Update in

Heart Failure
July 12, 2007
Abnet M.
 Objectives
 Define Heart Failure
 Know the 5 year mortality rate for heart failure
 Distinguish between New York Heart
Association classes (I – IV) and the new
American College of Cardiology stages (A – D)
 Review and become familiar with treatment
options
 Know the three beta-blockers demonstrating
benefit, and the two that are FDA approved
 Objectives
 Know indications for an ICD
 Know percent of patients who have diastolic
dysfunction
 Patient Presentation
 Mr. Smith is a 67 yo male with a history of
hypertension and diabetes who now presents to your
clinic with mild dyspnea at the end of his 1 mile walk.
No chest pain. He has occasional pedal edema.
 VS – stable
 Lungs – CTA, normal work of breathing
 CV – RRR, nl S1 S2, no MRG heard
 Extremities - 1-2+ pitting edema.

 Where do you go from here?

 Pre-lecture Needs Assessment

 What are the four NYHA classes of HF?

 What are the four ACC stages of HF?
 Which medication classes are routinely
prescribed in heart failure?
 Which three beta-blockers are approved to
treat HF?
 Define Heart Failure
 “Heart failure is a complex syndrome that can result
from any structural or functional cardiac disorder that
impairs the ability of the ventricle to fill with or eject
blood.” 1
 The cardinal symptoms are dyspnea and fatigue,
while the predominant clinical sign is fluid retention
(rales, elevated jugular venous pulsations, and pedal
edema). Given that not all patients are volume
overloaded at the time of diagnosis (diastolic
dysfunction), the term “heart failure” is now
preferred over “congestive heart failure.”
Hunt S, et al, ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American
1

Heart
Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001, ACC web site, accessed
November 12, 2004.
 Epidemiology of Heart Failure
 Approximately 5 million patients in the USA have
HF, with a yearly incidence of close to 500,000.
 It is primarily a disease of the elderly, with 6-10%
patients over 65 years old being diagnosed with HF.
 80% of hospitalized patients with HF are > 65yo.
 Heart failure is the most common Medicare DRG.
 Epidemiology of Heart Failure
 “…one-year mortality of approximately 45
percent.” 2
 “Survival ranges from 80% at 2 years for
patients rendered free of congestion to less
than 50% at 6 months for patients with
refractory symptoms.” 3

2
Jessup M, Brozena S, Medical Progress: Heart Failure, NEJM, 348(20): 2007-18, 2003.
3
Nohria A, et al, Medical Management of Advanced Heart Failure, JAMA, 287(5): 628-40,
2002.
 Epidemiology of Heart Failure
 “Heart failure admission rates are rising, and the
prognosis of heart failure has been compared
with that of malignancy, with a 6-year mortality
rate of 84% in men and 77% in women.” 4
 Heart failure kills people much more surely than
most cancers!
 Coronary artery disease is the cause of two
thirds of left ventricular systolic dysfunction

Mair F, et al, Evaluation of suspected left ventricular systolic dysfunction, JFP, 51(5): 466-71, 2002
 Diagnosing Heart Failure
Symptoms
 Decreased exercise tolerance
 Fluid retention
 Fatigue
 Incidentally noted left ventricular dysfunction
in an asymptomatic patient
 Diagnosing Heart Failure
Clinical Signs
 Elevated jugular venous pressure
 Pulmonary rales
 S3
 S3 – volume overload
 S4 – pressure overload
 Peripheral edema
 Diagnosing
Heart Failure

Clinical Signs
 Auscultatory Findings
 S3
 S4
 http://www.egeneralmedical.com/listohearmur
.html
 Rales
 http://www.wilkes.med.ucla.edu/intro.html
Common EKG
Findings
CXR findings in
Heart Failure
 Diagnosing Heart Failure
 Many different terms:
 Left vs right-sided failure
 Backward vs forward failure
 Volume vs pressure overload
 Systolic vs diastolic dysfunction – there is a lot
of overlap as many patients have aspects of
both entities
 Echocardiography
 A generally accepted definition of depressed
systolic function is an ejection fraction < 40%,
from the ACC guideline on the use of
echocardiography.
 Note that this is not a useful definition in
diastolic dysfunction as the EF may actually
be increased in diastolic dysfunction.
 Heart Failure Stages
vs
NYHA Classes
ACC-AHA Stage NYHA Functional Classification
A: At high risk for HF but without structural None
heart disease or symptoms of HF (Eg,
patients with HTN or CAD)

B: Structural heart disease but without I: Asymptomatic

symptoms of HF

C: Structural heart disease with prior or current II: Symptomatic with moderate exertion
symptoms of HF
III: Symptomatic with minimal exertion

