2. Management gfgggfdffgggof HFrEF.pptx

MANAGEMENT OF HFREF
Brook A. June/2016
Braunwald 10th ed.
ESC 2016 guideline

DEFINITION
 HF is a clinical syndrome characterized by
typical symptoms (e.g. breathlessness, ankle
swelling and fatigue) that may be accompanied by
signs (e.g. elevated jugular venous pressure,
pulmonary crackles and peripheral oedema)
caused by a structural and/or functional cardiac
abnormality, resulting in a reduced cardiac
output and/or elevated intracardiac pressures at
rest or during stress

DEFINITION
 The current definition of HF restricts itself to
stages at which clinical symptoms are apparent.
 Before clinical symptoms become apparent,
patients canpresentwithasymptomatic
structuralorfunctional cardiac abnormalities
[systolic or diastolic left ventricular (LV)
dysfunction], which are precursors ofHF

TERMINOLOGIES
 The main terminology used to describe HF is
historical and is based on measurement of the
LVEF.
 HF comprises a wide range of patients, from
those with normal LVEF [typically considered asv
≥50%; HF with preserved EF (HFpEF)] to those
with reduced LVEF [typically considered as
<40%; HF with reduced EF (HFrEF)]
 Patients with an LVEF in the range of 40–49%
represent a ‘grey area’, which we now define as
HFmrEF

TERMINOLOGIES
 Differentiation of patients with HF based on
LVEF is important due to different underlying
aetiologies, demographics, co-morbidities and
response to therapies.
 Most clinical trials published after 1990
selected patients based on LVEF [usually
measured using echocardiography, a radionuclide
technique or cardiac magnetic resonance (CMR)],
and it is only in patients with HFrEF that
therapies have been shown to reduce both
morbidity and mortality.

TERMINOLOGIES
 The diagnosis of HFpEF is more challenging than
the diagnosis of HFrEF.
 Patients with HFpEF generally do not have a
dilated LV, but instead often have an increase in
LV wall thickness and/or increased left atrial
(LA) size as a sign of increased filling pressures.
 Most have additional ‘evidence’ of impaired LV
filling or suction capacity, also classified as
diastolic dysfunction, which is generally
accepted as the likely cause of HF in these
patients (hence the term ‘diastolic HF’).

TERMINOLOGIES
 However, most patients with HFrEF (previously
referred to as ‘systolic HF’) also have diastolic
dysfunction, and subtle abnormalities of systolic
function have been shown in patients with
HFpEF.
 Hence the preference for stating preserved or
reduced LVEF over preserved or reduced
‘systolic function’.

TERMINOLOGIES
 In previous guidelines it was acknowledged that a
grey area exists between HFrEF and HFpEF.
 These patients have an LVEF that ranges from
40 to 49%, hence the term HFmrEF.
 Identifying HFmrEF as a separate group will
stimulate research into the underlying
characteristics, pathophysiology and treatment
of this group of patients.
 Patients with HFmrEF most probably have
primarily mild systolic dysfunction, but with
features of diastolic dysfunction

TERMINOLOGIES
 HF: describes the symptomatic syndrome, graded
according to the New York Heart Association (NYHA)
functional classification
 However, a patient can be rendered asymptomatic by
treatment.
 Asymptomatic LV systolic dysfunction: a patient who has
never exhibited the typical symptoms and/or signs of HF
and with a reduced LVEF
 Chronic HF: Patients who have had HF for some time
 Stable HF: A treated patient with symptoms and signs
that have remained generally unchanged for at least 1
month
 If chronic stable HF deteriorates, the patient may be
described as ‘decompensated’ and this may happen
suddenly or slowly, often leading to hospital admission, an
event of considerable prognostic importance.

TERMINOLOGIES
 New-onset (‘de novo’) HF may also present
acutely, for example, as a consequence of acute
myocardial infarction (AMI), or in a subacute
(gradual) fashion, for example, in patients with a
dilated cardiomyopathy (DCM), who often have
symptoms for weeks or months before the
diagnosis becomes clear.
 Although symptoms and signs of HF may resolve,
the underlying cardiac dysfunction may not, and
patients remain at the risk of recurrent
‘decompensation’.

TERMINOLOGIES
 Occasionally, however, a patient may have HF
due to a problem that resolves completely (e.g.
acute viral myocarditis, takotsubo
cardiomyopathy or tachycardiomyopathy).
 Other patients, particularly those with
‘idiopathic’ DCM, may also show substantial or
even complete recovery of LV systolic function
with modern disease modifying therapy [including
ACEIs, beta-blocker, mineralocorticoid receptor
antagonist (MRA), ivabradine and/or CRT].

TERMINOLOGIES
 ‘Congestive HF’ is a term that is sometimes used,
and may describe acute or chronic HF with
evidence of volume overload.
 Many or all of these terms may be accurately
applied to the same patient at different times,
depending upon their stage of illness.

TERMINOLOGIES
 The NYHA functional classification has been
used to describe the severity of symptoms and
exercise intolerance.
 However, symptom severity correlates poorly with
many measures of LV function
 Although there is a clear relationship between the
severity of symptoms and survival, patients with mild
symptoms may still have an increased risk of
hospitalization and death.
 Sometimes the term ‘advanced HF’ is used to
characterize patients with severe symptoms,
recurrent decompensation and severe cardiac
dysfunction

TERMINOLOGIES
Func’l
Capacity
Objective Assessment
Class I Patients with cardiac disease but without resulting limitation of
physical activity. Ordinary physical activity does not cause undue
fatigue, palpitations, dyspnea, or anginal pain.
Class II Patients with cardiac disease resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary physical
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III Patients with cardiac disease resulting in marked limitation of
physical activity. They are comfortable at rest. Less than ordinary
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV Patients with cardiac disease resulting in inability to carry on any
physical activity without discomfort. Symptoms of heart failure or
the anginal syndrome may be present even at rest. If any
physical activity is undertaken, discomfort is increased.

TERMINOLOGIES
 The American College of Cardiology
Foundation/American Heart Association
(ACCF/AHA) classification describes stages of
HF development based on structural changes and
symptoms
 The Killip classification may be used to describe
the severity of the patient’s condition in the
acute setting after myocardial infarction

EPIDEMIOLOGY, ETIOLOGY &
PROGNOSIS

EPIDEMIOLOGY
 The prevalence of HF depends on the definition
applied, but is approximately1–2% of the adult
population in developed countries, rising to ≥10%
among people >70 years of age.
 Among people >65 years of age presenting to primary
care with breathlessness on exertion, one in six will
have unrecognized HF (mainly HFpEF)
 The lifetime risk of HF at age 55 years is 33% for
men and 28% for women.
 The proportion of patients with HFpEF ranges from
22 to 73%, depending on the definition applied, the
clinical setting (primary care, hospital clinic, hospital
admission), age and sex of the studied population,
previous myocardial infarction and the year of
publication

EPIDEMIOLOGY
 Data on temporal trends based on hospitalized
patients suggest that the incidence of HF may be
decreasing, more for HFrEF than for HFpEF.
 HFpEF and HFrEF seem to have different
epidemiological and aetiological profiles.
 Compared with HFrEF, patients with HFpEF are
 Older,
 More often women and
 More commonly have a history of hypertension and atrial
fibrillation (AF),
 While a history of myocardial infarction is less common.
 The characteristics of patients with HFmrEF are
between those with HFrEF and HFpEF, but further
studies are needed to better characterize this
population.

EPIDEMIOLOGY
 The aetiology of HF is diverse within and among world
regions.
 There is no agreed single classification system for the
causes of HF, with much overlap between potential
categories.
 Many patients will have several different pathologies—
cardiovascular and non-cardiovascular—that conspire to
cause HF.
 Identification of these diverse pathologies should be part
of the diagnostic workup, as they may offer specific
therapeutic opportunities.
 Many patients with HF and ischaemic heart disease (IHD)
have a history of myocardial infarction or
revascularization.
 However, a normal coronary angiogram does not exclude
myocardial scar (e.g. by CMR imaging) or impaired coronary
microcirculation as alternative evidence for IHD

EPIDEMIOLOGY
 In 20% to 30% of the cases of HFrEF, the exact
etiologic basis is not known.
 These patients are referred to as having
nonischemic, dilated, or idiopathic cardiomyopathy if
the cause is unknown
 Previous viral infection or toxin exposure (e.g.,
with excess alcohol consumption or use of
chemotherapeutic agents also may lead to a
dilated cardiomyopathy.

EPIDEMIOLOGY
 Although excessive alcohol consumption can
promote cardiomyopathy, alcohol consumption
per se is not associated with increased risk for
HF and may protect against the development of
HF when consumed in moderation

EPIDEMIOLOGY
 It also is becoming increasingly clear that a large
number of cases of dilated cardiomyopathy are
secondary to specific genetic defects, most
notably those in the cytoskeleton
 Most of the forms of familial dilated
cardiomyopathy are inherited in autosomal
dominant fashion.
 Mutations of genes encoding cytoskeletal
proteins (desmin, cardiac myosin, vinculin) and
nuclear membrane proteins (lamin) have been
identified thus far.

EPIDEMIOLOGY
 Dilated cardiomyopathy also is associated with
Duchenne’s, Becker’s, and limb-girdle muscular
dystrophies

EPIDEMIOLOGY
 In clinical practice, a clear distinction between
acquired and inherited cardiomyopathies remains
challenging.
 In most patients with a definite clinical diagnosis of
HF, there is no confirmatory role for routine genetic
testing,
 But genetic counselling is recommended in patients
with hypertrophic cardiomyopathy (HCM), ‘idiopathic’
DCM or arrhythmogenic right ventricular
cardiomyopathy (ARVC), since the outcomes of these
tests may have clinical implications.

