

MADIT II Survival in Patients with Prior MI and LVEF ≤ 30%

Moss AJ. et al. N Engl J Med 2002; 346:877

HR = 0.69

P = 0.007

00

0.10.1

0.20.2

0.30.3

0.40.4

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

Mo

rtal

ity

Mo

rtal

ity

Months of follow-upMonths of follow-up

AmiodaroneAmiodarone

ICD TherapyICD Therapy

PlaceboPlacebo

HR 97.5% CI P-ValueAmiodarone vs Placebo 1.01 0.86, 1.30 0.529ICD Therapy vs Placebo 0.77 0.62, 0.96 0.007

SCD-HeFT - Mortality

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

00 1212 2424 3636 4848 6060

Mo

rtal

ity

Mo

rtal

ity

Months of follow-upMonths of follow-up

ICD TherapyICD Therapy

PlaceboPlacebo

00 1212 2424 3636 4848 6060Months of follow-upMonths of follow-up

Mortality by NYHA Class: ICD vs. Placebo

Class II Class III

HR 97.5% CI0.54 0.40, 0.74

HR 97.5% CI1.16 0.84, 1.61

32%

46%

20%

48%

Sudden Cardiac Death

SCD-HeFT Heart Failure Trial

ICD Therapy for Primary Prevention

• Recommended in patients with non-ischemic dilated cardiomyopathy or ischemic heart disease with LVEF ≤ 35% and NYHA FC I – III symptoms

• Patients should have a reasonable expectation of survival with good functional status for more than 1 year.

• In patients with CAD, – Need to wait at least 40 days post-MI before implanting– Need to wait 3 months following CABG or PCI

• In patients with non-ischemic cardiomyopathy, CMS requires that patients wait 3 months since onset of heart failure

• Limitations: inappropriate shocks, RV pacing, post-shock worsening heart failure, lead complications

Cardiac Resynchronization Therapy

• ~ 30 - 40 % of patients with low EF and FC III-IV symptoms have a QRS duration of > 120 msec

• QRS prolongation is a manifestation of abnormal cardiac conduction and has been used to identify patients with dyssynchronous ventricular contraction

• Mechanical synchrony can be restored with atrial synchronized biventricular pacing (RV and LV lead)

Cardiac Resynchronization Therapy

• In patients with NYHA FC 2-4 HF, LVEF ≤ 35% and QRS ≥ 150 msec, CRT has been shown to: improve ventricular function; decrease MR; improve sxs, 6 minute walk distance, FC, and LV function; decrease neurohormonal activation; and decrease HF hospitalization

• Meta-analysis (McAlister et al. JAMA2007; 297: 2502) of 14 randomized clinical trials of CRT demonstrated:– 37% decrease in hospitalization– 22% decrease in all-cause mortality

Optimal Management of HFrEF• ACEI at target dose enalapril (10 mg bid or

equivalent) – if intolerant, ARB at target dose (losartan 50 mg bid or equivalent)

• Diuretics to relieve pulmonary and systemic venous congestion

• Spironolactone or eplerenone with careful monitoring of potassium

• Primary prevention ICD for LVEF < 36%• CRT-D for QRS ≥ 150 msec and LVEF≤ 35%

Predictors of Outcome in Patients with Heart Failure

• Ejection Fraction• NYHA FC• Recurrent hospitalization• Low systolic blood pressure, pulse pressure, proportional

pulse pressure• Inability to initiate or need to withdrawal β-blockers or

ACEI/ARB• Elevated BUN and creatinine• Right heart failure• Diuretic dose• Seattle Heart Failure Model

The Seattle Heart Failure Model

• Multivariate risk model to predict 1, 2, and 3 year survival in heart failure patients using easily obtainable clinical characteristics, therapy, and lab parameters

• Derived from 1125 patients from the PRAISE Trial, prospectively validated in five additional cohorts (9942 patients)

• Parameters included:

Clinical: age, weight gender, NYHA FC, LVEF, systolic BP, presence of coronary disease

Therapy: ACEI, ARB, -blocker, statin, allopurinol, aldosterone blocker, diuretic dose, ICD, BiV Pacer or ICD