D: Refractory HF requiring specialized IV: Symptomatic at rest (cardiac cripple)

interventions
Stages of Heart Failure
Heart Failure Treatment Options
 Angiotensin Converting Enzyme Inhibitors
(ACEIs)
 Beta-blockers
 Diuretics
 Digoxin
 Angiotensin Receptor Blockers (ARBs)
 Other medications
Site of Action
of
Medications
ACEIs
 ACEIs
 They are the most studied class with years of
experience and large patient numbers in RCTs.
Proven benefit to decrease mortality and
hospitalization for HF.
 ACEIs
 A comparison of enalapril with hydralazine-isosirbide
dinitrate in the treatment of chronic congestive heart
failure.
 804 men on digoxin and diuretics were randomized to
receive enalapril or hydralazine and isosorbide
dinitrate. The enalapril arm demonstrated an 18%
mortality rate at 2 years compared with 25% for the
hydralazine and isosorbide dinitrate arm.
 Cohn JN, NEJM, 325(5): 303-10, 1991
 ACEIs – what dose?
 ATLAS: Patients with NYHA class II to IV with and
EF< or = 30% were assigned to either low dose (2.5 –
5.0mg) or high dose (32.5 – 35mg) of lisinopril for up
to five years. Patients on the higher dose had a
nonsignificant decrease in mortality of 8% with a
significant 12% decrease in death or hospitalization
for any reason, as well as 24% fewer hospitalizations
for heart failure.
 Packer M, Circulation, 100(23): 2312-8, 1999
 ACEIs – what dose?
 Outcome of patients with congestive heart
failure treated with standard versus high doses
of enalapril: a multicenter study.
 There were no differences in mortality or
hospitalizations between patients treated with
up to 20 mg or those treated with up to 60 mg
of enalapril.
 Nanas J, JACC, 36: 2090-5, 2000.
 ACEIs
 HOPE Trial: The use of ramipril in patients
with multiple cardiac risk factors without
known CHF or left ventricular dysfunction
reduces the risk of death from any cause, MI,
stroke, and heart failure.
 HOPE investigators, NEJM, 342(3): 145-153,
2000
 Consider in patients with Stage A Heart Failure
Beta-blockers
 Beta-blockers
 Beta-1 selective = metoprolol and bisoprolol
 Alpha-1 and beta-nonselective = carvedilol.
 Beta-blockers reduce the risk of death and the
hospitalization. All three have shown benefit.
 Beta-blockers
 US Carvedilol Heart Failure Study Group:
Carvedilol was added to background therapy
of ACEI, diuretics, and digoxin. Patients
receiving carvedilol experienced a 65%
decrease in mortality, a 27% decrease in
hospitalizations, and a 38% decrease in the
combination of the two.
 Packer M, NEJM, 334(21): 1349-55, 1996.
 Beta-blockers
 CIBIS-II: Bisoprolol was added to standard
therapy (diuretics and ACEIs) in patients with
NYHA III or IV with EF < 35%. Study was
stopped early because of the benefit. The
hazard ratio of death was 0.56 vs placebo.
 Anon., Lancet, 353(9146): 9-13, 1999.
 Beta-blockers
 MERIT-HF: Patients had NYHA class II to IV,
an EF<40%, and were stabilized with optimum
medical therapy. Patients were randomized to
receive the beta-1 blocker metoprolol CR/XL.
Patients in therapy experienced a 19% decrease in
mortality or all-cause hospitalizations and a 31%
decrease in HF hospitalizations.
 Hjalmarson A, JAMA, 283(10): 1295-1302, 2000.
 Beta-blockers
 CAPRICORN: Effect of carvedilol on outcome after
myocardial infarction in patients with left-ventricular
dysfunction: the CAPRICORN randomized trial.
 1959 patients post MI with EF<40% were
randomized to carvedilol or placebo. All-cause (ARR
3%) and cardiovascular mortality, as well as non-fatal
MI were reduced in patients on carvedilol.
 Dargie H, Lancet, 357(9266): 1385-90, 2001.
 Beta-blockers
 COPERNICUS: Effect of carvedilol on the morbidity of
patients with severe chronic heart failure: results of the
carvedilol prospective randomized cumulative survival study.
 2289 patients with severe heart failure (EF<25%) were
randomized to receive carvedilol or placebo for an average of
ten months. Mortality from cardiovascular causes and heart
failure mortality or hospitalization were both decreased by
27% and 31% respectively. In euvolemic patients with
symptoms at rest or on minimal exertion, the addition of
carvedilol to conventional therapy ameliorates the severity of
heart failure and reduces the risk of clinical deterioration,
hospitalization, and other serious adverse clinical events.
 Packer M, Circulation, 106(17):2194-9, 2002.
 Beta-blockers
 COMET: Comparison of carvedilol and metoprolol
on clinical outcomes in patients with chronic heart
failure in the Carvedilol Or Metoprolol European
Trial.
 1511 patients on standard HF therapy with EF<35%
were randomized to receive carvedilol or metoprolol.
After 5 years, all cause mortality was 34% with
carvedilol and 40% with metoprolol. The composite
endpoint of all-cause mortality and hospitalization
was the same in both groups.
 Poole-Wilson P, Lancet, 362(9377):7-13, 2003
Diuretics
 Diuretics
 No dedicated RCTs to evaluate the use of loop
diuretics. (Perhaps unethical now that their
use is standard of care)
 Diuretics are added when patients experience
symptoms or signs of volume overload.
 Diuretics
 Furosemide (Lasix) usually the first line,
although HCTZ could be used.
 Only loop diuretics are effective when the