EPIDEMIOLOGY
 In patients with HF (both hospitalized and
ambulatory), most deaths are due to
cardiovascular causes, mainly sudden death and
worsening HF.
 All-cause mortality is generally higher in HFrEF
than HFpEF
 Hospitalizations are often due to non-
cardiovascular causes, particularly in patients
with HFpEF.
 Hospitalization for cardiovascular causes did not
change from 2000 to 2010, whereas those with
non-cardiovascular causes increased.

PROGNOSIS
 Estimation of prognosis for morbidity, disability
and death helps patients, their families and
clinicians decide on the appropriate type and
timing of therapies (in particular, decisions about
a rapid transition to advanced therapies) and
assists with planning of health and social
services and resources.
 Numerous prognostic markers of death and/or
HF hospitalization have been identified in
patients with HF
 However, their clinical applicability is limited and
precise risk stratification in HF remains challenging

PROGNOSIS
 Although several recent reports have suggested that
the mortality for patients with HF is subsiding, the
overall mortality rate remains higher than for many
cancers, including those involving the bladder, breast,
uterus, and prostate.
 In the Framingham Heart Study, the median survival was
1.7 years for men and 3.2 years for women, with only 25%
of men and 38% of women surviving 5 years.
 European studies have confirmed a similar poor longterm
prognosis
 More recent data from the Framingham Heart Study have
examined long-term trends in the survival of patients with
HF and shown improved survival in both men and women,
with an overall decline in mortality of approximately 12 %
per decade from 1950 to 1999

PROGNOSIS
 Sex
 The role of sex in HF prognosis remains a
controversial issue with respect to HF outcomes.
 Nonetheless, the aggregate data suggest that women
with HF have a better overall prognosis than do men.
 However, women appear to have a greater degree of
functional incapacity for the same degree of LV
dysfunction and also have higher prevalence of HF
with a normal EF

PROGNOSIS
 Race
 Controversy also has arisen regarding the impact of race
on outcome, with higher mortality rates being reported in
blacks in some but not all studies.
 Blacks with HF present at an earlier age and have more
advanced LV dysfunction and a worse New York Heart
Association (NYHA) functional class at the time of diagnosis.
 Although the reasons for these differences are not
known, as noted previously, differences in HF etiology
might explain some of these observations.
 Additional socioeconomic factors also may potentially
influence outcomes in black patients, such as geographic
location and access to health care.
 Age is one of the strongest and most consistent
predictors of adverse outcome in HF

PROGNOSIS
 Many other factors have been associated with
increased mortality in patients with HF*
 To this end, several multivariate models for
predicting the HF prognosis have been developed
and validated.
 One such model is the Seattle Heart Failure
Model

PROGNOSIS
 Seattle Heart Failure Model
 Derived by retrospectively investigating predictors
of survival among patients with HF in clinical trials.
 The Seattle Heart Failure Model provides an
accurate estimate of 1-, 2-, and 3-year survival rates
with the use of easily obtained clinical,
pharmacologic, device, and laboratory
characteristics

PROGNOSIS
 Although obesity is a risk factor for the
development of HF, obese patients with HF seem
to enjoy a more favorable clinical prognosis.
 The association between obesity, a traditional
cardiovascular risk factor, and improved clinical
outcomes in patients with HF (i.e., reverse
epidemiology) has been called the “obesity
paradox.”

BIOMARKERS AND PROGNOSIS
 Strong inverse correlations have been reported
between survival and plasma levels of
 Norepinephrine, renin, arginine vasopressin (AVP),
aldosterone, atrial and brain natriuretic peptides (ANP and
BNP) and N-terminal pro–B-type natriuretic peptide (NT-
proBNP), endothelin-1, and inflammatory markers such as
tumor necrosis factor (TNF), soluble TNF receptors, C-
reactive protein, galactin-3, pentraxin-3, and soluble ST2
 Markers of oxidative stress, such as oxidized low-
density lipoprotein and serum uric acid, also have
been associated with worsening clinical status and
impaired survival in patients with chronic HF.

 Cardiac troponins T and I, sensitive markers of
myocyte damage, may be elevated in patients
with nonischemic HF and predict adverse cardiac
outcomes
 The association between a low hemoglobin or
hematocrit and adverse HF outcomes also has
long been recognized
 And recently has garnered considerable attention
after several reports illustrated the independent
prognostic value of anemia in patients with HF with
either reduced or normal ejection fraction*

 Anemia
 Published estimates of the prevalence of anemia
(defined as a hemoglobin concentration less than 13
g/dL in men and less than 12 g/dL in women) in
patients with HF vary widely, ranging from 4% to
50%, depending on the population studied and the
definition of anemia that is used.
 In general, anemia is associated with more HF
symptoms, worse NYHA functional status, greater
risk of HF hospitalization, and reduced survival

 Anemia
 Unclear, however, is whether anemia is a cause of
decreased survival or simply a marker of more
advanced disease.
 The underlying cause for anemia probably is
multifactorial, including
 Reduced sensitivity to erythropoietin receptors,
 The presence of a hematopoiesis inhibitor, and/or
 A defective iron supply for erythropoiesis
 Although a “transfusion threshold” for maintaining
the hematocrit above 30% in patients with
cardiovascular disease generally has been accepted,
this clinical practice has been based more on expert
opinion rather than on direct evidence that
documents the efficacy of this form of therapy*

 Renal Insufficiency
 Renal insufficiency is associated with poorer outcomes in
patients with HF; some uncertainty remains, however,
regarding whether renal impairment is a simply a marker
for worsening HF or whether renal impairment might be
causally linked to worsening HF.
 Although more common in patients hospitalized for HF, at
least some degree of renal impairment is still present in
approximately one half of stable outpatients with HF.
 Patients with renal hypoperfusion or intrinsic renal disease
show an impaired response to diuretics and
angiotensinconverting enzyme (ACE) inhibitors and are at
increased risk for adverse effects during treatment with
digitalis.

 In a recent metaanalysis a majority of patients with
HF had some degree of renal impairment.
 These patients represented a high-risk group with an
approximately 50% increased relative mortality risk when
compared with patients who had normal renal function.
 Similar findings were observed in the Acute
Decompensated Heart Failure National Registry
(ADHERE)

 In the second prospective Randomized study of
Ibopamine on Mortality and Efficacy, impaired renal
function was a stronger predictor of mortality than
impaired LV function and NYHA functional class in
patients with advanced HF
 Thus renal insufficiency is a strong, independent
predictor of adverse outcomes in patients with
HF.

SYMPTOMS & SIGNS
 HF should be viewed as a
continuum comprising four
interrelated stages

ESSENTIAL INITIAL INVESTIGATIONS
 Natriuretic peptides
 Useful especially in the non-acute setting when
echocardiography is not immediately available
 Elevated NPs help establish an initial working
diagnosis, identifying those who require further
cardiac investigation; patients with values below the
cutpoint for the exclusion of important cardiac
dysfunction do not require echocardiography
 Patients with normal plasma NP concentrations are
unlikely to have HF.

 Diagnostic values apply similarly to HFrEF and
HFpEF; on average, values are lower for HFpEF than
for HFrEF.
 At the mentioned exclusionary cut-points, the
negative predictive values are very similar and high
(0.94–0.98) in both the non-acute and acute setting,
but the positive predictive values are lower both in
the non-acute setting (0.44–0.57) and in the acute
setting (0.66–0.67)
 Therefore, the use of NPs is recommended for
ruling-out HF, but not to establish the diagnosis

 There are numerous cardiovascular and non-
cardiovascular causes of elevated NPs that may
weaken their diagnostic utility in HF.
 Among them, AF, age and renal failure are the most
important factors impeding the interpretation of NP
measurements
 On the other hand, NP levels may be
disproportionally low in obese patients

 ECG
 An abnormal ECG increases the likelihood of the
diagnosis of HF, but has low specificity
 Some abnormalities on the ECG provide information
on aetiology (e.g. myocardial infarction), and findings
on the ECG might provide indications for therapy
(e.g. anticoagulation for AF, pacing for bradycardia,
CRT if broadened QRS complex)
 HF is unlikely in patients presenting with a
completely normal ECG (sensitivity 89%)
 Therefore, the routine use of an ECG is mainly
recommended to rule out HF.

 Echocardiography
 The most useful, widely available test in patients
with suspected HF to establish the diagnosis.
 It provides immediate information on chamber
volumes, ventricular systolic and diastolic function,
wall thickness, valve function and pulmonary
hypertension
 This information is crucial in establishing the
diagnosis and in determining appropriate treatment

DIAGNOSIS OF HFPEF
 The diagnosis of HFpEF remains challenging.
LVEF is normal and signs and symptoms for HF
are often non-specific and do not discriminate
well between HF and other clinical conditions
 The diagnosis of chronic HFpEF, especially in the
typical elderly patient with co-morbidities and no
obvious signs of central fluid overload, is
cumbersome and a validated gold standard is
missing

DIAGNOSIS OF HFPEF
 To improve the specificity of diagnosing HFpEF,
the clinical diagnosis needs to be supported by
objective measures of cardiac dysfunction at
rest or during exercise.
 The diagnosis of HFpEF requires the following
conditions to be fulfilled:
1. The presence of symptoms and/or signs of HF
2. A ‘preserved’ EF (defined as LVEF ≥50% or 40–49%
for HFmrEF)
3. Elevated levels of NPs
4. Objective evidence of other cardiac functional and
structural alterations underlying HF

DIAGNOSIS OF HFPEF
 In case of uncertainty, a stress test or
invasively measured elevated LV filling pressure
may be needed to confirm the diagnosis
 The cut-off of 50% for a diagnosis of HFpEF is
arbitrary; patients with an LVEF between 40 and
49% are often classified as HFpEF in clinical
trials

DIAGNOSIS OF HFPEF
 The resting ECG may reveal abnormalities such
as AF, LV hypertrophy and repolarisation
abnormalities.
 A normal ECG and/or plasma concentrations of BNP
<35 pg/mL and/or NT-proBNP <125 pg/mL make a
diagnosis of HFpEF, HFmrEF or HFrEF unlikely
 The next step comprises an advanced workup in
case of initial evidence of HFpEF/HFmrEF and
consists of objective demonstration of
structural and/or functional alterations of the
heart as the underlying cause for the clinical
presentation.

