Cardiology - What`s New in Medicine

Report
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
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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 hands
Low BP
Low pulse pr
Tachycardia
Confusion
Agitation
PND, Orthopnea, Edema, JVD, Rales, Effusions
Heart Failure Disease Progression:
ACC/AHA Heart Failure Stages
D
C
B
A
Refractory
End-Stage HF:
Marked symptoms
at rest despite maximal
medical therapy
Symptomatic HF: Known structural
heart disease, shortness of breath and
fatigue, reduced exercise tolerance
Asymptomatic LVD: Previous MI, LV systolic
dysfunction, asymptomatic valvular disease
High Risk: Hypertension, coronary artery disease, diabetes,
family history of cardiomyopathy
LV=left ventricular, MI=myocardial infarction
Adapted from Yancy CW et al. Prim Care Spec Ed 2002;6:15-19.
Causes of Heart Failure with Reduced EF
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Coronary artery disease
Ischemic cardiomyopathy
Hypertensive heart disease
Idiopathic cardiomyopathy
Familial cardiomyopathy
Valvular Cardiomyopathy
– Aortic stenosis
– Aortic insufficiency
– Mitral regurgitation
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•
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•
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
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–
–
–
–
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 Pathophysiology
Fall in LV Performance
 Cardiac output
Myocardial Injury
Activation of RAAS and SNS
( ET1, AVP, cytokines)
Peripheral Vasoconstriction
Na/Water Retention
Myocardial Toxicity
 Gene Expression
Morbidity and Mortality
Remodeling and
Progressive
Worsening of
LV Function
Heart Failure Symptoms
Effect of ACEI in Patients with CHF
CONSENSUS and SOLVD
CONSENSUS*
SOLVD Treatment†
NYHA Class IV
NYHA Class II-III
Mortality (%)
80
Placebo
(n=126)
60
Placebo
(n=1284)
Enalapril
(n=126)
40
Enalapril
(n=1285)
20
0
0
6
12
18
24
Months
30
36
42
48
*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.
ACEI in Patients with Systolic Dysfunction
Garg 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: ATLAS
Packer 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 = 0.128
CV mortality
0.90 P = 0.073
Mortality and Hosp
0.88 P = 0.002
Mortality 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
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
Pitt, B. et al. N Engl J Med 1999;341:709-717
Eplerenone 25 – 50 mg qd in Patients with Recent AMI, EF
 40% and CHF or Diabetes – The EPHESUS Trial
22
20
18
16
14
Placebo
Eplerenone
Cumulative 12
Incidence (%)
10
8
Total Mortality RR = 0.85; P = 0.008
6
SCD RR = 0.79; P = 0.03
4
2
0
0
3
6
9
12 15 18 21 24 27 30 33 36
Months Since Randomization
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 Hyperkalemia
and Death
After Publication
of RALES
500% in
spironolactone Rx
(p<0.001)
275% in
hosp for hyperkalemia
(p<0.001)
285% in death
due 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
The DIG Trial: Survival by Gender
HR = 1.23
Rathore, S. S. et al. N Engl J Med 2002;347:1403-1411
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
CIBIS II
HR =0.68
Lancet 1999; 353:9-13
MERIT-HF
Placebo
Metoprolol CR/XL
Cumulative mortality (%)
HR = 0.65
HR SCD = 0.60
Follow-up (months)
Lancet 1999; 353:2001- 07
COPERNICUS
HR = 0.65
HR SCD = 0.67
Packer, M. et al. N Engl J Med 2001;344:1651-1658
Not all -blockers Work
BEST
N Engl J Med 2001; 344: 1659-67
Xamoterol Study Group
Lancet 1990;336:1-6
Carvedilol vs Metoprolol: LV Function
Metra M et al. Circulation. 2000;102:546–551.
LVEF
LV EDV
0
*
14
-5
***
12
-10
-15
10
***
mL/m2
Absolute Change From
Baseline LVEF units (%)
16
8
LV ESV
-20
6
-25
4
-30
2
-35
**
***
***
***
-40
0
Metoprolol†
(n=61)
Carvedilol
(n=61)
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
*P<.05; **P<.01; ***P<.001.