Labs: Hgb, % lymphocytes, uric acid, total cholesterol, serum sodium

Levy et al. Circulation 2006; 113: 1424-33

The Seattle Heart Failure Modelhttp://depts.washington.edu/shfm/

Levy, W. C. et al. Circulation 2006;113:1424-1433

Potential Targets for New Drugs

HFpEF - Clinical Picture• Most prevalent in older women with a history of

hypertension, diabetes and/or coronary artery disease, frequently with a history of atrial fibrillation

• Dyspnea at rest and with activity• Recurrent hospitalization for CHF, not

uncommonly presenting with acute pulmonary edema

• Labile and poorly controlled hypertension• Accentuated sodium and diuretic sensitivity• Atrial fibrillation poorly tolerated

Causes of Heart Failure with Normal EF• Myocardial Disease

Hypertension-associated hypertrophyAgeIschemic heart disease (ischemia/scarring)Diabetes/metabolic syndromeHypertrophic cardiomyopathyRestrictive cardiomyopathyInfiltrative cardiomyopathies (amyloid, hemochromatosis,sarcoid)

• Valvular Heart DiseaseAcute aortic insufficiencyAortic stenosisMitral stenosisAcute mitral regurgitation

• Pericardial diseaseConstriction, tamponade

• High output states Anemia, hyperthyroidism, Paget disease, AV fistulae

Aurigemma, G. P. et al. Circulation 2006;113:296-304

LV diastolic pressure-volume data

HFpEF - Outcomes• Diastolic dysfunction without heart failure

associated with increased risk; community based study demonstrated hazard ratios for all-cause mortality of 8.31 and 10.17 for mild and moderate-severe diastolic dysfunction (Redfield et al. JAMA 2003;289:194-202)

• Hospitalization: 18% at 3.5 years (CHARM); in some studies, readmission rates may be as high as 50%

• One year mortality 5 – 8% in HFpEF vs. 10 – 15% in HFrEF

• Risk factors: advanced age, NYHA FC IV symptoms, CAD, decreased GFR

HFpEF: Treatment• There are few clinical trials available to guide the management

of patients with DHF - in fact, there is no clear evidence that patients with primary diastolic heart failure benefit from any specific drug regimen

• A primary goal of therapy is control of symptoms by reducing cardiac filling pressures at rest and with activity without reducing cardiac output.

• In the absence of data from controlled clinical trials, the management of DHF should be based on the control of factors known to have an important effect on ventricular relaxation/filling pressures – blood pressure, heart rate, atrial rhythm, intravascular volume, and myocardial ischemia

• Underlying or exacerbating conditions should be treated – hypertension, CAD, aortic stenosis, diabetes, anemia, obesity, sleep apnea, pulmonary disease

Hypertension• Reducing blood pressure improves myocardial

relaxation, lowers end-systolic and diastolic volume, reduces ischemia, and results in regression of LV hypertrophy

• Target BP: < 130 mmHg systolic; < 80 mmHg diastolic

• ACEI/ARB: BP, improve LV relaxation, long-term may improve in hypertrophy and fibrosis

• Beta-blockers/CCBs: BP, reduce ischemia, HR• Aldosterone receptor blockers: BP and may

reduce hypertrophy and fibrosis

HFpEF: Treatment• Diuretics should be used to relieve pulmonary

congestion – patients with DHF may be at greater risk of hypotension given preload dependant stroke volume and the steep slope of the diastolic filling curve

• Nitrates: lower diastolic filling pressures, may improve LV compliance and reduce ischemia

• Coronary revascularization should be considered in patients with angina or significant ischemia

• Atrial fibrillation: rate control; potential benefit of restoration of sinus rhythm

• Reduction of HR below 60 – 80 bpm is not indicated; diastolic filling period is prolonged but ventricular filling may not be increased

Lowering SBP in DHF

Little and Brucks. Prog Cardiovasc Dis 2005; 47:380 - 8

TOPCAT: composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure in patients with HF

and a LVEF ≥ 45% randomized to spironolactone vs placebo

Pitt et al. N Engl J Med.2014 370:1383-92

HFpEF- Conclusions

• HFpEF is a common cause of heart failure, especially in older women and patients with chronic hypertension