DIAGNOSIS OF HFPEF
 Key structural alterations are
 A left atrial volume index (LAVI) >34 mL/m2 or
 A left ventricular mass index (LVMI) ≥115 g/m2 for
males and ≥95 g/m2 for females.
 Key functional alterations are
 An E/e′ ≥13 and
 A mean e’ septal and lateral wall <9 cm/s
 Other (indirect) echocardiographically derived
measurements are longitudinal strain or tricuspid
regurgitation velocity (TRV)

DIAGNOSIS OF HFPEF
 A diastolic stress test can be performed with
echocardiography, typically using a semi-supine
bicycle ergometer exercise protocol with
assessment of LV (E/e′) and pulmonary artery
pressures (TRV), systolic dysfunction
(longitudinal strain), stroke volume and cardiac
output changes with exercise*

DIAGNOSIS OF HFPEF
 Alternatively, invasive haemodynamics at rest
with assessment of filling pressures [pulmonary
capillary wedge pressure (PCWP) ≥15 mmHg or
left ventricular end diastolic pressure (LVEDP)
≥16 mmHg] followed by exercise haemodynamics
 If below these thresholds, with assessment of
changes in filling pressures, pulmonary artery
systolic pressure, stroke volume and cardiac
output, can be performed

DIAGNOSIS OF HFPEF
 The diagnosis of HFpEF in patients with AF is
difficult.
 Since AF is associated with higher NP levels, the use of
NT-proBNP or BNP for diagnosing HFpEF probably needs
to be stratified by the presence of sinus rhythm (with
lower cut-offs) vs. AF (higher cut-offs).
 LAVI is increased by AF, and functional parameters of
diastolic dysfunction are less well established in AF, and
other cut-off values probably apply.
 On the other hand, AF might be a sign of the
presence of HFpEF, and patients with AF and HFpEF
often have similar patient characteristics.
 In addition, patients with HFpEF and AF might have more
advanced HF compared with patients with HFpEF and sinus
rhythm

DELAYING/PREVENTING HF
 There is considerable evidence that the onset of
HF may be delayed or prevented through
interventions aimed at modifying risk factors for
HF or treating asymptomatic LV systolic
dysfunction

 For patients at high risk for development of HF
(stage A), every effort should be made to
prevent HF
 Treat preventable conditions like hypertension,
hyperlipidemia, and diabetes
 In this regard, ACE inhibitors are particularly useful in
preventing HF in patients who have a history of
atherosclerotic vascular disease, diabetes mellitus, or
hypertension with associated cardiovascular risk factors
 Population Screening

 Hypertension control
 Many trials show that control of hypertension will delay
the onset of HF and some also show that it will prolong life
 Different antihypertensive drugs [diuretics, ACEIs,
angiotensin receptor blockers (ARBs), beta-blockers] have
been shown to be effective, especially in older people,
both in patients with and without a history of myocardial
infarction
 Along with the ongoing discussion on optimal target blood
pressure values in hypertensive non-diabetic subjects, the
recent SPRINT study has already demonstrated that
treating hypertension to a lower goal [SBP <120 mmHg vs.
<140 mmHg] in older hypertensive subjects (≥75 years of
age) or high-risk hypertensive patients reduces the risk of
cardiovascular disease, death and hospitalization for HF

 Empaglifozin for T2DM
 Recently, empaglifozin (an inhibitor of sodium-
glucose cotransporter 2), has been shown to improve
outcomes (including the reduction of mortality and
HF hospitalizations) in patients with type 2 diabetes.
 Other hypoglycaemic agents have not been shown
convincingly to reduce the risk of cardiovascular
events and may increase the risk of HF.
 Intensification of hypoglycaemic therapy to drive
down glycated haemoglobin (HbA1c) with agents
other than empagliflozin does not reduce the risk of
developing HF

 Smoking & Alcohol
 Although smoking cessation has not been shown to
reduce the risk of developing HF, the epidemiological
associations with the development of cardiovascular
disease suggest that such advice, if followed, would
be beneficial.
 The association between alcohol intake and the risk
of developing de novo HF is U-shaped, with the
lowest risk with modest alcohol consumption (up to 7
drinks/week).
 Greater alcohol intake may trigger the development of
toxic cardiomyopathy, and when present, complete
abstention from alcohol is recommended.

 Physical activity
 An inverse relationship between physical activity and
the risk of HF has been reported.
 A recent meta-analysis found that doses of physical
activity in excess of the guideline recommended
minimal levels may be required for more substantial
reductions in HF risk

 Statins
 Statins reduce the rate of cardiovascular events and
mortality; there is also reasonable evidence that
they prevent or delay the onset of HF.
 Antiplatelets
 Neither aspirin nor other antiplatelet agents, nor
revascularization, have been shown to reduce the
risk of developing HF or mortality in patients with
stable CAD.
 Treatment of Obesity
 Obesity is also a risk factor for HF, but the impact
of treatments of obesity on the development of HF
is unknown.

 ACEIs
 In patients with CAD, without LV systolic
dysfunction or HF, ACEIs prevent or delay the onset
of HF and reduce cardiovascular and all cause
mortality, although the benefit may be small in the
contemporary setting, especially in patients receiving
aspirin
 Up-titration of renin–angiotensin system antagonists
and beta-blockers to maximum tolerated dosages
may improve outcomes, including HF, in patients with
increased plasma concentrations of NPs

 ACEIs
 In asymptomatic patients with chronically reduced
LVEF, regardless of its aetiology, an ACEI can
reduce the risk of HF requiring hospitalization.
 This has not yet been shown for beta-blockers or
MRAs.

 A primary percutaneous coronary intervention
(PCI) at the earliest phase of an ST segment
elevation myocardial infarction (STEMI) to
reduce infarct size decreases the risk of
developing a substantial reduction in LVEF and
subsequent development of HFrEF.
 Initiation of an ACEI, a beta-blocker and an
MRA immediately after a myocardial infarction,
especially when it is associated with LV systolic
dysfunction, reduces the rate of hospitalization
for HF and mortality, as do statins

 ICD
 In patients with asymptomatic LV systolic
dysfunction (LVEF<30%) of ischaemic origin who are
≥40 days after an AMI, an implantable cardioverter-
defibrillator (ICD) is recommended to prolong life

 Population Screening
 At present, only limited information is available to
support the screening of broad populations to detect
undiagnosed HF and/or asymptomatic LV dysfunction
 NPs are left out due to low positive predictive value*
 Whom to screen?
 Patients who are at very high risk of a developing
cardiomyopathy (e.g., those with a strong family history of
cardiomyopathy or those receiving cardiotoxic
interventions) are appropriate targets for more aggressive
screening such as 2D echocardiography to assess LV
function.
 The routine periodic assessment of LV function in other
patients is not currently recommended, however.

 Population Screening
 How to screen?
 Several sophisticated clinical scoring systems have been
developed to screen for HF in population-based studies,
including
 The Framingham criteria:, which screen for HF on the
basis of clinical criteria, and
 The National Health and Nutrition Survey (NHANES)
criteria: which use self-reporting of symptoms to
identify patients with HF
 Additional laboratory tests, however, are often required

TRANSIENT HF (LV DYSFUNCTION)
 Some conditions result in HF while the LV has
normal function/structure
 Eg. Commonly postoperatively after cardiac surgery
or in the setting of severe brain injury, or after a
systemic infection.
 Mechanism
 Some form of “stunning” of functional myocardium or
 Activation of proinflammatory cytokines that are
capable of suppressing LV function

TRANSIENT HF (LV DYSFUNCTION)
 Emotional stress can also precipitate severe,
reversible LV dysfunction that is accompanied by
chest pain, pulmonary edema, and cardiogenic
shock in patients without coronary disease
(takotsubo syndrome).
 In this setting, LV dysfunction is thought to be
secondary to the deleterious effects of
catecholamines after heightened sympathetic
stimulation

OBJECTIVES
 The main goals of treatment for HF are to
 Reduce symptoms,
 Prolong survival,
 Improve the quality of life, and
 Prevent disease progression.
 Once structural heart disease has developed
(stages B to D), the choice of therapy for
patients with HFrEF depends on their NYHA
functional classification*

OBJECTIVES
 For patients who have developed LV systolic
dysfunction but remain asymptomatic (NYHA class
I), the goal should be to slow disease progression by
blocking neurohormonal systems that lead to cardiac
remodeling
 For patients who have developed symptoms (NYHA
class II to IV), the primary goal should be to
alleviate fluid retention, lessen disability, and reduce
the risk of further disease progression and death.
 These goals generally require a strategy that combines
diuretics (to control salt and water retention) with
neurohormonal interventions (to minimize cardiac
remodeling).

GENERAL MEASURES
 Identify and treat causes of the underlying
structural/functional abnormalities
 Screen for and treat comorbid illnesses
hypertension and diabetes that are believed to
underlie the structural heart disease.
 Identify factors that provoke worsening HF in
previously stable patients (see table below)

 Although documented evidence of the effects of
immunization in patients with HF is lacking, these
patients are at high risk for developing
pneumococcal pneumonia and influenza.
 Accordingly, clinicians should consider
recommending influenza and pneumococcal
vaccines to their patients with HF, to prevent
respiratory infections.