†Metoprolol tartrate.
-Blockers – Time Course of Improvement
45
40
LVEF %
35
30
25
20
15
10
5
0
0
1 day
1 month
3 months
Hall et al JACC 1995; 25:1154-61
18
months
-Blocker Dose: MOCHA
Bristow, M. R. et al. Circulation 1996;94:2807-2816
Change in LVEF
6 Month Mortality
Primary endpoint of mortality
40
Metoprolol tartrate
Mortality (%)
30
(85 mg qd)
20
Carvedilol
(42 mg qd)
hazard ratio 0.83,
95% CI 0.74-0.93, P = 0.0017
10
0
0
Number at risk
Carvedilol
1511
Metoprolol
1518
1
2
3
4
5
1002
933
383
352
Time (years)
1367
1359
1259
1234
1155
1105
-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
HR 0.57
NEJM 2004;351:2049 -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 nonAfrican 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
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~ 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%
HR = 0.69
P = 0.007
Moss AJ. et al. N Engl J Med 2002; 346:877
SCD-HeFT - Mortality
0.4
Amiodarone vs Placebo
ICD Therapy vs Placebo
Mortality
0.3
HR
1.01
0.77
97.5% CI
0.86, 1.30
0.62, 0.96
P-Value
0.529
0.007
0.2
0.1
Amiodarone
ICD Therapy
0
Placebo
0
6
12
18
24
30
36
42
Months of follow-up
48
54
60
Sudden Cardiac Death
SCD-HeFT
Mortality by NYHA Class:
ICD vs. Placebo
Heart Failure Trial
Class II
ICD Therapy
0.5
HR
1.16
Placebo
0.4
Mortality
Class III
0.3
HR
0.54
97.5% CI
0.40, 0.74
0.2
48%
46%
97.5% CI
0.84, 1.61
32%
20%
0.1
0
0
12
24
36
48
Months of follow-up
60
0
12
24
36
48
Months of follow-up
60
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
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•
•
•
•
•
•
•
•
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
The Seattle Heart Failure Model
http://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 hypertrophy
Age
Ischemic heart disease (ischemia/scarring)
Diabetes/metabolic syndrome
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy
Infiltrative cardiomyopathies (amyloid, hemochromatosis,sarcoid)
• Valvular Heart Disease
Acute aortic insufficiency
Aortic stenosis
Mitral stenosis
Acute mitral regurgitation
• Pericardial disease
Constriction, tamponade
• High output states
Anemia, hyperthyroidism, Paget disease, AV fistulae
LV diastolic pressure-volume data
Aurigemma, G. P. et al. Circulation 2006;113:296-304
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, longterm 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
REMATCH Medical Therapy
n = 61
N Engl J Med 2001; 345:1435-43
OHSU Outpatient
n = 36
J Cardiac Failure 2003; 180 – 7
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 (nonpulsatile)
• Requires anticoagulation
• Can produce up to 10L/min
• FDA approved
HeartWare HVAD
• Miniature Implantable
LVAD
• Intrapericardial
• Magnetic/Hydrodynamic
impellar suspension
• 10 liters per minute
• In Clinical Trials
Improving Survival in LVAD Trials
100
90
HM II BTT Starling HFSA 2009
Percent Survival
80
HM II BTT Pagani JACC 2009
70
HM II BTT Miller NEJM 2007
60
HM II DT Slaughter NEJM 2009
50
40
VE DT LVAD REMATCH Rose NEJM 2001
30
XVE DT LVAD Slaughter NEJM 2009
20
Novacor DT LVAD INTrEPID Rogers JACC 2007
10
OMM REMATCH Rose NEJM 2001
OMM INTrEPID Rogers JACC 2007
0
0
6
12
Months
18
24
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%
ATLAS: Kaplan-Meier Analysis for Death
Packer, M. et al. Circulation 1999;100:2312-2318
HeartMate II BTT Trials
N Engl J Med 2007;357:885-96.