• Underlying pathophysiology is multifactorial but hypertension, aging and LV hypertrophy play important roles

• Morbidity and mortality are similar in patients with systolic and diastolic heart failure

• Little data from controlled clinical trials• Treatment includes control of hypertension,

diuretics, management of ischemia, management of atrial fibrillation

Stage D Heart Failure

• Truly refractory heart failure despite optimal medical therapy

• 1 year survival < 50% with optimal medical therapy

• ~ 75, 000 – 200,000 patients in the U.S

Stage D Heart Failure

• LVEF < 25-30%• Symptoms dyspnea and/or fatigue

at rest or with minimal exertion• Inability to perform most

activities of daily living• Repeat/prolonged hospitalizations

for ADHF• Cardiac cachexia

• Diuretic resistance, refractory volume overload

• Progressive end-organ dysfunction – most commonly renal dysfunction

• Withdrawal of ACEI/ARB or beta blockers for hypotension or renal dysfunction

• Persistent symptoms despite optimal medical therapy

What do patients with Stage D heart failure look like?

• “Cold and Wet”• Come to clinic in a wheel

chair• Frail• Cachectic• Tachycardic• SBP < 90 mmHg• Cold hands

• Pulmonary rales (but not always); elevated JVP

• Abdominal distention• Lower extremity edema• Elevated BUN and

creatinine• Elevated transaminases

Stage D Heart Failure: Therapeutic Options

• Heart transplant• Inotropic support• Mechanical Circulatory Support• Palliative Care/Hospice

Heart Transplant

• Heart transplant – Remains the “gold standard” – 1 year survival 90% and 10 year survival > 50%– limited number of organs available: 2,300 U.S.– Many patients with refractory heart failure are not

candidates for transplant because of advanced age or comorbitity

Not contraindications to Heart Transplant

• Age 65 -70 years • Renal insufficiency

– bridge to improvement– combined heart-kidney transplant

• Prior malignancy • Diabetes• Hepatitis without cirrhosis• HIV infection• Sarcoid or amyloid-related cardiomyopathy

Inotropic Support

• Inotropic support– Improves symptoms and end-organ function– Ambulatory setting– Atrial and ventricular arrhythmias– No improvement in survival– Poor intermediate term outcomes

Stage D HF: Inotropic Support

J Cardiac Failure 2003; 180 – 7N Engl J Med 2001; 345:1435-43

REMATCH Medical Therapy OHSU Outpatient

n = 61 n = 36

Mechanical Circulatory Support

• Near totally implantable devices for long-term support in patients with Stage D HF

• Used as “Bridge To Transplant (BTT)” or “Destination Therapy (DT)”

• Small, continuous flow, non-pulsatile devices• Durable, can function for years.• Improved survival as BTT and DT in randomized trials in

Stage D heart failure• Complications: right heart failure, GI bleeding, device

infection, stroke, pump thrombosis

HeartMate II

• Axial flow pump (non-pulsatile)

• Requires anticoagulation• Can produce up to 10L/min• FDA approved

N Engl J Med 2007;357:885-96.

HeartWare HVAD

• Miniature Implantable LVAD

• Intrapericardial• Magnetic/Hydrodynamic

impellar suspension• 10 liters per minute• In Clinical Trials

Improving Survival in LVAD Trials

Months

0 6 12 18 24

Per

cen

t S

urv

ival

0

10

20

30

40

50

60

70

80

90

100

HM II BTT Miller NEJM 2007

HM II DT Slaughter NEJM 2009

HM II BTT Pagani JACC 2009

HM II BTT Starling HFSA 2009

VE DT LVAD REMATCH Rose NEJM 2001

XVE DT LVAD Slaughter NEJM 2009

OMM REMATCH Rose NEJM 2001

OMM INTrEPID Rogers JACC 2007

Novacor DT LVAD INTrEPID Rogers JACC 2007

Triggers For Referral for Advanced Heart Failure Therapies

• Two or more HF hospitalizations in the last 6 months• High diuretic dose: > 160 mg of furosemide daily• Poor renal function: BUN > 40 mg/dL; creatinine > 1.8

mg/dL• Systolic BP < 90 mmHg• Need for inotropic support• Inability to initiate ACEI or -blockers • Need to stop or decrease ACE inhibitors or -blockers• Very low LVEF – especially in younger patients• SHFM Mortality >15%