GENERAL MEASURES
ACTIVITY
 Although heavy physical labor is not
recommended in HF, routine modest exercise has
been shown to be beneficial in selected patients
with NYHA class I to III HF.
 HF-ACTION trial
 A Controlled Trial Investigating Outcomes of
Exercise Training
 No significant improvement in all-cause mortality or
all-cause hospitalization
 A trend toward decreased cardiovascular mortality
or HF related hospitalizations (HR, 0.87 [95% CI,
0.74 to 0.99]; P = .06)
 Significant improvement in quality of life

GENERAL MEASURES
ACTIVITY
 For euvolemic patients, regular isotonic exercise such
as walking or riding a stationary-bicycle ergometer
may be useful as an adjunctive therapy to improve
clinical status after exercise testing has determined
the safety of such training (i.e., the patient does not
develop significant ischemia or arrhythmias).
 Exercise training is not recommended, however, in
patients with HFrEF
 Who have had a major cardiovascular event or procedure
within the past 6 weeks;
 Receiving cardiac devices that limit the ability to achieve
target heart rates; or
 With significant arrhythmia or ischemia during baseline
cardiopulmonary exercise testing.

GENERAL MEASURES
DIET
 Sodium restriction
 Dietary restriction of sodium (to 2 to 3 g daily) is
recommended in all patients with the clinical
syndrome of HF and either preserved or depressed
EF.
 Further restriction (<2 g daily) may be considered in
moderate to severe HF.
 Fluid restriction
 Generally is unnecessary except in the setting of
hyponatremia (<130 mEq/liter)
 Causes of hyponatremia
 Activation of the renin-angiotensin system,
 Excessive secretion of AVP, or
 Loss of salt in excess of water from previous diuretic use.

GENERAL MEASURES
DIET
 Fluid restriction ctd
 Fluid restriction (<2 liters/day) should be considered
in hyponatremic patients (<130 mEq/liter), or for
those patients whose fluid retention is difficult to
control despite high doses of diuretics and sodium
restriction.
 Calorie supplementation
 Recommended for patients with advanced HF and
unintentional weight loss or muscle wasting (cardiac
cachexia)
 However, anabolic steroids are not recommended for
these patients because of the potential problems
with volume retention

GENERAL MEASURES
DIET
 Calorie supplementation ctd
 The measurement of nitrogen balance, caloric intake,
and prealbumin may be useful in determining
appropriate nutritional supplementation.
 The use of dietary supplements (“nutriceuticals”)
should be avoided in the management of symptomatic
HF because of the lack of proven benefit and the
potential for significant interactions with proven HF
therapeutics

PHARMACOLOGICAL TREATMENT OF
HFREF

OBJECTIVES
 The goals of treatment in patients with HF are
to
 To improve their clinical status, functional capacity
and quality of life,
 Prevent hospital admission and reduce mortality.
 It is now recognized that preventing HF
hospitalization and improving functional capacity
are important benefits to be considered if a
mortality excess is ruled out

NEURO-HORMONAL ANTAGONISTS (ACEIS,
MRAS AND BETA-BLOCKERS
 Have been shown to improve survival in patients
with HFrEF
 Recommended for the treatment of every
patient with HFrEF, unless contraindicated or
not tolerated.
 ACEIs have been shown to reduce mortality and
morbidity in patients with HFrEF and are
recommended unless contraindicated or not
tolerated in all symptomatic patients.

NEURO-HORMONAL ANTAGONISTS CTD
 ACEIs should be up-titrated to the maximum
tolerated dose in order to achieve adequate
inhibition of the renin–angiotensin–aldosterone
system (RAAS)
 There is evidence that in clinical practice the
majority of patients receive suboptimal doses of
ACEI.
 ACEIs are also recommended in patients with
asymptomatic LV systolic dysfunction to reduce
the risk of HF development, HF hospitalization
and death

 A new compound (LCZ696) that combines the
moieties of an ARB (valsartan) and a neprilysin
(NEP) inhibitor (sacubitril) has recently been
shown to be superior to an ACEI (enalapril) in
reducing the risk of death and of hospitalization
for HF in a single trial with strict
inclusion/exclusion criteria.162
 Sacubitril/valsartan is therefore recommended
to replace ACEIs in ambulatory HFrEF patients
who remain symptomatic despite optimal therapy
and who fit these trial criteria.

 ARBs have not been consistently proven to
reduce mortality in patients with HFrEF and
their use should be restricted to patients
intolerant of an ACEI or those who take an ACEI
but are unable to tolerate an MRA

IVABRADINE
 Ivabradine is a heart rate–lowering agent that acts
by selectively blocking the cardiac pacemaker If
(“funny”) current that controls the spontaneous
diastolic depolarization of the sinoatrial node.
 Ivabradine blocks If channels in a concentration-
dependent manner by entering the channel pore from
the intracellular side and thus can only block the
channel when it is open.
 The magnitude of If inhibition is directly related to
the frequency of channel opening and would
therefore be expected to be most effective at
higher heart rates.

IVABRADINE
 Initially developed and approved as an antianginal
agent in Europe
 also was shown to improve outcomes in the
Systolic Heart Failure Treatment with the If
Inhibitor Ivabradine Trial (SHIFT)

IVABRADINE
 SHIFT trial
 Enrolled symptomatic patients with an LVEF of 35% or
less who were in sinus rhythm with heart rate of 70
beats/min or higher and on standard medical therapy for
HF (including beta blockers)
 Ivabradine (uptitrated to a maximal dosage of 7.5 mg
twice daily) reduced the primary composite outcome of
cardiovascular death and HF hospitalization by 18%
(HR, 0.82 [95% CI 0.75 to 0.90]; P < .0001)
 The composite endpoint was driven primarily by reducing
hospital admissions for worsening HF (HR, 0.74 [95% CI,
0.66 to 0.83]; P < .0001), as indicated by the lack of
decrease in cardiovascular deaths (HR, 0.91 [95% CI, 0.80
to 1.03]; P = .13) or all-cause death

IVABRADINE
 SHIFT trial
 The study included patients with HFrEF (NYHA class
II-IV, albeit with only a modest representation of
NYHA class IV HF)
 Ivabradine lowered heart rate by approximately 10
beats/min
 However, only 26% of the patients in the trial were
on optimal doses of beta blockers, it is possible that
titrating beta blockers to recommended dose may
have reduced the HF hospitalizations to a similar
degree

IVABRADINE
 Additional safety evidence for ivabradine comes
from the morbidity-mortality evaluation of the
If inhibitor Ivabradine in patients with coronary
disease and LV dysfunction (BEAUTIFUL) trial
 BEAUTIFUL Trial
 More than 10,000 patients with coronary heart
disease and an EF below 40%
 Ivabradine 7.5 mg twice daily or placebo.
 Although this trial did not meet its primary endpoint
of reducing cardiovascular death, MI, or HF
hospitalization, the drug was well tolerated in this
patient population.

IVABRADINE
 Ivabradin reduces the elevated heart rate often
seen in HFrEF and has also been shown to
improve outcomes, and should be considered
when appropriate
 The above medications should be used in
conjunction with diuretics in patients with
symptoms and/or signs of congestion.
 The use of diuretics should be modulated according
to the patient’s clinical status.

BETA-BLOCKERS
 Beta-blockers reduce mortality and morbidity in
symptomatic patients with HFrEF, despite treatment
with an ACEI and, in most cases, a diuretic, but have
not been tested in congested or decompensated
patients
 There is consensus that beta-blockers and ACEIs are
complementary, and can be started together as soon
as the diagnosis of HFrEF is made.
 There is no evidence favouring the initiation of
treatment with a beta-blocker before an ACEI has
been started

BETA-BLOCKERS
 Beta-blockers should be initiated in clinically
stable patients at a low dose and gradually up-
titrated to the maximum tolerated dose.
 In patients admitted due to acute HF (AHF)
beta-blockers should be cautiously initiated in
hospital, once the patient is stabilized.

BETA-BLOCKERS
 An individual patient data meta-analysis of all
the major betablocker trials in HFrEF has shown
no benefit on hospital admissions and mortality
in the subgroup of patients with HFrEF who are
in AF
 However, since this is a retrospective subgroup
analysis, and because beta-blockers did not
increase the risk, the guideline committee
decided not to make a separate recommendation
according to heart rhythm

BETA-BLOCKERS
 Beta-blockers should be considered for rate
control in patients with HFrEF and AF, especially
in those with high heart rate
 Beta-blockers are recommended in patients with
a history of myocardial infarction and
asymptomatic LV systolic dysfunction to reduce
the risk of death

MINERALOCORTICOID/ALDOSTERONE
RECEPTOR ANTAGONISTS
 MRAs (spironolactone and eplerenone) block
receptors that bind aldosterone and, with
different degrees of affinity, other steroid
hormone (e.g. corticosteroids, androgens)
receptors.
 Spironolactone or eplerenone are recommended
in all symptomatic patients (despite treatment
with an ACEI and a beta-blocker) with HFrEF
and LVEF ≤35%, to reduce mortality and HF
hospitalization.

MINERALOCORTICOID/ALDOSTERONE
RECEPTOR ANTAGONISTS
 Caution should be exercised when MRAs are used
in patients with impaired renal function and in
those with serum potassium levels >5.0 mmol/L.
 Regular checks of serum potassium levels and renal
function should be performed according to clinical
status.

OTHER TREATMENT
DIURETICS
 Diuretics are recommended to reduce the signs
and symptoms of congestion in patients with
HFrEF, but their effects on mortality and
morbidity have not been studied in RCTs.
 Loop diuretics produce a more intense and
shorter diuresis than thiazides, although they
act synergistically and the combination may be
used to treat resistant oedema.
 However, adverse effects are more likely and
these combinations should only be used with
care.

OTHER TREATMENT
DIURETICS
 The aim of diuretic therapy is to achieve and
maintain euvolaemia with the lowest achievable
dose.
 The dose of the diuretic must be adjusted
according to the individual needs over time.
 In selected asymptomatic
euvolaemic/hypovolaemic patients, the use of a
diuretic drug might be (temporarily)
discontinued.
 Patients can be trained to self-adjust their diuretic
dose based on monitoring of symptoms/signs of
congestion and daily weight measurements.