•
•
•
133 patients at 26
centers
All patients listed for
transplantation (BTT)
Principal outcome
achieved on 100
patients (transplanted,
on waiting list,
recovered, or selfwithdrawn from txp
list)
J Am Coll Cardiol 2009;54:312–21
•
•
•
281 patients at 28
J Am Coll Cardiol 2011;57:1890–8
•
First 169 patients
centers
implanted following
All patients listed for
FDA approval for BTT
transplantation (BTT)
in 2008
18 month follow-up
•
77 centers (not all trial
centers)
data examined
•
Compared to
concurrent
INTERMACS patients
•
1 year follow-up
HeartMate II Results
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
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
Actuarial Survival
100
90
Log-rank Test p=0.008
Percent Survival
80
70
60
CF LVAD
50
40
30
PF LVAD
20
10
0
0
6
12
Months
18
24
Actuarial Survival vs. REMATCH
100
90
Percent Survival
80
70
CF LVAD
60
50
40
LVAD REMATCH
30
20
PF LVAD
10
OMM REMATCH
0
0
6
12
Months
* N Engl J Med 2001; 345:1435-43
18
24
Actuarial Survival vs. REMATCH
100
90
Percent Survival
80
70
CF LVAD
60
50
40
LVAD REMATCH
30
20
PF LVAD
10
OMM REMATCH
0
0
6
12
Months
* N Engl J Med 2001; 345:1435-43
18
24
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
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 carefree 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.
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
Absolute
•
•
•
•
•
•
•
•
Active infection
Disabling CVA
Severe PVD
COPD
Restrictive cardiomyopathy
Active substance/drug abuse with
recidivism
Inadequate social support
•
•
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 - 0.89
CV death - 0.95
CHF 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 years
Men 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
HR = 0.63
CARE - HF
NEJM 2005; 352: 1539 -49
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
Amiodarone Placebo
• 1 Year
• 2 Years
• 2.5 Years
• 3 Years
• 4 Years
• 5 Years
8.6%
15.4%
19.3%
24.0%
29.5%
34.0%
5.9%
14.5%
18.2%
22.4%
29.1%
36.1%
ICD
6.2%
11.6%
14.2%
17.1%
22.3%
28.9%
Placebo – Placebo
Amiodarone – ICD
-2.7%
-0.9%
-1.1%
-1.6%
-0.4%
2.1%
-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: MOCHA
Bristow 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
ATLAS: Kaplan-Meier Analysis Showing Time to
Death or Hospitalization
Packer, M. et al. Circulation 1999;100:2312-2318
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-CRT
N 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-CRT
N Engl J Med 2009; 361:1329 - 38
CHARM Programme
3 component trials comparing
Candesartan to placebo
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF 40%
ACE inhibitor
intolerant
LVEF 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Primary outcome:
CV death or CHF hosp
CHARM-Added: Primary outcome
CV death or CHF hospitalisation
50
%
Placebo
40
30
538 (42.3%)
483 (37.9%)
Candesartan
20
10
Adjusted HR 0.85, p=0.010
CV Death HR 0.84, p=0.029
0
0
Number at risk
Candesartan
1276
Placebo
1272
1
2
3
1176
1136
1063
1013
948
906
3.5 years
457
422
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
Spironolactone in Patients with Advanced
Heart Failure – The Rales Trial
HR= 0.70
HR SCD = 0.71
HR CV H = 0.70
Pitt, B. et al. N Engl J Med 1999;341:709-717
EPHESUS: Study Design
AMI, Rales (or DM ), LVEF 40%, Standard Therapy
Eplerenone
25–50 mg QD
n = 3100
Randomize 3–14 days
Post AMI
1012 Deaths
Placebo
n = 3100
• 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
Primary End Points:
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
C. CV death
B. CV death or hospitalization
D. SCD
Recent Trials of CRT
Do 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-CRT
N Engl J Med 2009; 361:1329 - 38
MADIT-CRT
N 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

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