CrCl drops below 30cc/min.
 Diuretics and the neurohormonal
basis of heart failure
 RALES Trial: Spironolactone was added to therapy
in patients with severe heart failure and an EF<35%
being treated with ACEIs, diuretics, and (in most
cases) digoxin. The study was stopped early after
demonstrating an absolute decrease in mortality of
11% (RR = 0.70) and an relative decrease in
hospitalization of 35% (RR = 0.65). 10% of males
had gynecomastia or mastalgia. Minimal
hyperkalemia was reported.
 Pitt B, NEJM, 341(10): 709-17, 1999.
 Diuretics and the neurohormonal
basis of heart failure
 Ephesus trial - The use of eplerenone in patients
post-MI who had an EF<40% and clinical signs
of heart failure showed benefit. Patients on the
medication experienced and absolute risk
reduction in mortality of 2.3% (RRR = 14%).
 Pitt B, et al. Eplerenone, a selective aldosterone
blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl
J Med, 348:1309-21, 2003.
Digoxin
 Digoxin
 RADIANCE Study: Patients on a stable
regimen of digoxin, ACEI, and diuretic were
randomized to removal of digoxin or
maintenance of therapy. Those patients off
digoxin experienced a significant increase in
worsening heart failure and decreased
measures of functional capacity.
 Packer M, NEJM, 329(1): 1-7, 1993.
 Digoxin
 Digitalis Intervention Group: Patients on
ACEI and diuretics were randomized to
receive digoxin or placebo. Overall mortality
was similar in both groups. However, digoxin
did decrease the risk of worsening heart failure
and hospitalization.
 Rekha G, NEJM, 336(8): 525-33, 1997.
ARBs
 Angiotensin Receptor Blockers
(ARBs)
 The ARBs – studies have shown that they
have efficacy close to that of ACEIs.
 ARBs are frequently used in patients who
cannot tolerate ACEIs (cough, h/o
angioedema).
 They are expensive.
 ARBs
 ELITE: Evaluation of losartan in the elderly. 722
patients older than 65 with EF<40% and ACEI naïve
were randomized to losartan or captopril, in addition
to standard therapies (ACEIs, diuretics, digoxin,
nitrates and hydralazine). Patients on losartan has
less side effects, a nonsignificant decrease in death
and/or hospital admission for heart failure, and a
significant decrease in all-cause mortality (risk
reduction = 46%). Admissions for heart failure were
the same in both groups.
 Pitt B, Lancet, 349(9054): 747-52, 1997
 ARBs
 ELITE-II: Effect of losartan compared with captoril
on mortality in patients with symptomatic heart
failure: a randomized trial – the Losartan Heart
Failure Survival Study. 3152 patients 60 years or
older with NYHA class II to IV heart failure and
EF<40% were randomized to losartan or captopril.
The mortality and rates of sudden death or
resuscitated arrests were the same in both groups.
 Pitt B, Lancet, 355(9215): 1582-7, 2000
 ARBs
 LIFE trial: Hypertensive patients were treated
with either losartan or atenolol. Patients were
followed for at least four years. 508 patients
on losartan experienced the composite
endpoint of death, MI, or stroke, compared
with 588 patients on atenolol (RR = 0.87).
 Dahlof B, Lancet, 359(9311): 995-1003, 2002.
 ARBs
 Val-HeFT: A randomized trial of the angiotensin-
receptor blocker valsartan in chronic heart failure.
5010 patients with NYHA class II to IV HF were
randomized to receive valsartan or placebo in
addition to standard therapy. Overall mortality was
the same. Hospitalizations were 4.4% less.
Treatment with valsartan improved NYHA class, EF,
signs and symptoms of HF, and quality of life. Post
hoc analysis showed the valsartan had a favorable
outlook in patients receiving ACEI or beta-blockade
but an adverse effect in patients receiving both.
 Cohn J, et al, NEJM, 345(23): 1667-75, 2001
 ARBs
 CHARM-Alternative Trial (Candesartan
substituted for ACEI in ACEI intolerant
patients).
 2028 patients with symptomatic heart failure
and EF<40% were randomized to candesartan
or placebo, in addition to standard therapy.
After 3 years, cardiovascular mortality and
hospital admissions for CHF were both less
(3% and 8% absolute risk reduction).
 ARBs
 CHARM-Added Trial
 In this trial, 2548 patients taking ACEIs with a
decreased EF<40% were randomized to receive
candesartan or placebo in addition to the ACEI.
 Cardiovascular and noncardiovascular mortality
were reduced significantly in the candesartan
group (ARR = 4%, RRR = 10%), as were
hospitalizations.
 ARBs
 CHARM-Preserved Trial: Candasartan in Heart
failure Assessment of Reduction in Mortality and
morbidity study. (A trio of trials.)
 In this trial, 3023 patients with a preserved EF>40%
were randomized to receive candesartan or placebo.
Cardiovascular and noncardiovascular mortality were
the same in both groups, while hospitalizations were
modestly decreased.
 Yusuf S, Lancet, 362: 777-81, 2003.
 ARBs
 VALIANT trial – valsartan is as effective as
captopril post-MI in patients with decreased EF.
 Pfeffer MA et al, NEJM, 349: 1893-906, 2003
 RESOLVD trial – candesartan with enalapril
and ER metoprolol demonstrated the most
improvement in EF from baseline. No clinical
outcomes.
 McKelvie RS et al, Eur Heart J, 24: 1727-34, 2003
Number Needed to Treat* for Different Drugs in CHF