OTHER TREATMENT
ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITOR
 A new therapeutic class of agents acting on the
RAAS and the neutral endopeptidase system has
been developed [angiotensin receptor neprilysin
inhibitor (ARNI)].
 Neprilysin is an endopeptidase that degrades
natriuretic peptides, bradykinin, and
adrenomedullin. Thus, neprilysin inhibition would
increase the levels of these peptides increase
and counteract the neurohormonal activation
seen in heart failure

OTHER TREATMENT
 High circulating A-type natriuretic peptide
(ANP) and BNP exert physiologic effects
through binding to NP receptors and the
augmented generation of cGMP, thereby
enhancing diuresis, natriuresis and myocardial
relaxation and anti-remodelling.
 ANP and BNP also inhibit renin and aldosterone
secretion.
 Selective AT1-receptor blockade reduces
vasoconstriction, sodium and water retention and
myocardial hypertrophy

OTHER TREATMENT
 The first in class is LCZ696, which is a molecule
that combines the moieties of valsartan and
sacubitril (neprilysin inhibitor) in a single
substance.

OTHER TREATMENT
 2014: PARADIGM-HF Trial
 Long-term effects of sacubitril/valsartan vs
Enalapril on morbidity and mortality*
 Sacubitril/valsartan (97/103 mg b.i.d.) was superior
to ACEI (enalapril 10mg b.i.d.) in reducing
hospitalizations for worsening HF, cardiovascular
mortality and overall mortality.
 Sacubitril/valsartan is therefore recommended
in patients with HFrEF who fit this profile

OTHER TREATMENT
 Possible safety issues
 Symptomatic hypotension
 Angioedema
 Cerebral amyloid deposition
 By decreasing degradation of beta amyloid peptide
 Long term safety needs to be assessed
 Combined treatment with an ACEI (or ARB) and
sacubitril/valsartan is contraindicated (due to
higher risk of angioedema)

OTHER TREATMENT
ANGIOTENSIN II TYPE I RECEPTOR BLOCKERS
 ARBs are recommended only as an alternative in
patients intolerant of an ACEI
 Candesartan has been shown to reduce
cardiovascular mortality
 Valsartan showed an effect on hospitalization
for HF (but not on all-cause hospitalizations) in
patients with HFrEF receiving background
ACEIs.
 The combination of ACEI/ARB for HFrEF was
reviewed by the EMA, which suggested that benefits
are thought to outweigh risks only in a select group
of patients with HFrEF in whom other treatments
are unsuitable.

OTHER TREATMENT
ANGIOTENSIN II TYPE I RECEPTOR BLOCKERS
 Therefore, ARBs are indicated for the
treatment of HFrEF only in patients who cannot
tolerate an ACEI because of serious side
effects.
 The combination of ACEI/ARB should be
restricted to symptomatic HFrEF patients
receiving a beta-blocker who are unable to
tolerate an MRA, and must be used under strict
supervision

OTHER TREATMENT
HYDRALAZINE/ISOSORBIDE DINITRATE
 There is no clear evidence to suggest the use of this
fixed-dose combination therapy in all patients with
HFrEF.
 Evidence on the clinical utility of this combination is
scanty and comes from one relatively small RCT
conducted exclusively in men and before ACEIs or
beta-blockers were used to treat HF.
 A subsequent RCT conducted in self-identified black
patients (defined as being of African descent)
showed that addition of the combination of
hydralazine and isosorbide dinitrate to conventional
therapy (ACEI, beta-blocker and MRA) reduced
mortality and HF hospitalizations in patients with
HFrEF and NYHA Classes III–IV.
 The results of this study are difficult to translate to
patients of other racial or ethnic origins.

OTHER TREATMENT
HYDRALAZINE/ISOSORBIDE DINITRATE
 Additionally, a combination of hydralazine and
isosorbide dinitrate may be considered in
symptomatic patients with HFrEF who can
tolerate neither ACEI nor ARB (or they are
contraindicated) to reduce mortality.
 However, this recommendation is based on the
results of the Veterans Administration
Cooperative Study, which recruited symptomatic
HFrEF patients who received only digoxin and
diuretics

TREATMENTS WITH LESS CERTAIN BENEFIT
DIGOXIN
 Digoxin may be considered in patients in sinus
rhythm with symptomatic HFrEF to reduce the
risk of hospitalization (both all-cause and HF
hospitalizations), although its effect on top of
beta-blockers has never been tested
 The effects of digoxin in patients with HFrEF
and AF have not been studied in RCTs, and
recent studies have suggested potentially higher
risk of events (mortality and HF hospitalization)
in patients with AF receiving digoxin

DIGOXIN
 In patients with symptomatic HF and AF, digoxin
may be useful to slow a rapid ventricular rate,
but it is only recommended for the treatment of
patients with HFrEF and AF with rapid
ventricular rate when other therapeutic options
cannot be pursued.
 Of note, the optimal ventricular rate for patients
with HF and AF has not been well established, but
the prevailing evidence suggests that strict rate
control might be deleterious.
 A resting ventricular rate in the range of 70–90 bpm
is recommended based on current opinion, although
one trial suggested that a resting ventricular rate of
up to 110 bpm might still be acceptable.

DIGOXIN
 Given its distribution and clearance, caution
should be exerted in females, in the elderly and
in patients with reduced renal function.
 In the latter patients, digitoxin should be preferred.

N-3 POLYUNSATURATED FATTY ACIDS
 A large body of experimental evidence suggests
that n-3 polyunsaturated fatty acids (n-3
PUFAs) have favorable effects on inflammation
 Including a reduction in endothelial activation and
production of inflammatory cytokines, platelet
aggregation, autonomic tone, blood pressure, heart
rate, and LV function.
 Preparations differ in composition and dose.
 Only preparations with eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA) as ethyl esters of
at least 85% (850 mg/g) have shown an effect on
the cumulative endpoint of cardiovascular death and
hospitalization.

N-3 POLYUNSATURATED FATTY ACIDS
 GISSI-HF Trial
 Gruppo Italiano per lo Studio della Sopravvivenza
nell’Insufficienza Cardiaca Heart Failure
 Long-term administration of 1 g/day of omega n-3
PUFAs resulted in a significant reduction in both all-
cause mortality (adjusted HR, 0.91 [95.5% CI, 0.83
to 0.99]; P = .041) and all-cause mortality and
cardiovascular admissions (adjusted HR, 0.92 [99%
CI, 0.849 to 0.999]; P = .009), in all of the
predefined subgroups, including patients with HF
associated with nonischemic cardiomyopathy
 However, in view of the small treatment effect
of n-3 PUFAs, they are not endorsed by current
practice guidelines.

TREATMENTS NOT RECOMMENDED
(UNPROVEN BENEFIT) IN HFREF
 Statins
 Although statins reduce mortality and morbidity in
patients with atherosclerotic disease, statins are not
effective in improving the prognosis in patients with
HFrEF.
 Most statin trials excluded patients with HF
(because it was uncertain that they would benefit).
 The two major trials that studied the effect of
statin treatment in patients with chronic HF did not
demonstrate any evidence of benefit.
 Therefore, evidence does not support the initiation
of statins in most patients with chronic HF

 Oral anticoagulants and antiplatelet therapy
 Other than in patients with AF (both HFrEF and
HFpEF), there is no evidence that an oral
anticoagulant reduces mortality/morbidity compared
with placebo or aspirin
 Patients with HFrEF receiving oral anticoagulation because
of concurrent AF or risk of venous thromboembolism
should continue anticoagulation.
 Similarly, there is no evidence on the benefits of
antiplatelet drugs (including acetylsalicylic acid) in
patients with HF without accompanying CAD,
whereas there is a substantial risk of
gastrointestinal bleeding, particularly in elderly
subjects, related with this treatment.

 Renin inhibitors
 Aliskiren is an orally active direct renin inhibitor
that appears to suppress the renin-angiotensin
system to a similar degree to that effected by ACE
inhibitors
 Although the benefits of ACE inhibitors and ARBs in
HF have been clearly established, these agents
provoke a compensatory increase in renin and
downstream intermediaries of the reninangiotensin-
aldosterone system that may attenuate the effects
of ACE inhibitors and ARBs (“RAAS escape”)

 Renin inhibitors- Aliskiren
 ALOFT Trial: Aliskiren significantly (P < .01)
decreased NT-proBNP in urinary aldosterone
excretion
 On the basis of these promising early results,
several large pivotal outcomes trials were initiated
to determine whether adding aliskiren to standard
HF therapy would improve clinical outcomes

 ASTRONAUT Study
 The Aliskiren Trial on Acute Heart Failure Outcomes
 Enrolled patients with an LVEF of 40% or less and elevated
natriuretic peptide (BNP) of 400 pg/mL or higher or NT-
proBNP of 1600 pg/mL or greater) who were being discharged
from the hospital after admission for ADHF
 Primary endpoint: Cardiovascular death or HF rehospitalization
at 6 months.
 No significant difference in the primary endpoint was
observed in the aliskiren (titrated up to 300 mg/day)-treated
group compared with patients treated with standard medical
therapy for HF at 6 months (HR, 0.92 [95% CI, 0.76 to 1.12]; P
= .41) or at 12 months (HR, 0.93 [95% CI, 0.79 to 1.09]; P =
.36).
 Moreover, the rates of hyperkalemia, hypotension, and renal
impairment/renal failure were higher in the aliskiren group
than in the placebo group.