Packer, M. et al. Circulation 1999;100:2312-2318

ATLAS: Kaplan-Meier Analysis for Death

HeartMate II BTT Trials

• 133 patients at 26 centers

• All patients listed for transplantation (BTT)

• Principal outcome achieved on 100 patients (transplanted, on waiting list, recovered, or self-withdrawn from txp list)

N Engl J Med 2007;357:885-96. J Am Coll Cardiol 2009;54:312–21

• 281 patients at 28

centers

• All patients listed for

transplantation (BTT)

• 18 month follow-up

data examined

• First 169 patients

implanted following

FDA approval for BTT

in 2008

• 77 centers (not all trial

centers)

• Compared to

concurrent

INTERMACS patients

• 1 year follow-up

J Am Coll Cardiol 2011;57:1890–8

HeartMate II Results

J AmColl Cardiol 2011;57:1890–8

HeartMate II DT Trial

• 200 patients in 38 centers• 2:1 randomization between HM2 and HM XVE

(134 HM2, 66 XVE)• NYHA Class IV patients ineligible for

transplantation• Primary end-point was 2 year survival free of

disabling CVA or requiring device replacement

N Engl J Med 2009;361:2241-51

HeartMate II DT Trial

• 200 patients in 38 centers• 2:1 randomization between HM2 and HM XVE

(134 HM2, 66 XVE)• NYHA Class IV patients ineligible for

transplantation• Primary end-point was 2 year survival free of

disabling CVA or requiring device replacement

N Engl J Med 2009;361:2241-51

Months

0 6 12 18 24

Perc

en

t S

urv

ival

0

10

20

30

40

50

60

70

80

90

100

CF LVAD

PF LVAD

Log-rank Test p=0.008

Actuarial Survival

Months

0 6 12 18 24

Per

cen

t S

urv

ival

0

10

20

30

40

50

60

70

80

90

100

CF LVAD

PF LVAD

OMM REMATCH

LVAD REMATCH

* N Engl J Med 2001; 345:1435-43

Actuarial Survival vs. REMATCH

N Engl J Med 2009;361:2241-51

Months

0 6 12 18 24

Per

cen

t S

urv

ival

0

10

20

30

40

50

60

70

80

90

100

CF LVAD

PF LVAD

OMM REMATCH

LVAD REMATCH

* N Engl J Med 2001; 345:1435-43

Actuarial Survival vs. REMATCH

N Engl J Med 2009;361:2241-51

Results of HM2 DT Trial

• Greater than 2 fold improvement in survival at 2 years compared to the pulsatile flow LVAD

• Continuous flow LVADs were associated with a reduction in clinically meaningful adverse event rates

• Continuous flow LVAD patients experienced early and sustained improvement in exercise capacity, functional class and quality of life

N Engl J Med 2009;361:2241-51

Patient Selection FOR MCS: Goals

Being alive and out of the hospital without a stroke or concern of a TIA while remaining free of infection and bleeding and able to ambulate unlimited distances without symptoms of heart failure enjoying the care-free life of a high school senior and able to think clearly about big thoughts remaining untethered from the VAD indefinitely and awaiting myocardial recovery while saving the healthcare system money.

- Joe Rogers, MD, Duke University Medical Center

Ideal Candidate?• Sick but not too sick• Not too much right heart failure• Not too much renal dysfunction• Not malnourished• Not too septic• Not supported on mechanical ventilation for too long• Not too much cerebral underperfusion• Not too much noncompliance

CMS Criteria for DT

• NYHA Class IV heart failure• LVEF < 25%• VO2max < 14 ml/kg/min

• Failure of OMM for 45 of last 60 days• IABP dependent for 7 days• Inotrope dependent for 14 days

NYHA Class IV

• Short of breath at rest or minimal activity

• Intolerant or refractory to advanced heart failure pharmacotherapy (ACE-I, ARB, β-blocker)