ACE inhibitors14 6 One death over one year in patients with NYHA class III
and IV failure

10 One death over one year in patients with NYHA class I or

0 II failure

Beta blockers15 23 One death over one year

13 One hospitalization over one year

Spironolactone2 9 One death over two years in patients with NYHA class IV
failure

Hydralazine and isosorbide 14 One death over one year

dinitrate13

Digoxin16 9 Emergency department visits or hospitalizations

*--Number needed to treat (NNT) is the number of patients who need to be treated to prevent one
outcome from occurring. NNT=100/absolute risk reduction.
 African-American Heart Failure
Trial A-HeFT
 AA patients already on standard therapy were
randomized to receive isosorbide dinitrate and
hydralazine or placebo.
 The trial was stopped early after three years
when a significant benefit was realized: absolute
reduction in all-cause mortality of 4%.

 Taylor AL, et al, NEJM, 351(20): 2049-75, 2004

Now, let’s have some
shocking news…
 Yes, we’re talking
about ICDs
Implantable cardioverter-defibrillator
 SCD-HeFT trial
Sudden Cardiac Death in Heart
Failure Trial Investigators
 2521 pts with NYHA class II or III were
randomized to placebo, amiodarone, or ICD.
 Pts were already receiving standard medical
therapy
 Deaths
 Placebo group = 244 (29%)
 Amiodarone = 240 (28%)

 ICD = 182 (22%)

Bardy, G, et al, SCD-HeFT, NEJM, January 20, 2005; 352: 3, pp 225-237
 SCD-HeFT trial
Sudden Cardiac Death in Heart
Failure Trial Investigators
 The ICD group had a 23% relative risk
reduction, or an absolute risk reduction of 7.2%.
 NNT for benefit = ?
 So, who should get an ICD?
 Current Indications for ICD
 Patients at high risk for ventricular
arrhythmias
 Patients with EF < 35% and NYHA class II or
III heart failure
 Patients with a history of MI and EF < 30%