 ATMOSPHERE Trial
 Efficacy and Safety of Aliskiren and Aliskiren/Enalapril
Combination on Morbi-mortality in Patients with Chronic
Heart Failure study
 Currenly ongoing phase III study that will evaluate the
efficacy and safety of both aliskiren monotherapy and
aliskiren-enalapril combination therapy as compared with
enalapril monotherapy to reduce cardiovascular death and
HF-related hospitalizations in NYHA class II to IV HF
patients

TREATMENTS BELIEVED TO CAUSE HARM IN
HFREF
 Calcium-channel blockers
 Non-dihydropyridine calcium-channel blockers (CCBs)
are not indicated for the treatment of patients with
HFrEF.
 Diltiazem and verapamil have been shown to be unsafe in
patients with HFrEF.214
 There is a variety of dihydropyridine CCBs; some are
known to increase sympathetic tone and they may
have a negative safety profile in HFrEF.
 There is only evidence on safety for amlodipine215 and
felodipine216 in patients with HFrEF, and they can be used
only if there is a compelling indication in patients with
HFrEF

IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR
 A high proportion of deaths among patients with HF,
especially those with milder symptoms, occur
suddenly and unexpectedly.
 Many of these are due to electrical disturbances,
including ventricular arrhythmias, bradycardia and
asystole, although some are due to coronary, cerebral
or aortic vascular events.
 Treatments that improve or delay the progression of
cardiovascular disease will reduce the annual rate of
sudden death, but they may have little effect on
lifetime risk and will not treat arrhythmic events
when they occur.

ICDS
 ICDs are effective in preventing bradycardia
and correcting potentially lethal ventricular
arrhythmias.
 Some antiarrhythmic drugs might reduce the
rate of tachyarrhythmias and sudden death, but
they do not reduce overall mortality and may
increase it.

ICDS
 Secondary prevention of sudden cardiac death
 Compared with amiodarone treatment, ICDs reduce
mortality in survivors of cardiac arrest and in
patients who have experienced sustained
symptomatic ventricular arrhythmias.
 An ICD is recommended in such patients when the
intent is to increase survival
 The decision to implant should take into account
 The patient’s view and their quality of life,
 The LVEF (survival benefit is uncertain when the LVEF is
>35%) and
 The absence of other diseases likely to cause death within
the following year.223–225

ICDS
 Primary prevention of sudden cardiac death
 Although amiodarone may have reduced mortality in
older trials of HF,242,243 contemporary studies
conducted since the widespread introduction of
beta-blockers suggest that it does not reduce
mortality in patients with HFrEF.227,244,245
 Dronedarone and class I antiarrhythmic agents
should not be used for prevention of arrhythmias in
this population.
 Some guideline-recommended therapies, including
betablockers, MRAs, sacubitril/valsartan and
pacemakers with CRT (CRT-Ps), reduce the risk of
sudden death

ICDS
 Patients with a QRS duration ≥130 ms should be
considered for a defibrillator with CRT (CRT-D)
rather than ICD.
 Patients with longer QRS durations may also receive
greater benefit from an ICD, but these patients
should often receive a CRT device

ICDS
 Two RCTs showed no benefit in patients who had an
ICD implanted within 40 days after a myocardial
infarction.158,228
 Although sudden arrhythmic deaths were reduced,
this was balanced by an increase in non-arrhythmic
deaths.
 Accordingly, an ICD is contraindicated in this time
period.
 A wearable defibrillator may be considered if the
patient is deemed to be at high risk of ventricular
fibrillation, although evidence from randomized
trials is lacking.239–241

ICDS
 ICD implantation is recommended only after a
sufficient trial (minimum 3 months) of optimal
medical therapy (OMT) has failed to increase the
LVEF to >35%.
 However, one of the two landmark papers on which
these recommendations are based included patients
with an LVEF >30%.
 Fewer than 400 patients with an LVEF of 30–35%
were included in the landmark studies, and although
there was no statistical interaction between
treatment effect and LVEF, the evidence of benefit
is less robust in this group of patients.

ICDS
 ICD therapy is not recommended in patients in
NYHA Class IV with severe symptoms refractory to
pharmacological therapy who are not candidates for
CRT, a ventricular assist device or cardiac
transplantation, because such patients have a very
limited life expectancy and are likely to die from
pump failure.
 Patients with serious co-morbidities who are unlikely
to survive substantially more than 1 year are unlikely
to obtain substantial benefit from an ICD

ICDS
 Patients should be counselled as to
 The purpose of an ICD,
 Complications related to implantation and device activation
(predominantly inappropriate shocks) and
 Under what circumstances it might be deactivated
(terminal disease) or explanted (infection, recovery of LV
function
 If HF deteriorates, deactivation of a patient’s ICD
may be considered after appropriate discussion with
the patient and caregiver(s).

ICDS
 If the ICD generator reaches its end of life or
requires explantation, it should not automatically be
replaced.
 Patients should be carefully evaluated by an experienced
cardiologist before generator replacement.
 Treatment goals may have changed and the risk of fatal
arrhythmia may be lower or the risk of non-arrhythmic
death higher.
 It is a matter of some controversy whether patients
whose LVEF has greatly improved and who have not
required device therapy during the lifetime of the
ICD should have another device implanted

ICDS
 Subcutaneous defibrillators may be as effective as
conventional ICDs with a lower risk from the
implantation procedure.
 They may be the preferred option for patients with
difficult access or who require ICD explantation due to
infection.
 Patients must be carefully selected, as they have
limited capacity to treat serious bradyarrhythmia
and can deliver neither antitachycardia pacing nor
CRT.
 Substantial RCTs with these devices and more data
on safety and efficacy are awaited

ICDS
 A wearable ICD
 An external defibrillator with leads and electrode pads
attached to a wearable vest
 Able to recognize and interrupt VT/ventricular fibrillation
may be considered for a limited period of time in selected
patients with HF who are at high risk for sudden death but
otherwise are not suitable for ICD implantation (e.g. those
with poor LVEF after acute myocardial damage until LV
function recovers, patients scheduled for heart
transplantation)
 However, no prospective RCTs evaluating this device
have been reported

CARDIAC RESYNCHRONIZATION THERAPY
 CRT improves cardiac performance in
appropriately selected patients and improves
symptoms and well-being and reduces morbidity
and mortality
 Of the improvement in quality-adjusted life-
years (QALYs) with CRT among patients with
moderate to severe HF,
 Two-thirds may be attributed to improved quality of
life and
 One-third to increased longevity

CRT
 Only the COMPANION265 and CARE-HF trials262,263
compared the effect of CRT to guideline-advised
medical therapy.
 Most other trials have compared CRT-D to ICD, and
a few have compared CRT-P to backup pacing.
 The prevention of lethal bradycardia might be an
important mechanism of benefit shared by all pacing
devices.
 In CARE-HF, at baseline, 25% of patients had a
resting heart rate of ≤60 bpm.262–264
 If prevention of bradycardia is important, the effect
of CRT will appear greater in trials where there is no
device in the control group.

CRT
 Most studies of CRT have specified that the
LVEF should be <35%, but RAFT267 and MADIT-
CRT268,269 specified an LVEF <30%, while
REVERSE270–272 specified < 40% and BLOCK-
HF274 < 50%.
 Relatively few patients with an LVEF of 35–40%
have been randomized, but an individual
participant data (IPD) meta-analysis suggests no
diminution of the effect of CRT in this group.

CRT
 Not all patients respond favourably to CRT
 Several characteristics predict improvement in
morbidity and mortality, and the extent of
reverse remodelling is one of the most important
mechanisms of action of CRT.
 Patients with ischaemic aetiology will have less
improvement in LV function due to myocardial scar
tissue, which is less likely to undergo favourable
remodelling288
 Conversely, women may be more likely to respond
than men, possibly due to smaller body and heart size

CRT
 QRS width predicts CRT response and was the
inclusion criterion in all randomized trials.
 But QRS morphology has also been related to a
beneficial response to CRT.
 Several studies have shown that patients with left
bundle branch block (LBBB) morphology are more
likely to respond favourably to CRT, whereas there is
less certainty about patients with non-LBBB
morphology.
 However, patients with LBBB morphology often have
wider QRS duration, and there is a current debate
about whether QRS duration or QRS morphology is
the main predictor of a beneficial response to CRT

CRT
 Evidence from two IPD meta-analyses indicates
that after accounting for QRS duration, there is
little evidence to suggest that QRS morphology
or aetiology of disease influence the effect of
CRT on morbidity or mortality266,273
 In addition, none of the landmark trials selected
patients for inclusion according to QRS
morphology, sex or ischaemic aetiology, nor were
they powered for subgroup analyses.

CRT
 The Echo-CRT283,284 trial and an IPD meta-
analysis266 suggest possible harm from CRT when
QRS duration is <130 ms, thus implantation of
CRT is not recommended if QRS duration is <130
ms.

CRT
 If a patient is scheduled to receive an ICD and is
in sinus rhythm with a QRS duration ≥130 ms,
CRT-D should be considered if QRS is between
130 and 149 ms and is recommended if QRS is
≥150 ms.
 However, if the primary reason for implanting a
CRT is for the relief of symptoms, then the
clinician should choose CRT-P or CRT-D,
whichever they consider appropriate*
 Clinical practice varies widely among countries.
 The only randomized trial to compare CRT-P and
CRT-D265 failed to demonstrate a difference in
morbidity or mortality between these technologies

CRT
 If the primary reason for implanting CRT is to
improve prognosis, then the majority of evidence
lies with CRT-D for patients in NYHA Class II
and with CRT-P for patients in NYHA Classes
III–IV.
 It is unclear whether CRT
 Reduces the need for an ICD (by reducing the
arrhythmia burden) or
 Increases the benefit from an ICD (by reducing
mortality rates from worsening HF, leading to longer
exposure to the risk of arrhythmia)

CRT
 When LVEF is reduced, RV pacing may
exacerbate cardiac dyssynchrony.
 This can be prevented by CRT, which might improve
patient outcomes.
 However, a difference in outcome was not observed
between CRT and RV pacing in a subgroup analysis of
RAFT or in patients without HFrEF in BioPACE291
 On balance, CRT rather than RV pacing is
recommended for patients with HFrEF
regardless of NYHA class who have an indication
for ventricular pacing in order to reduce
morbidity, although no clear effect on mortality
was observed.

CRT
 Patients with HFrEF who have received a
conventional pacemaker or an ICD and
subsequently develop worsening HF with a high
proportion of RV pacing, despite OMT, should be
considered for upgrading to CRT.
 Only two small trials have compared
pharmacological therapy alone vs. CRT in patients
with AF, with conflicting results.