• Heart-failure related hospitalization in the last 6 months

• Cardiorenal syndrome• Refractory Volume overload• Cardiac cachexia• Refractory malignant arrhythmias• Inotrope dependence• IABP dependence

Contraindications to VAD

Relative

• Active infection• Disabling CVA• Severe PVD• COPD• Restrictive cardiomyopathy• Active substance/drug abuse with

recidivism• Inadequate social support

Absolute

• Life expectancy < 3 years due to cause other than HF

• Persistent vegetative state• Non-cardiac cirrhosis

Not contraindications to VAD

• Pulmonary HTN• Renal Insufficiency (Cr >

3.5) • Recent Substance

Use/Abuse • Low Grade Malignancy

(life expectancy > 5 years)

• Obesity (BMI > 40) • Recent non-hemorrhagic

CVA• Cardiac hepatopathy and

ascites

Potential Targets for New Drugs

CHARM-Preserved

• Average f/u: 36.6 months• Hazard ratios:

CV death or CHF hospitalization - 0.89CV death - 0.95CHF hospitalization - 0.84 (p = 0.047)

• Patients enrolled more closely resemble patients with systolic dysfunction in terms of age, gender, and etiology of heart failure

CHARM-Preserved Trial• 3023 patients with Class II – IV heart failure, LVEF

> 40%, and a h/o hospitalization for CV cause• Randomized to candesartan vs placebo• Target candesartan dose 32 mg qd• Primary outcome: CV death or CHF hospitalization• Clinical characteristics:

Age 67.2 yearsMen 60%Ischemic etiology 56.4%Hypertensive etiology 22.3%h/o MI 45%

DHF: Diagnostic Criteria

• Clinical evidence of heart failure- Signs and symptoms of volume overload- Plasma BNP or chest x-ray- Cardiopulmonary exercise testing

• Normal or mildly reduced LVEF ( 40 -50%)• Absence of valvular/pericardial disease on echo• Confirmatory evidence of diastolic dysfunction

- Echo Doppler or cardiac catheterization- LV hypertrophy- Left atrial enlargement (in the absence of afib)- History of hypertension

Diastolic Heart Failure: Causes

• Hypertension-associated hypertrophy• Age• Ischemic heart disease (ischemia/scarring)• Diabetes/metabolic syndrome• Hypertrophic cardiomyopathy• Restrictive cardiomyopathy• Infiltrative cardiomyopathies (amyloid,

hemochromatosis)• Most patients with DHF have a history of chronic

hypertension that is the primary cause of their cardiac dysfunction

Diastolic Heart Failure:The Scope of the Problem

• 5 million patients with CHF • Incidence doubles with each decade after age 45• 1,000,000 hospitalizations/year for acute

decompensated heart failure (ADHF)• CHF is leading DRG• $29 - 50 billion annual cost • ~ 50% of patients with heart failure have normal or

near normal left ventricular systolic function; these patients have been described as having “heart failure with preserved systolic function” or “diastolic heart failure (DHF)”

SCD: CRT vs CRT-D

CARE

Companion

Ellenbogen, et al. JACC 2005; 46: 2199 – 203.

A-HeFT: Mechanism?

NEJM 2004; 351

A-HeFT - Rationale

• Prognosis worse for AA with CHF• Probably less benefit from ACEI• Less activation of RAAS• Lower bioavailability of NO• More benefit from ISDN/Hydralazine in V-HeFT

trials• Hydralazine inhibits the formation of reactive

oxygen species that interact with NO

Heart Failure Pathophysiology• Myocardial injury• Decreased cardiac output• Neurohormonal activation – RAAS, SNS• Vasoconstriction; sodium and water retention• Pulmonary congestion• Secondary mitral regurgitation, right heart failure• Ventricular remodeling – progressive worsening in

cardiac structure and function associated with abnormal myocardila gene expression and myocardial toxicity

• End-organ dysfunction

SFHM 1 year mortality of > 15%

CRT-D in Context

Ellenbogen, et al. JACC 2005; 46: 2199 – 203

CARE - HFNEJM 2005; 352: 1539 -49

HR = 0.63

HR = 0.64

CARE-HF Results

The patients in the CRT Group had:• 37% reduction in mortality/hospitalization • 36% reduction in all-cause mortality• Improved QOL and NHYA FC• Increase in LVEF of 7%• Lower ventricular volumes• Less mitral regurgitation