Goldberger, Z, Implantable Cardioverter-Defibrillators, JAMA,

February 15, 2006; 295:7, pp 809 - 818
 ADHF
 Oxygen and ventilatory support  — Patients with ADHF and a
decreased oxygen saturation should be treated with supplemental
oxygen.
 Patients with significant hypoxia or respiratory distress are generally
treated with high flow oxygen via a nonrebreather facemask; later
oxygen is titrated to patient comfort and an oxygen saturation of at
least 90 percent.
 For patients with ADHF and respiratory failure, we recommend a trial
of noninvasive positive pressure ventilation (NPPV) if emergent
intubation is not indicated, no contraindications to NPPV exist , and
personnel with experience in NPPV are available
 Patients with respiratory failure due to ADHF who fail NPPV, do not
tolerate NPPV, or have contraindications to NPPV require
endotracheal intubation for conventional mechanical ventilation.
 Diuretic dosing should be individualized and titrated according to response
and patient status. Patients who are treated with loop diuretics chronically
are usually treated with a higher dose in the acute setting; the intravenous
dose should be equal to or greater than (eg, 2.5 times) their maintenance
oral dose (eg, an intravenous furosemide dose of 40 to 100 mg for a patient
who had been taking 40 mg orally per day) [ 4 ]. In the DOSE trial of
intravenous furosemide in patients with ADHF, there was an almost
significant trend toward greater improvement in patients’ global
assessment of symptoms in the high dose (2.5 times the patients’ prior
dose) group compared to the low dose (equal the prior dose) group as
discussed below
 Peak diuresis typically occurs 30 minutes after administration.
Most patients will require additional diuresis through the
course of their care. Diuretic administration two or more times
per day may be necessary.
 Hemodynamic effects  — By reducing intravascular volume,
diuresis will eventually lower central venous and pulmonary
capillary wedge pressures. In addition, furosemideand possibly
other loop diuretics also have an initial morphine -like effect in
acute pulmonary edema, causing venodilation that can decrease
pulmonary congestion prior to the onset of diuresis [ 8 ]. This
effect appears to be mediated by enhanced release of
prostaglandins.
 Reductions in right and left heart filling pressures with diuresis are
frequently associated with augmented forward stroke volume and
cardiac output related to decreases in functional tricuspid and mitral
regurgitation and reduction in right ventricular volume with relief of
left ventricular compression and improved left ventricular
distensibility 
 However, during diuresis some patients experience symptomatic hypotension
with decreasing cardiac output and systemic blood pressure due to a lag in
reequilibration of intravascular volume via movement of fluid from the interstitial
space. Patients with HF with preserved LV ejection fraction (LVEF) or restrictive
physiology may be more sensitive to diuresis-induced reductions in preload.
Diuretics may enhance the hypotensive effects of ACE inhibitor or angiotensin
receptor blocker (ARB) therapy even when volume overload persists. Careful
monitoring during diuresis is required to prevent adverse hemodynamic effects
 Effects on renal function  — The blood urea nitrogen (BUN)
and serum creatinine often rise during diuretic treatment of
ADHF and careful monitoring is recommended. In the absence
of other causes for an elevated BUN, a disproportionate rise in
BUN relative to serum creatinine (BUN/serum creatinine ratio
>20:1) suggests a prerenal state with increased passive
reabsorption of urea. An initial rise in BUN may be
accompanied by a stable serum creatinine, reflecting preserved
glomerular filtration rate (GFR). Further elevations in BUN
along with a rise in serum creatinine are likely if diuresis is
continued in such patients.
 Most HF patients with hyponatremia have volume overload, rather than
volume depletion. The HFSA guidelines recommend fluid restriction
(<2 L/day) in HF patients with moderate hyponatremia (serum sodium
<130 meq/L) and volume overload and suggest that fluid restriction should
be considered to assist in treatment of fluid overload in other patients [ 2].
Stricter fluid restriction may be considered in patients with severe (serum
sodium <125meq/L) or worsening hyponatremia, although patient
tolerance of strict fluid restriction may be limited.
 Vasodilators  — 
 Vasodilators, including nesiritide , nitroglycerin ,
and nitroprusside , can reduce filling pressures, improve
symptoms, and facilitate diuresis.
 In patients with acute decompensated heart failure who are not
hypotensive, we suggest the use of a vasodilator in addition to
diuretic therapy with close hemodynamic monitoring
When using vasodilators in patients with ADHF, we favor the
following approach:
 Intravenous nitroglycerin is generally recommended. Nitrate
administration is contraindicated after use of PDE-5 inhibitors
such as sildenafil .
 In selected cases when there is a need for significant afterload
reduction (eg, hypertensive emergency, acute aortic or mitral
regurgitation), we recommendnitroprusside , although the risk
of cyanide or thiocyanate toxicity limit its use.
 For most patients hospitalized with acute heart failure (HF),
we recommend nottreating with nesiritide. In carefully
selected patients with appropriate hemodynamics (without
hypotension or cardiogenic shock) who remain symptomatic
despite routine therapy, a trial of nesiritide may be helpful as
an alternative to other vasodilator therapy
( nitroglycerin or nitroprusside) Nesiritide has a longer
effective half-life than nitroglycerin or nitroprusside, so side
effects such as hypotension may persist longer. 
 Intravenous vasodilators ( nitroglycerin or nitroprusside ) and diuretics are
recommended for rapid symptom relief in patients with acute pulmonary
edema or severe hypertension.
 In the absence of symptomatic hypotension, intravenous nitroglycerin ,
nitroprusside or nesiritide may be considered as an addition to diuretic
therapy for rapid improvement of congestive symptoms in patients admitted
with ADHF.
 Frequent blood pressure monitoring is recommended with vasodilator
agents. Dosage of these agents should be decreased if symptomatic
hypotension develops. Once symptomatic hypotension is resolved,
reintroduction and titration may be considered.
 Intravenous nitroprusside , nitroglycerin or nesiritide may be considered in
patients with ADHF and advanced HF who have persistent severe HF
despite aggressive treatment with diuretics and standard oral therapies.
 For most patients hospitalized with acute heart failure (HF), we
recommend not treating with nesiritide . In carefully selected patients with
appropriate hemodynamics (without hypotension or cardiogenic shock)
who remain symptomatic despite routine therapy, a trial of nesiritide may
be helpful as an alternative to other vasodilator therapy ( nitroglycerin or
nitroprusside ). Nesiritide has a longer effective half-life than nitroglycerin
or nitroprusside, so side effects such as hypotension may persist longer.
 Initiation of therapy  — Although some have advocated early use of ACE
inhibitor in patients with acute decompensated heart failure, we do not
recommend this approach. There are limited data on the safety and efficacy
of initiating new ACE inhibitor or ARB therapy in the early phase of
therapy of ADHF (ie, the first 12 to 24 hours)
 ACE inhibitors/ARBs and beta blockers  — ACE inhibitors,
ARBs, and beta blockers require special consideration in
patients with decompensated heart failure. The approach to
their use depends upon whether the patient has primarily
systolic or diastolic dysfunction
 Systolic dysfunction  — In patients with chronic HF due to
systolic dysfunction the long-term use
ACE inhibitors/ARBs and beta blockers reduces mortality, but
there are short-term risks to the use of these medications in the
setting of acute HF
 We approach the use of these
medications in this setting in the
following manner:
 For patients who are not already taking an ACE inhibitor or
ARB, we suggest that they NOT be initiated at the time of
presentation with an episode of ADHF ( Grade 2C). An oral
ACE inhibitor or ARB can usually be started within 24 to 48
hours, once the patient is hemodynamically stable.
 For patients who are not already taking a beta blocker, we
suggest that they NOT be initiated at the time of presentation
with an episode of ADHF ( Grade 2B ). Beta blockers are
generally started later than ACE inhibitors or ARBs, when the
patient is euvolemic, usually shortly before discharge.
 For patients who are already taking an ACE inhibitor or ARB,
we suggest that maintenance of oral therapy be cautiously
continued ( Grade 2C ). However, the dose should be decreased
or the drug discontinued if hypotension, acute renal failure, or
hyperkalemia is present. (See 'Continued therapy' above.)
 For patients who are already taking a beta blocker, management
depends upon the severity of HF decompensation and
hemodynamic instability (see 'Beta blockers'above):
 For patients with severe decompensation (eg, severe volume
overload and/orrequiring inotropic support), we suggest
withholding beta blockers ( Grade 2C ).
 For patients with moderate-to-severe decompensation, we suggest
decreasing or withholding beta blocker therapy
 For patients with mild decompensation without hypotension or
evidence of hypoperfusion, we suggest continuation of beta
blocker as tolerated ( Grade 2C ).
 Aldosterone antagonist therapy ( spironolactone or eplerenone )
reduces mortality when included in long-term management of
selected patients with systolic HF who can be carefully monitored
for serum potassium and renal function. In patients already taking
an aldosterone antagonist, such therapy can generally be continued
during an episode of acute decompensation, with appropriate
monitoring of blood pressure, renal function, and electrolytes. For
patients not taking an aldosterone antagonist who have an
indication for therapy, we favor initiation prior to discharge
Diastolic dysfunction  — As noted above, patients with ADHF
are treated similarly whether they have primarily systolic or
diastolic dysfunction. However, in patients with diastolic
dysfunction, long-term use of ACE inhibitors/ARBs and beta
blockers does not provide the same benefit as in patients with HF
due to systolic dysfunction. The efficacy of aldosterone
antagonist therapy in this population is under investigation. On
the other hand, the short term risks of beta blockers are less
concerning and treatment of hypertension and tachycardia are
particularly important. Thus, antihypertensive agents and beta
blockers may be useful in acute as well as chronic HF in patients
with primarily diastolic dysfunction
 Inotropic agents — The intravenous inotropic agents such as dobutamine and/or
milrinone may be helpful in selected patients with severe LV systolic
dysfunction and low output syndrome (diminished peripheral perfusion and end-
organ dysfunction) for whom treatment may be limited by marginal systemic
blood pressure or inadequate response to vasodilator and diuretic therapy
 Similarly, the 2010 HFSA guidelines for ADHF include the following
recommendations for use of inotropes [ 2 ]:

 Intravenous inotropes ( milrinone or dobutamine ) may be considered to relieve

symptoms and improve end-organ function in patients with advanced HF
characterized by LV dilation, reduced LVEF, and diminished peripheral
perfusion or end-organ dysfunction (low output syndrome), particularly if these
patients have marginal systolic blood pressure (<90 mmHg), have symptomatic
hypotension despite adequate filling pressure, or are unresponsive to, or
intolerant of, intravenous vasodilators.
 Intravenous inotropes may be considered in similar patients (ie,
patients with depressed systolic function and marginal cardiac
output) with evidence of fluid overload if they respond poorly to
intravenous diuretics or manifest diminished or worsening renal
function.
 When adjunctive therapy is needed in other patients with ADHF
(eg, patients with preserved cardiac output), administration of
vasodilators should be considered instead of intravenous inotropes.
 Intravenous inotropes are not recommended unless left heart filling
pressures are known to be elevated or cardiac index is severely
impaired based on direct measurement or clear clinical signs.
 Administration of intravenous inotropes ( milrinone or dobutamine ) in the
setting of ADHF should be accompanied by continuous or frequent blood
pressure monitoring and continuous monitoring of cardiac rhythm.
 If symptomatic hypotension or worsening tachyarrhythmias develop during
administration of these agents, discontinuation or dose reduction should be
considered.
 Inotropes are not indicated for treatment of ADHF in the setting of preserved
systolic function.