CRT
 Several studies have indicated that CRT is
superior to RV pacing in patients undergoing
atrio-ventricular (AV) node ablation
 However, CRT is not an indication to carry out
AV node ablation except in rare cases when
ventricular rate remains persistently high
(>110bpm) despite attempts at pharmacological
rate control.
 A subgroup analysis of patients with AF from the
RAFT study found no benefit from CRT-D compared
with ICD, although less than half of patients had
>90% biventricular capture

CRT
 Observational studies report that when
biventricular capture is <98%, the prognosis of
patients with CRT declines.
 Whether this association reflects
 A loss of resynchronization (which might be
remedied by device programming),
 Poor placing of the LV lead (which might be avoided
at implantation) or
 Greater difficulty in pacing severely diseased
myocardium (which might not be amenable to the
above) is uncertain.
 This observation has not been confirmed in a
randomized trial

CRT
 Imaging tests for dyssynchrony have not yet
been shown to be of value in selecting patients
for CRT.
 Patients with extensive myocardial scar will have less
improvement in LV function with CRT, but this is true
of any treatment for HFrEF and does not reliably
predict less clinical benefit
 Pacing thresholds are higher in scarred
myocardium and, if possible, lead placement
should avoid such regions.
 Although patients with extensive scarring have an
intrinsically worse prognosis, there is little evidence
that they obtain less prognostic benefit from CRT

OTHER DEVICES
 Currently, the evidence is considered
insufficient to support specific guideline
recommendations for other therapeutic
technologies
 These include
 Baroreflex activation therapy
 Vagal stimulation
 Diaphragmatic pacing and
 Cardiac contractility modulation*

MANAGEMENT OF PATIENTS WHO
REMAIN SYMPTOMATIC
 As noted, an ACE inhibitor (or an ARB) plus a
beta blocker should be standard background
therapy for patients with HFrEF.
 Additional pharmacologic therapy (polypharmacy)
or device therapy should be considered in
patients who have persistent symptoms or
progressive worsening despite optimized therapy
with an ACE inhibitor and beta blocker

REMAIN SYMPTOMATIC
 Agents that may be considered for part of
additional therapy include
1. An ARB (NYHA class II to IV),
2. Mineralocorticoid receptor antagonists (NYHA
class II to IV),
3. Combination of hydralazine and isosorbide dinitrate
(NYHA class II to IV) or
4. Digitalis
 Thus the choice of specific agent will be
influenced in part by clinical considerations,
including renal function, serum potassium
concentration, blood pressure, and race

REMAIN SYMPTOMATIC
 Because mineralocorticoid receptor antagonists
have a greater impact on morbidity/mortality
than ARBs, ARBs are no longer the agents of
first choice in patients with HF and an EF of
40% or less who remain symptomatic despite
optimal treatment with an ACE inhibitor.
 The triple combination of an ACE inhibitor, an
ARB, and an aldosterone antagonist is not
recommended because of the associated risk of
hyperkalemia.

REMAIN SYMPTOMATIC
 Digoxin
 Recommended for patients with symptomatic LV
systolic dysfunction who have concomitant atrial
fibrillation
 Should be considered for patients who have signs or
symptoms of HF while receiving standard therapy,
including ACE inhibitors and beta blockers

STAGE D HF- DEFINITION
 Also known as “advanced HF,” “End-stage HF” and
“refractory HF.”
 AHA/ACC: “Patients with truly refractory HF who
might be eligible for specialized, advanced treatment
strategies, such as MCS, procedures to facilitate
fluid removal, continuous inotropic infusions, or
cardiac transplantation or other innovative or
experimental surgical procedures, or for end-of-life
care, such as hospice
 The European Society of Cardiology has developed a
definition of advanced HF with objective criteria
that can be useful (See next slide)

STAGE D HF- DEFINITION
 There are clinical clues that may assist clinicians
in identifying patients who are progressing
toward advanced HF (Table 24).
 The Interagency Registry for Mechanically
Assisted Circulatory Support (INTERMACS) has
developed 7 profiles that further stratify
patients with advanced HF (Table 13.2)

STAGE D HF- IMP’T CONSIDERATIONS
 Thorough evaluation is needed to ascertain that
the diagnosis is correct and that there are no
remediable etiologies or alternative explanations
for advanced symptoms.
 For example, it is important to determine that HF
and not a concomitant pulmonary disorder is the
basis of dyspnea.
 Similarly, in those with presumed cardiac cachexia,
other causes of weight loss should be ruled out.
Likewise, other reversible factors such as thyroid
disorders should be treated.

STAGE D HF- IMP’T CONSIDERATIONS
 Severely symptomatic patients presenting with a
new diagnosis of HF can often improve
substantially if they are initially stabilized.
 Patients should also be evaluated for
nonadherence to medications, sodium restriction,
and/or daily weight monitoring.
 Finally, a careful review of prior medical
management should be conducted to verify that
all evidence based therapies likely to improve
clinical status have been considered.

STAGE D HF- TREATMENT
 Treatment options
 Advanced therapy
 Palliative care

 Inotropic Support
 Despite improving hemodynamic compromise, positive
inotropic agents have not demonstrated improved
outcomes in patients with HF in either the hospital
or outpatient setting
 Regardless of their mechanism of action (e.g.,
inhibition of phosphodiesterase, stimulation of
adrenergic or dopaminergic receptors, calcium
sensitization), chronic oral inotrope treatment
increased mortality, mostly related to arrhythmic
events.

 Inotropic Support
 Parenteral inotropes, however, remain as an option to
help the subset of patients with HF who are
refractory to other therapies and are suffering
consequences from end-organ hypoperfusion.
 Inotropes should be considered only in such patients
with systolic dysfunction who have low cardiac index
and evidence of systemic hypoperfusion and/or
congestion
 To minimize adverse effects, lower doses are preferred.
 Similarly, the ongoing need for inotropic support and
the possibility of discontinuation should be regularly
assessed

 Mechanical Circulatory Support
 MCS has emerged as a viable therapeutic option for
patients with advanced stage D HFrEF refractory to
optimal GDMT and cardiac device intervention.
 Since its initial use 50 years ago for postcardiotomy
shock, the implantable VAD continues to evolve.
 Designed to assist the native heart, VADs are
differentiated by the implant location
(intracorporeal versus extracorporeal), approach
(percutaneous versus surgical), flow characteristic
(pulsatile versus continuous), pump mechanism
(volume displacement, axial, centrifugal), and the
ventricle(s) supported (left, right, biventricular).

 VADs are effective in both the short-term (hours to
days) management of acute decompensated,
hemodynamically unstable HFrEF that is refractory
to inotropic support, and the long-term (months to
years) management of stage D chronic HFrEF.
 Nondurable, or temporary, MCS provides an
opportunity for decisions about the appropriateness
of transition to definitive management such as
cardiac surgery or durable, that is, permanent, MCS
or, in the case of improvement and recovery,
suitability for device removal.
 Nondurable MCS thereby may be helpful as either a
bridge to decision or a bridge to recovery.

 More common scenarios for MCS, however, are long-
term strategies, including
1. Bridge to transplantation,
2. Bridge to candidacy, and
3. Destination therapy.
 Bridge to transport and destination therapy have
the strongest evidence base with respect to
survival, functional capacity, and HRQOL benefits

 Cardiac Transplantation
 Cardiac transplantation is considered the gold
standard for the treatment of refractory end-stage
HF.
 The greatest survival benefit is seen in those
patients who are at highest risk of death from
advanced HF

SPECIAL POPULATION
 Women
 Poorly represented in clinical trials.
 Women with HF are more likely to be older, have a
preserved EF and nonischemic etiology for their HF
 Although some studies have reported that HF
outcomes are worse for women with than for men,
the aggregate data suggest that women have a
survival advantage when they develop HF.

SPECIAL POPULATION
 Women
 Although the explanation for this observation is
unclear it may be related to sex differences in
etiology for HF.
 Nonetheless, although women appear to have a
survival advantage after the diagnosis of HF, they
experience increased morbidity, with worse quality
of life, and have increased depression.
 Moreover, women are at increased risk of developing
HF after acute MI

SPECIAL POPULATION
 Women
 Pooled analysis of several large-scale prospective
clinical trials with beta blockers and ACE inhibitors
suggests that these agents provide similar survival
benefits in women with systolic dysfunction and in
men.

SPECIAL POPULATION
 Race/Ethnicity
 Several retrospective analyses have highlighted
differences between African American and white
populations in response to some standard HF
therapies.
 Unfortunately, data for Hispanic and Asian HF populations
are limited.
 Retrospective analyses from SOLVD and V-HeFT
suggested that African Americans do not benefit
from ACE inhibitors.
 By contrast, post hoc analysis of studies with
approved beta blockers has shown that African
American patients benefit, although the magnitude
of the effect appears to be diminished relative to
Caucasians.

SPECIAL POPULATION
 Race/Ethnicity
 The African- American Heart Failure Trial (A-HeFT)
 Compared the adjunctive use of a proprietary formulation
of isosorbide dinitrate and hydralazine against a standard
HF regimen of ACE inhibitors, beta blockers, and diuretics
in African Americans with NYHA class III or IV HF
 Primary endpoint: A composite score made up of weighted
values for death from any cause, a first hospitalization for
HF, and change in the quality of life.
 The study was terminated early because
 Significant 43% reduction in the rate of death from any
cause and
 Significant 33% relative reduction in the rate of first
 hospitalization for HF

SPECIAL POPULATION
 Race/Ethnicity
 The effect of this combination of isosorbide
dinitrate and hydralazine in other patients with HF
who are being treated with standard therapy is not
known, because the population studied in A-HeFT was
limited to African Americans.
 However, there is no reason to believe that this benefit is
limited to blacks.