CARE-HF(NEJM 2005; 352: 1539 – 49)

• CRT vs medical therapy• Patients in NSR with FC III or IV symptoms of

heart failure, QRS 120 msec (with echo findings of dyssynchrony if QRS 120-149 msec), and LVEF 35%

• Primary endpoint: mortality or CV hospitalization• Secondary endpoint: all-cause mortality• 813 patients at 82 centers in Europe• Age 66, Ischemic 35%, FC IV 6%, LVEF 25%• ACEI/ARB 95%, beta-blockers 72%, digoxin 43%

spironolactone 57%

SCD - HeFT

• Placebo vs single lead ICD vs amiodarone• Patients with symptomatic heart failure

(NYHA FC II – III) and LVEF 35%• Importance of optimal medical therapy

emphasized• 2521 patients• Mean follow-up 45.8 months• Vital status available: 100%• 666 deaths

Kaplan-Meier Event Rates

• 1 Year• 2 Years• 2.5 Years• 3 Years• 4 Years• 5 Years

Amiodarone Placebo ICDPlacebo –

Amiodarone

6.2%11.6%14.2%17.1%22.3%28.9%

-2.7%-0.9%-1.1%-1.6%-0.4% 2.1%

8.6%15.4%19.3%24.0%29.5%34.0%

5.9%14.5%18.2%22.4%29.1%36.1%

Placebo – ICD

-0.3% 2.9% 4.0% 5.3% 6.8% 7.2%

MADIT II(Moss et al. NEJM 2002; 346: 877 –83)

• ICD vs conventional therapy (randomized 3:2) • Prior MI ( 1 mo), LVEF 30%• No requirement for EP testing or Holter screening• End-point – total mortality • 1232 patients • Clinical characteristics: age 64 yrs, male 84%, NYHA

FC I/II/III/IV 37/35/24/4%, LVEF 23 %, ACEI 70%, beta-blockers 70%

• Average follow-up: 20 months• 202 deaths

A-HeFT

• Study prematurely stopped on recommendation of DSMB

• Average follow-up 10 months• Mortality: 10.2 vs 6.2%; 54 vs 32 deaths (HR =

0.57; P=0.02)• First hospitalization: 16.4 vs 22.4% (HR = 0.67;

P=0.001)• Improvement in QOL

COMET

• Carvedilol vs metoprolol tartrate• Patients with NYHA FC II – IV symptoms on

standard treatment, LVEF < 35%, one CV hospitalization in previous two years

• Stable diuretic dose > 2 weeks, ACEI > 4 weeks• Target dose: carvedilol 25 mg bid, metoprolol 50 mg

bid• End-points: mortality, mortality or hospitalization• 3029 patients, Age – 62 years, LVEF 26%• Average follow-up – 58 months

-Blocker Dose: MOCHABristow et al. Circulation 1996; 94: 2807 -16

• 345 patients with mild – moderate heart failure• Randomized to placebo vs Carvedilol 6.25mg,

12.5 mg or 25 mg po bid• Followed for six months• Primary end-point 6 minute walk test and 9

minute self-powered treadmill test• LVEF and mortality also assessed

BEST

NEJM 2001; 344:1659-67

Packer, M. et al. Circulation 1999;100:2312-2318

ATLAS: Kaplan-Meier Analysis Showing Time to Death or Hospitalization

DIG Trial – Death or Hospitalization

N Engl J Med 1997; 336:525-33

Assessment of Volume Status

• Volume overload is the major cause of symptoms and hospitalization but difficult to assess in patients with chronic heart failure

• JVD, rales and edema relatively specific but not sensitive physical findings in volume overloaded patients

• CXR is also specific but not sensitive• Biomarkers- BNP, NT-proBNP • Thoracic impedance• Pressure sensors

Volume Overload

• Poor cardiac output, decrease in kidney blood flow, neurohormonal activation, thirst and secondary mitral regurgitation