 Morphine therapy is not mentioned in the 2010 HFSA guidelines on

management of ADHF or in the 2009 ACC/AHA focused update.
 Given the limited evidence of benefits and potential risks of morphine , we
suggest generally avoiding morphine therapy in the treatment of ADHF
without acute MI.
 Mechanical cardiac assistance  — Patients with cardiogenic
pulmonary edema who are also in cardiogenic shock should be
considered candidates for mechanical circulatory support.
These patients usually have a cardiac index less than
2.0 L/min per m2, a systolic arterial pressure below 90 mmHg,
and a pulmonary capillary wedge pressure above 18 mmHg,
despite adequate pharmacologic therapy.
 The two major mechanical modalities used in this setting are
intraaortic balloon counterpulsation and an internally
implanted left ventricular assist device
 ultrafiltration was an effective method for fluid volume
removal, which provided similar amounts of weight loss to
stepped pharmacologic therapy, it was inferior to stepped
pharmacologic therapy for preservation of renal function at 96
hours and was associated with a higher rate of adverse events
 Vasopressin receptor antagonists have been investigated as an
adjunct to diuretics and other standard therapies in patients with
ADHF as a means of countering arterial vasoconstriction,
hyponatremia, and water retention. However, such treatment is
controversial and not included in the HFSA guidelines. The
2008 ESC guidelines suggest consideration of tolvaptan for HF
patients with hyponatremia in an ungraded recommendation
Tolvaptan is the most studied agent in this setting. 
 The stepped pharmacologic care algorithm included bolus plus
high doses of continuous infusion loop diuretic, the addition of
metolazone , and selective use of inotrope or vasodilator
therapy. The primary endpoint was the bivariate change in the
serum creatinine level and body weight from baseline to 96
hours after enrollment.
Recent Clinical Data
Effect on Survival and Hospitalization
of Initiating Treatment for Chronic
Heart Failure With Bisoprolol
Followed by Enalapril, as Compared
With the Opposite Sequence (CIBIS
III)
CIBIS = Cardiac Insufficiency
Bisoprolol Study
Willenheimer, R, et al, CIBIS III,
Circulation, October 18, 2005; 112: pp1-10
 CIBIS III
 In general, beta-blockers are considered as
add-on therapy to patients already on ACEIs
and diuretics.
 What are the beta-blockers that have proven
efficacious for HF?
 Carvedilol (Coreg)
 6.25 – 25 mg bid, start at 3.125mg bid and titrate every 2
weeks
 Metoprolol (Lopressor, Toprol XL)
 Metoprolol XL is the drug that has been studied
 Toprol XL 12.5 – 200 mg qday
 Metoprolol 50 – 200mg bid – not FDA approved
 Bisoprolol (Not FDA approved)
 Zebeta 2.5 - 20 mg qday and generic at same doses
 Bisoprolol/HCTZ is Ziac – 2.5/6.25, 5/6.25, 10/6.25
 One tab qday
 CIBIS III
 1010 treatment naïve patients with mild to
moderate heart failure and EF <35%
randomized to open-label monotherapy with
bisoprolol (10mg qday) or enalapril (10mg
bid) for six months. Then the two were
combined for 6 to 24 months.
 Study end-points:
 All-cause mortality
 Hospitalization
 CIBIS III
 In the per-protocol study:
 Bisoprolol first – 163 patients had a primary end point
 Of these, 65 died
 Enalapril first – 165 patients had a primary end-point
 Of these, 73 died
 -0.7% absolute difference in patients having a primary end
point
 What is the NNT? There is a nice reward for this
 Hazard ratio of 0.88 of death
 Hazard ratio of 0.95 of hospitalization
 Summary Points
 Heart failure has a prognosis similar to that of
cancer. As such, treat it aggressively.
 There is a new staging system to classify heart
failure:
 Stage A – at risk but no structural heart disease (HD)
 Stage B – no symptoms but structural HD present
 Stage C – patient with symptomatic HF

 Stage D – refractory heart failure

 Summary Points
 Standard medication classes for HF include:
 ACEIs
 Beta blockers