SPECIAL POPULATION
 Elderly Persons
 Elderly patients are more likely than younger
patients to present with atypical symptoms such as
altered mental status, depression, or poor executive
functioning.
 The therapeutic approach to HFrEF in elderly
persons should be, in principle, identical to that in
younger patients with respect to the choice of
pharmacologic therapy.
 However, altered pharmacokinetic and pharmacodynamic
properties of cardiovascular drugs in the elderly may
require that these therapies be applied more cautiously,
with reductions in drug dosages when appropriate

SPECIAL POPULATION
 Elderly Persons
 Other complicating factors may include blunting of
baroreceptor function and orthostatic dysregulation
of blood pressure, which may make it difficult to use
target doses of some neurohormonal antagonists.
 Multidisciplinary HF programs have been successful
in decreasing the rate of readmission and associated
morbidity in elderly patients

MANAGEMENT OF AF IN HF
 AF- the commonest arrythmia
 occurs in 15% to 30% of patients with HF
 May lead to worsening HF increases risk of
thromboembolic events especially stroke
 AF-CHF Trial*-Roy et al 2008
 Rate vs Rhythm control in patients with chronic HF
and a history of AF
 Rhythm control (pharmacologic or electrical
cardioversion) was not shown to be superior to rate
control with respect to reducing death from
cardiovascular causes (HR rhythm control group, 1.06
[95% CI, 0.86 to 1.30]; P =.59)

 AF-CHF Trial ctd
 Secondary outcomes also were similar in the rate and
rhythm control groups, including death from any
cause, stroke, worsening HF, and the composite of
death from cardiovascular causes, stroke, and
worsening HF.

 Accordingly, a rhythm control strategy is best
suited for use in
 Patients with a reversible secondary cause of AF
 Patients who cannot tolerate symptoms of AF after
optimization of rate control and HF therapy
 What to use for rate control for AF in HF?
 BBs preferred to digoxin b/c of their
 Better impact on morbidity and mortality
 Provide better rate control during exercise
 The combination of digoxin and a BB is more
effective than a BB alone in controlling the
ventricular rate at rest

 What to use for rate control for AF in HF?
 When BBs cannot be used, amiodarone has been
recommended by some clinicians
 But chronic use has potentially significant risks, including
thyroid disease and lung toxicity
 The short-term intravenous administration of
diltiazem or amiodarone has been used for the acute
treatment of patients with AF with FVR
 However, the negative inotropic effects of
nondihydropyridine CCBs such as diltiazem and verapamil
must be considered if these agents are used

 Target ventricular rate
 The optimum control of ventricular rate in patients
with HF and atrial fibrillation is unclear at present.
 A resting ventricular response of 60 to 80 beats/min
and a ventricular response between 90 and 115
beats/min during moderate exercise has been
suggested by some experts
 However, the RACE II (Rate Control vs Electrical
cardioversion for AF) study did not show a
difference in a composite of clinical outcomes when a
strategy of strict rate control (<80 beats/min at
rest and <110 beats/min during a 6-minute walk) was
compared with lenient rate control.

Absolute difference of −2.0 percentage
points (90% CI, −7.6 to 3.5)

 With the recognition that sustained tachycardia
can lead to a cardiomyopathy, atrioventricular
node ablation and cardiac resynchronization
therapy (CRT) have been suggested for control
of ventricular rate in extreme cases of a rapid
ventricular response with atrial fibrillation

ANTIARRYTHMIC AGENTS IN HF
 Most antiarrhythmic agents, with the exception
of amiodarone and dofetilide, have negative
inotropic effects and are proarrhythmic.
 Amiodarone
 A class III antiarrhythmic that has little or no
negative inotropic and/or proarrhythmic effects
 Effective against most supraventricular arrhythmias
 Amiodarone is the preferred drug for treatment to
restore and maintain sinus rhythm and may improve
the success of electrical cardioversion in patients
with HF.

 Amiodarone ctd
 Amiodarone increases the level of phenytoin and
digoxin and will prolong the INR in patients taking
warfarin.
 Therefore it often is necessary to reduce the dose of
these drugs by as much as 50% on initiation of therapy
with amiodarone.
 The risk of adverse events, such as hyperthyroidism,
hypothyroidism, pulmonary fibrosis, and hepatitis, is
relatively low, particularly when lower doses of
amiodarone are used (100 to 200 mg/day).

 Dronedarone
 A novel antiarrhythmic drug that reduces the
incidence of atrial fibrillation and atrial flutter and
has electrophysiologic properties that are similar to
those of amiodarone
 But does not contain iodine, with the attendant risk of
iodine-related adverse reactions.
 Dronedarone was significantly more effective than
placebo in maintaining sinus rhythm in several studies
 However, ANDROMEDA trial terminated
prematurely because of a twofold increase in
mortality the Dronedarone treated patients

 Dronedarone
 The excess mortality was predominantly related to
worsening of HF.
 As a result of this study, dronedarone is
contraindicated in patients with NYHA class IV HF,
or those with NYHA class II or III HF who have had
a recent episode of HF-related decompensation.

 Because of the increased likelihood of
proarrhythmic effects of antiarrhythmic agents
in patients with LV dysfunction, it is preferable
to treat ventricular arrhythmias with
implantable cardioverter-defibrillators (ICDs),
either alone or in combination with amiodarone

SLEEP DISORDERED BREATHING
 Patients with HFrEF (EF < 40%) commonly
exhibit sleep-disordered breathing:
 Approximately 40% of patients exhibit central sleep
apneas (CSAs), commonly referred to as Cheyne-
Stokes breathing, and
 Another 10% exhibit obstructive sleep apneas
(OSA).

 CSA
 Associated with Cheyne- Stokes respiration is a
form of periodic breathing, in which central apneas
and hypopneas alternate with periods of
hyperventilation that exhibit a waxing-waning
pattern of tidal volume.
 Risk factors for the development of CSA in patients
with HF include
 Male sex,
 Age older than 60 years,
 The presence of atrial fibrillation, and hypocapnia.

 Fig.- Pathophysiology of CSA and Cheyne-Stokes
respiration in HF.
 HF leads to increased LV filling pressure. The
resulting pulmonary congestion activates lung vagal
irritant receptors, which stimulate hyperventilation
and hypocapnia.
 Superimposed arousals cause further abrupt
increases in ventilation and drive the arterial partial
pressure of carbon dioxide (PaCO2) below the
threshold for ventilation, triggering central apnea.
 CSAs are sustained by recurrent arousal resulting
from apnea-induced hypoxia and the increased
effort to breathe during the ventilatory phase
secondary to pulmonary congestion and reduced lung
compliance.
 Increased sympathetic activity causes increases in
blood pressure (BP) and heart rate (HR) and
increases myocardial O2 demand in the presence of
reduced supply.

 CSA
 The main clinical significance of CSA in HF is its
association with increased mortality.
 Whether this is simply because Cheyne-Stokes
respiration with CSA is a reflection of advanced
disease with poor LV function, or whether its
presence constitutes a separate and additive adverse
influence on outcomes, is not clear.
 This statement notwithstanding, multivariate
analyses suggest that CSA remains an independent
risk factor for death or cardiac transplantation,
even after controlling for potentially confounding
risk factors.

 CSA
 The potential mechanism(s) for adverse outcomes in
patients with HF and CSA may be attributed to
marked neurohumoral activation (especially
norepinephrine).
 Studies have suggested that Cheyne-Stokes
respirations can resolve with proper treatment of
HF.
 However, if the patient continues to have symptoms
related to sleep-disordered breathing (sleep-onset
or sleep-maintenance insomnia) despite optimization
of HF therapies, a comprehensive overnight sleep
studypolysomnography is indicated.

TREATMENT
 OSA: Current guidelines recommend continuous
positive airway pressure (CPAP) therapy to
improve functional capacity and quality of life in
patients with HF and OSA
 CSA: No consensus has emerged regarding how
CSA should be treated in these patients.

TREATMENT
 CSA
 Optimize drug therapy for HF
 This is because CSA is to some extent a manifestation of
advanced HF
 Like aggressive diuresis (to relieve cardiac filling
pressures), use of ACE inhibitors/ARBs and beta blockers,
which may lessen the severity of CSA.
 Caution on aggressive diuresis, a resulting metabolic
alkalosis can worsen/predispose to CSA*

TREATMENT
 CSA
 Use of nocturnal oxygen and devices that provide
continuous positive airway pressure (for upto 1
month) has been reported to
 Alleviate CSA,
 Abolish apnea-related hypoxia,
 Decrease nocturnal norepinephrine levels,
 Produce symptomatic and functional improvement in
patients with HF

TREATMENT
 CSA
 However, the effects of supplemental oxygen on
cardiovascular endpoints over more prolonged
periods have not been assessed.
 Although no direct evidence for prevention of HF by
treatment of sleep-disturbed breathing is lacking,
treatment with CPAP breathing has been shown to
improve LV structure and function in patients with
either obstructive or central sleep apnea disturbed-
breathing syndrome

TREATMENT
 CSA
 Despite these objective measurements of improvement
with CPAP, this treatment modality did not lead to
prolongation of life in the Canadian Continuous Positive
Airway Pressure for Patients with Central Sleep Apnea and
Heart Failure (CANPAP) trial,
 Discontinued early after concerns about the early divergence
of transplantation free survival favoring the control group.
 No difference in the primary endpoint of death or
transplantation (P = .54), nor was there a significant
difference in the frequency of hospitalization between groups
(0.56 versus 0.61 hospitalization/patient-year; P = .45).
 A post hoc analysis of the CANPAP study, however,
suggested that adequate suppression of CSA by CPAP was
associated with improved heart transplant–free survival.

TREATMENT
 CSA
 Thus the data remain unclear whether elimination of
apnea will lead to improved clinical outcomes.
 The other therapies that have been proposed for
sleep-disordered breathing in HF include
 Nocturnal oxygen, CO2 administration (by adding dead
space),
 Theophylline,
 Acetazolamide and
 Diaphragmatic pacing
 These interventions have not yet been systematically
studied in outcome-based prospective randomized
trials

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