• left atrial and wedge pressures results in transudation of fluid into the lung that causes a decrease in lung compliance and activation of pressure receptors which result in dyspnea

• Volume overload is bad because it causes symptoms and hospitalization (and may worsen angina, secondary MR, pulmonary hypertension, and remodeling)

MADIT-CRTN Engl J Med 2009; 361:1329 - 38

• 1089 patients with ischemic or nonischemic cardiomyopathy, FC I – II symptoms, EF ≤ 30%, QRS ≥ 130 msec randomized 3:2 to CRT-D vs ICD

• Primary end point death or heart failure event• Average fu 2.4 years• HR for primary end point 0.66 (P=0.001)• HR for nonfatal HF event 0.59 (P<0.001)• HR for all cause mortality 1.00 (P=.99)• Benefit seen only in subgroup with QRS > 150 msec

MADIT-CRTN Engl J Med 2009; 361:1329 - 38

n=3025LVEF >40%

ACE inhibitor treated/not treated

CHARM Added

CHARMPreserved

CHARM Programme3 component trials comparing

Candesartan to placebo

CHARMAlternative

n=2028

LVEF £40% ACE inhibitor

intolerant

n=2548

LVEF £40%ACE inhibitor

treated

Primary outcome:CV death or CHF hosp

CHARM-Added: Primary outcomeCV death or CHF hospitalisation

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

Number at risk

Candesartan 1276 1176 1063 948 457

Placebo 1272 1136 1013 906 422

3.5

Adjusted HR 0.85, p=0.010

CV Death HR 0.84, p=0.029

483 (37.9%)538 (42.3%)

%

CHARM Added - Observations

• NYHA FC 3 - 73%• Mean BP 125 mmHg• Enalapril dose 17 mg qd• Beta-blocker use 55%• Digoxin use 78% • Spironolactone use 17%• Not clear if ACEI plus ARB should be standard of

care

Aldosterone Antagonism – The Rales Trial

• Spironolactone 25 mg qd vs. placebo• NYHA FC III – IV, h/o FC IV, LVEF < 35%,

creatinine < 2.5 mg/dL, K < 5.0 mmol/L • 1663 patients• Age 65 years; LVEF 25%; SBP 122 mmHg; FC III/IV

70/30; Creatinine 1.2 • 30% reduction in mortality with spironolactone• Improvement in symptoms and ventricular function• Hyperkalemia 2%• Gynecomastia in 9% of men

EPHESUS – Study Design• 6642 patients • Randomized 1:1 to receive eplerenone 25mg daily vs

placebo increased to 50 mg daily after four weeks (mean dose 42.6 mg qd)

• Potassium measured at 48 hours, one, four and five weeks and every three months – study drug decreased or held for K > 5.5 mmol/L

• Primary end points:- Death from any cause- CV death or first hospitalization for CV cause

• Trial designed to stop after 1012 deaths• Average follow-up: 16 months

The Rales Trial• Spironolactone 25 mg qd vs. placebo• 1663 patients• Inclusion criteria

- NYHA FC III – IV - h/o FC IV within previous six months - LVEF < 35%,

• Exclusions: Creatinine > 2.5 mg/dL; K > 5.0 mmol/L• Spironolactone started at 25 mg qd and could be

increased to 50 mg qd after 8 weeks if for worsening CHF

• K checked weeks 1,4,5,8, and 12; then every 3 months

Pitt, B. et al. N Engl J Med 1999;341:709-717

Spironolactone in Patients with Advanced Heart Failure – The Rales Trial

HR= 0.70

HR SCD = 0.71

HR CV H = 0.70

Primary End Points: • All-cause mortality• CV mortality + CV hospitalization

Secondary End Points: • CV mortality• CV hospitalizations• All-cause mortality + all-cause hospitalizations

Other End Points: • New onset of atrial fibrillation/flutter• NYHA functional class• QOL

Placebon = 3100

1012 Deaths

Randomize 3–14 days Post AMI

Eplerenone 25–50 mg QD

n = 3100

AMI, Rales (or DM ), LVEF £40%, Standard Therapy

.