 Diuretics if volume overloaded

 Consider digoxin, spironolactone

 Consider ARBs, especially in ACEI intolerant

patient
 Beta-blockers continue to look good for HF
 Summary Points
 Preserved EF is about as common as depressed
EF in heart failure.
 Many patients have diastolic dysfunction.
 Remember to also care for the patient as a
person, not just a disease.
 A gentle touch and a kind smile might feel
better than a lasix-induced diuresis 
Thank you for your
time
Additional material
 BNP
 The Breathing Not Properly study
 Maisel A, et al, Rapid Measurement of B-Type
Natriuretic Peptide in the Emergency Diagnosis of
Heart Failure, NEJM, 347(3): 161-7, 2002.
 A number > 100 is suggestive of heart failure.
 Some thought to using this prospectively to
screen for heart failure, stage B. No RCTs to
date.
 ACEIs
 CONSENSUS: Enalapril added to vasodilator
therapy decreased mortality by 27% in patients
with severe (NYHA IV) heart failure.
 Anon., NEJM, 316(23): 1429-35, 1987.
 ACEIs
 SAVE Trial: Effect of captopril on mortality and
morbidity in patients with left ventricular dysfunction
after myocardial infaction. Results of the Survival
And Ventricular Enlargement trial.
 2231 patients with an EF<40% who survived an MI
were randomized to receive captopril and followed
for 42 months. Risks for mortality (5% absolute risk
reduction), fatal and nonfatal major cardiovascular
events, development of severe heart failure, and
recurrent MI were all reduced.
 Pfeffer MA, NEJM, 327(10): 669-77, 1992
 ACEIs
 SOLVD Trial: Enalapril therapy in patients
with an EF< 35% not being treated for CHF
demonstrated a statistically significant
decrease in the combined endpoint of
development of clinical CHF and death. Of
note, when studying the end point of mortality,
there was no statistical difference between
enalapril and placebo.
 Anon., NEJM, 327(10): 685-91, 1992.
 Beta-blockers
 Differential effects of beta-blockers in patients with
heart failure: A prospective, randomized double-blind
comparison of the long-term effects of metoprolol
versus carvedilol.
 150 patients with EF <35% were randomized to
metoprolol or carvedilol. After 2 years, patients in
the carvedilol showed a 3.7% increase in EF, greater
stroke volume and decreased PCWP compared with
metoprolol. Conversely, metoprolol showed a greater
increase in exercise capacity. Mortality was similar
(small study).
 Metra M, Circulation, 102(5): 546-51, 2000.
Trends in Prevalence and Outcome of Heart
Failure with Preserved Ejection Fraction
 4596 patients admitted to Mayo Clinic
Hospitals from 1987 to 2001.
 53% had reduced ejection fraction
 47% had preserved ejection fraction
 Survival was slightly better among those with
preserved EF – adjusted hazard ration for
death = 0.96, p = 0.01.
Owan, TE, et al, Trends in Prevalence and Outcome of Heart Failure with
Preserved Ejection Fraction, NEJM, 355:3, July 20, 2006, pp 251-259
 Take home points
 Starting with an ACEI is still standard of care.
 However, future studies with FDA approved
drugs for heart failure in the USA may confirm
that beta-blockers are equally efficacious
(noninferior) to ACEIs for the initial treatment
of HF.
 Outcome of Heart Failure with
Preserved Ejection Fraction in a
Population-Based Study
 2802 patients admitted to 103 Canadian
hospitals from April 1999 to March 2001 with
a discharge diagnosis of heart failure.
 31% had ejection fraction (EF) > 50%
 More likely to be older, female, history of
HTN, history of atrial fibrillation
Bhatia, RS, et al, Outcome of Heart Failure with Preserved Ejection Fraction in a
Population-Based Study, NEJM, 355:3, July 20, 2006, pg 260-269
 Outcome of Heart Failure with
Preserved Ejection Fraction in a
Population-Based Study
 Mortality rate of preserved EF (>50%) vs
reduced EF (<40%) at 30 days
 5% vs 7% respectively
 At one year, the rates were 22% vs 26%,
p=0.07, not significantly different.
 Patients with preserved EF have similar rates
for mortality and readmission for heart failure
Bhatia, RS, et al, Outcome of Heart Failure with Preserved Ejection Fraction in a
Population-Based Study, NEJM, 355:3, July 20, 2006, pg 260-269
Systolic blood pressure on admission
and patient outcomes
 41,267 patients admitted for heart failure to
259 hospitals between March 2003 –
December 2004.
 Good numbers!
 21,149 (51%) had preserved systolic function
 Meaning, half the patients had diastolic
dysfunction

Gheorghiade, M, et al, Systolic Blood Pressure at Admission, Clinical Characteristics,

and Outcomes in Patients Hospitalized With Acute Heart Failure, JAMA, Nov. 8, 2006,
Vol. 296, No. 18, pp 2217-26
 Straw poll…
Sys 120 = outcome?
vs Sys 150 = outcome?
Who does better?
 Systolic blood pressure on admission
and patient outcomes
8 7.2%
7
Percent 6
mortality 5
3.6%
at 4
2.5%
discharge 3
1.7%
2
1
0
<120 120-139 140-161 >161

Systolic blood pressure at admission in

mmHg
 Interesting outcomes
 Lower systolic at admission directly correlated
with increased mortality
 Concept of the “J” curve in treatment of
hypertension
 So, what systolic blood pressure do we shoot for
in patients with stable heart failure in the clinic?
 Still use national guidelines but stay tuned
Systolic and Diastolic Heart Failure
in the Community
 Inpatients and outpatients diagnosed with heart failure
underwent echocardiographic testing between
September 10, 2003 and October 27, 2005.
 556 study participants
 Preserved EF > 50 % present in 308 (55%) of patients
 Associated with older age, female sex, no h/o MI
 Isolated diastolic dysfunction present in 242 of patients of
these patients – 44% of total number (556) and 78% of
patients with preserved EF
 EF < 50% in 248 patients (45%)
 Diastolic dysfunction present in 204 (83%) of these patients
Bursi, F, Systolic and Diastolic Heart Failure in the Community, JAMA, Nov. 8, 2006,
296:18, pp 2209-2216
 Systolic and Diastolic Heart Failure
in the Community
 Needham’s take on this data…
 A little more than half (55%) of patients had
preserved EF at the time of diagnosis of heart failure.
 Almost 80% of all patients with heart failure have
diastolic dysfunction, whether they have depressed or
preserved EF.
 Many patients will have a mix of systolic dysfunction
(depressed EF) and diastolic dysfunction.

Bursi, F, Systolic and Diastolic Heart Failure in the Community, JAMA, Nov. 8, 2006,
296:18, pp 2209-2216