EPHESUS: Study Design

Potassium measured at 48 hours, one, four and five weeks and every three months – study drug decreased or held for K > 5.5 mmol/L

EPHESUS

A. All-cause mortality B. CV death or hospitalization C. CV death D. SCD

Recent Trials of CRTDo patients with normal QRS width and mechanical

dyssynchrony benefit from CRT?• RethinQ (N Engl J Med 2007;357:2461-71):

172 patients with EF ≤ 35%, FC III symptoms, QRS< 130 msec and echo evidence of mechanical dyssynchrony randomized to ICD vs CRT-D. No difference in improvement in peak oxygen consumption at 6 months.

Is there a better way to predict response than QRS width?• PROSPECT (Circulation 2008; 117:2608-16):

Multicenter observational study to identify echocardiographic predictors of clinical response and reduction in LVESD in 498 patients who underwent CRT for standard indications. Low predictive accuracy for response for any echo measure of mechanic dyssynchrony

Recent Trials of CRT

Do patients with FC I – II symptoms benefit?• REVERSE (J Am Coll Cardiol 2008; 52: 1834 - 43):

262 patients with QRS ≥ 120 msec, LVEF ≤ 40%, FC I – II symptoms randomized to CRT “on’ or “off”. “on” patients had improvement in LV volumes and EF and a significant reduction in risk for first hospitalization for heart failure. No difference in survival, 6-minute walk distance of QOL.

MADIT-CRTN Engl J Med 2009; 361:1329 - 38

MADIT-CRTN Engl J Med 2009; 361:1329 - 38

CRT - Caveats

• Small number of FC IV patients in clinical trials (~320 patients in 9 randomized trials)

• Unsuccessful implants 8 –13%• Coronary sinus injury up to 6%• Periprocedural mortality 0.4%• Lead dislodgement or malfunction 9%• Heterogeneity of response • No benefit in ~ 30% of patients• Lead placement limited by CS anatomy• Approaches to achieve optimal clinical response to

CRT are in evolution

Cardiac Resynchronization Therapy • ~ 30 - 40 % of patients with low EF and FC III-IV

symptoms have a QRS duration of > 120 msec• QRS prolongation (delayed ventricular depolarization)

identifies a HF population likely to have mechanical ventricular dyssynchrony and mechanical inefficiency

• Mechanical synchrony can be restored with atrial synchronized biventricular pacing (RV and LV lead)

• CRT improves ventricular function acutely in 2/3 of patients

• CRT has been shown to improve sxs, 6 minute walk distance, FC, LV function, decrease neurohormonal activation, and decrease HF hospitalization in patients with moderate – severe HF and QRS prolongation

What Hasn’t Worked?

Vasopeptidase inhibition• OVERTURE: 5770 patients with FC II – IV symptoms

randomized to enalapril vs omapatrilat (an inhibitor of both ACE and neutral endopeptidase). No difference in survival.

Endothelin receptor antagonists• ENABLE I/II: low-dose bosentan (a non-selective

endothelin receptor antagonist) vs placebo in patients with FC III – IV symptoms and LVEF 35%. No benefit but early worsening of heart failure early after bosentan initiation

• EARTH: Darusentan four doses vs placebo in 642 patients with chronic heart failure. Well tolerated but no difference in LV ESV, symptoms, or outcome

What Hasn’t Worked?

TNF antagonism• RENEWAL: etanercept (TNF receptor antagonist) in

2048 patients with FC II – IV symptoms and LVEF 30%. No effect on survival or HF hospitalization.

• ATTACH: two doses of infliximab (an anti-TNF monoclonal antibody) in 150 patients with FC III – IV symptoms and LVEF 35%. No effect on clinical status but increase in hospitalization in the high dose group

Central sympathetic inhibition• MOXCON: moxonidine SR vs placebo in 4533 patients

with FC II – IV HF. Study stopped due to an early increase in deaths and adverse events with moxonidine

Other Issues

• Disease management strategies: patient education, dietary counseling, compliance tools, daily weights

• Treatment of sleep apnea• Treatment of anemia• Urinary retention• Physical activity and exercise training• Diuretic resistance: diuretic dose, ultrafiltration,

BNP infusions• Referral for treatment of Stage D heart failure

- Transplant- Destination LVAD support